Breast cancer

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Primarily a disease of the terminal duct lobular units.

Arises from the endothelial cells lining the excretory ducts (ductal carcinoma) of the mammary glands or from the glandular tissue itself (lobular carcinoma).

Accounts for nearly one in three cancers diagnosed among women in the United States.

Estimated that 300,590 individuals will be diagnosed with female breast cancer in 2023: 15.4% of all cancers.

in 2020 26 million cases of breast cancer were diagnosed, and 685,000 patients died of the disease.

Most cases are diagnosed between ages 55 and 64 years.

Most frequently diagnosed cause of death from cancer in women worldwide.

Approximately 350,000 women die from hormone receptor positive, epidermal growth factor receptor negative, metastatic breast cancer annually, worldwide.

Almost 2,000,000 new breast cancer diagnoses are made each year worldwide

Breast cancer is the most common non-cutaneous malignancy of women worldwide.

Hormone receptor positive and HER2 negative early breast cancer and cancer approximately 70% of all breast cancer diagnoses.

The ER drives tumor growth and progression, so that the first line therapy for postmenopausal patients with ER positive tumors is aimed at blocking the activity of the ER, by means of endocrine therapy.

The highest rates of breast cancer occur in Western countries (more than 100 cases per 100,000 women) and the lowest among Asian countries (10-15 cases per 100,000 women).

There is an estimated 685,000 global breast cancer deaths annually.

Accounts for 30% of all new cancers in women in 2020.

Accounts for 25% of cancer cases and 15% of cancer-related deaths worldwide.

Estimated 280, 000 cases  and over 43,000 deaths in US in 2022.

Estimated 43,000 deaths in 2021, and is the second leading cause of cancer related deaths after lung cancer.

The median age at breast cancer diagnosis is 62 years, and among patients with breast cancer the average age of death is 68 years.

Most older women with breast cancer die from other causes, but approximately 47% of all annual breast cancer deaths occur in women age 70 years or older.

Older women diagnosed with breast cancer have a greater likelihood of dying of diseases other than cancer itself.

The second leading cause of death from cancer in women in developed countries, and the leading cause of death from cancer in low and middle income countries, where a high proportion of women present with advanced disease with a poor prognosis.

Premenopausal patients represent 20% of all breast cancer patients.

Premenopausal BC is a biologically distinct form of the disease and the leading cause of cancer death in women aged 20-59 years worldwide.

As of 2019, nearly 3.5 million women have a history of breast cancer and they account for more than 40% of female cancer survivors.

A disease of aging with over 100,000 women 65 years or older developing breast cancer annually.

For women 70 years or older the probability of developing breast cancer over the next 10 years is one of 27 (3.7%).

Most lesions originate in the ductal or lobular epithelial cells and are caused by a series of genetic events resulting in aberrant regulation of cell cycling, inhibition of apoptosis, and development of the ability to invade surrounding tissues and to form angiogenesis (Hanahan).

Cancers that extend past the basement membrane barrier of tissue origin are considered invasive lesions.

The five-year survival rate is 99% for patients with a diagnosis of localized breast cancer with no nodal involvement.

Multi gene panels help in treatment choices and available assays are:the 21 Gene panel Oncotype DX, the 70-Gene panel MammaPrint, 50 gene panel PAM 50, the 12 gene panel EndoPrredict, and the Breast Cance Index.

Germ line or somatic mutations in tumor suppressor genes implicated in the development of breast cancer include BRCA1, BRCA2, p53 and PTEN, along with disruptions in estrogen receptor related signaling pathways and amplification or over expression of proto-oncogenes such as HER2 neu.

Higher rates of mutations are observed in patients with breast cancer and another primary cancer compared to those with single primary breast cancer. 

Estimated 7-9% of mutations are noted compared to 4-5% for those with multiple primary breast cancer and single breast cancer, respectively. 

CHEK2 mutations associated with BC, but is rare in the US.

CHEK2 mutations common in the Netherlands

Estrogen receptor expression in primary breast cancer confers a favorable prognosis independent of stage of cancer.

 

The strongest associations are  for breast cancer as people who regularly consumed mushrooms had a considerably reduced breast cancer risk. 

More than 70% of breast cancers are hormone receptor positive and human epidermal growth factor receptor 2 (HER2) negative.

ESR1 mutations are significant in cases of metastatic and relapsed cases of breast cancer, and indicative of, or possibly driving treatment resistant disease conditions.

Olaparib is efficacious for patients with BRCA mutation breast cancer-improves median progression free survival in patients with such mutations compared to chemotherapy.

PALB2 gene increase the risk for BC, with one in three chances of developing breast cancer by age 70.

BC a common feature of the Li-Fraumeni syndrome and Cowden syndrome, which are caused by PTEN mutations.

TP53 germline mutations resulting in the Li-Fraumeni syndrome, are estimated to account for 5-7% of all patients with very early onset breast cancer occurring in the 20-30 age group.

Mutations in BRCA1, BRCA2, TP53, PTEN, CDH1 and STK11 are high risk mutations that are associated with a more than 5-fold increase in breast cancer risk.

BRCA1 and BRCA2 are the most common of high-risk mutations and confer a greater than 11-fold increase i breast cancer risk.

All patients are being tested routinely for BRCA1 and BRCA2 with metastatic breast cancer because of the presence of checkpoint inhibitors and PARP inhibitors that may be effective in their management.

About 5% of breast cancer patients have a germline BRCA1/2 mutation and about 4.5% of patients have a mutation in another cancer predisposition gene.

A heterogeneous disease with a spectrum of activity from a disease that remains local throughout its course to one that is systemic when first detected.

Trop-2 is an antigen expressed in the majority of breast cancers, including triple negative breast cancer.

Breast cancer is divided into 18 different subtypes based on histology and morphologic characteristics.

Estrogen receptor alpha and the ESR1 gene are implicated in most breast cancer and ESR1 mutations are significant with respect to metastatic, and relapsed and resistant processes.

Recurrence is typically occur within the first five years of treatment for patients with hormone receptor negative disease, whereas recurrence can occur anytime, even decades, after treatment for patients with hormone receptor positive disease.

The average tumor size at initial presentation has decreased by 10% every five years and is presently 1.8 cm.

Approximately 60% of patients are diagnosed with a localized breast, and 33% are diagnosed when the tumor has spread to lymph nodes.

Suspicious breast cancer lymph nodes are often detected on clinical breast exam, mammography, or ultrasonography.

The five-year survival rate for breast cancers that have not spread beyond the breast is 99%.

Survival rates have steadily improved for early breast cancer in the localized stage I-Ii which makes up sixty two percent of new breast cancer cases, or regional disease stage III, thirty one percent of the cases, now have a five-year survival rate of 98% percent and 85.2 percent, respectively .

The five-year survival rate for breast cancer that has spread to the lymph nodes or nearby tissues is 84%.

Approximately 5% of patients are diagnosed with metastatic breast cancer, and these patients have a 5-year survival of 24% (SiegelR et al).

It is not clear that adding local radiation and surgery to a patient who presents with stage IV disease increases survival rate versus systemic therapy alone: survival rates are equal in most studies.

Incidence of metastatic breast cancer stable since 1975.

Leading cause of premature mortality in women.breast cancer mortality in the US.

There has been a decline in breast cancer deaths from 48 deaths per hundred thousand women in 1975, to 27 deaths per hundred thousand in 2019.

Approximately 6-10% of newly diagnosed patients are metastatic, whereas 20-50% with early breast cancer will eventually develop metastatic disease (Lu J et al).

Studies suggest metastatic disease rates of 15%  in patients  with stage II disease and greater than 40%  in patients  with stage III disease.

Stable incidence of metastatic breast cancer suggests probability of developing breast cancer is itself stable.

Screening mammography has been able to identify at an earlier stage, before symptoms appear, cancers destined to become metastatic.

First filter stations for lymphatic drainage of the breast are the axillary and internal mammary lymph nodes.

Incidence of. metastatic involvement of the internal mammary nodes is between 4-9% in patients with axillary node negative breast cancer and between 16-65% in patients with axillary node positive breast cancer.

Women 70 years of age and older comprise 30-40% of all breast-cancer patients.

The average age at diagnosis is now 61 years.

Mean age at diagnosis for women over 40 years of age or older has not changed over past 4 decades , at greater than 63 years.

Presently more than half of breast cancers in the United States are diagnosed on screening mammogram, and approximately 1/3 are diagnosed as a palpable mass.

Less common presentations of breast cancer are palpable axillary mass, nipple discharge, nipple inversion, breast asymmetry, breast skin erythema, and breast skin thickening.

62% of breast cancers are confined to the breast with diagnosis, while an additional 31% have spread to regional lymph nodes.

 

IL-6 levels predict distant breast cancer recurrence.

 

The inflammatory cytokine interleukin 6 may be a biomarker for distant recurrence of breast cancer among patients treated for stage II-III HER2-negative disease.

 

In a case-control study of 498 women with breast cancer treated with surgery and adjuvant chemotherapy, as well as endocrine therapy for women with estrogen receptor (ER)�positive tumors, those with higher serum levels of IL-6 at diagnosis had a significantly greater risk for disease recurrence than women with lower levels of the cytokine, 

 

This analysis indicating that higher levels of the cytokine IL-6 at diagnosis are associated with a significantly higher distant recurrence risk in high-risk stage II-III breast cancer despite optimal adjuvant systemic therapy.

Systemic inflammation is suspected as a contributing factor to cancer progression and disease recurrence.

Only 6% of breast cancer is metastatic at the time of diagnosis.

5 year survival was about 75% in 1975-1977 and nearly 90% in 2002-2008.

Survival of advanced disease has a relative 5 year survival rate of 24-26%.

The majority of deaths occur in women 65 years and older.

Stage I breast cancers are defined as a breast tumor smaller than 2 cm and no lymph node involvement and have a five-year breast cancer specific survival of at least 99%, at least 94%, and at least 85% for hormonal positive, ERBB2 positive, and triple negative subtypes,

5 year survival rates for metastatic breast cancer is @ 26%..

Approximately 25% of lymph node negative patients, and 50% with lymph node positive BC will ultimately develop recurrent disease.

Almost 30% of patients with axillary lymph node metastases will relapse within 5-10 years of primary treatment.

Probability of detecting radiographic imaging evidence of metastases in asymptomatic early breast cancer is low: 0.2%, 1.2%, and 8% in patients with stage I, II and III disease, respectively.

Guidelines suggest radiographic.staging for breast cancer be reserved for patients with clinical findings suspicious for metastatic disease or those with more advanced disease, either pathologically or clinically.

The routine use of PET imaging, CT scans in patients with DCIS and stage I and II BC are costly and not beneficial, and potentially harmful due to the need of for additional invasive procedures, overtreatment and unnecessary radiation exposure.

PET/CT versus CT has greatest sensitivity for the detection of regional nodal metastases and distant metastases and greater accuracy versus bone scan detection of bone metastases.

PET/CT scans in a retrospective study showed a 97.4% sensitivity and 91.2% specificity compared to 85.9% sensitivity and 67.3 specificity for other techniques including CT, ultrasound, radiographs, and bone scan in detecting distant metastases.

Approximately 15% of patients with clinical stage IIb breast cancer are upstaged  to stage IV breast cancer with use of PET/CT.

Micro metastatic hematogenous occurs in a substantial number of patients with operable BC and is independent of lymphatic involvement.

It is suggested that failure to control local disease will allow some tumors to disseminate later to distant sites.

30-40% of surgically grossly resected breast cancer masses with negative surgical margins will still have microscopic residual disease that can develop into the recurrent disease (Fisher B).

The greater the likelihood that systemic disease has occurred at the time of diagnosis the less likely that local therapy will influence patient�s survival.

Women have an 11% probability of developing breast cancer by age 80 years.

Lifetime breast cancer incidence is 7.8% and mortality 2.3%.

High levels of particulate air pollution associated with increased risk of breast cancer incidence.

One third of postmenopausal breast cancer cases are associated with risk factors that may be modifiable, including postmenopausal obesity, hormone replacement therapy, sedentary lifestyle, alcohol use and not breast-feeding.

Outcomes for localized vs. advanced disease: 5 year relative survival rates of 98.1% vs. 27.1%.

SEER data indicated that about 25% of patients with stage IV metastatic breast cancer survive for 5 years, including 25% of white and 16% of African American patients.

In 1980 a woman�s lifetime risk for breast cancer was 1 in 12 and now it is 1 in 8.

Statins lower risk of breast cancer, and for women with breast cancer, it increases survival.

If DCIS is included the risk of being diagnosed with breast cancer has almost doubled since 1980.

After Women�s Health Initiative study published in 2002 suggesting increased risk of breast cancer with combined conjugated equine estrogen and medroxyprogesterone in the postmenopausal women there was a marked decreased use of such hormones: within 1 year a substantial drop in the incidence of breast cancer has been observed.

Risk associated with current and long-term use of combination estrogen plus progesterone hormonal therapy with an excess risk of 5-9% per year of use (Lee S).

Current use of menopausal hormone therapy (MHT) to explains 7% of postmenopausal breast cancers, with over 90% of this burden explained by a long-term use of at least 5 years.

Risk increased among women who have experienced no pregnancy or only a few pregnancies, and among women who delay their first pregnancy until after age 25.

Obesity and physical inactivity are now major contributors to breast cancer risk, and it is estimated that increased adipose tissue accounts for about 17% of postmenopausal breast cancers in the United States, and that the combination of obesity and physical inactivity may account for one in every four breast cancer cases (World Cancer research fund/American Inst. For Cancer Prevention).

In a large meta-analysis of more than 210,000 individuals with early stage breast cancer, the rate of breast cancer specific mortality was 35% higher in women with obesity at the time of diagnosis than in women of normal weight.

Patients with diabetes, metabolic syndrome, and obesity have an increased risk of breast cancer.

Obesity in women older than 60 years is associated with a 55% increase in BC risk, from approximately 8% in non obese to approximatel 12% in obese women.

Positive association between obesity and BC among postmenopausal women and an inverse association between premenopausal women as regards general obesity, although central obesity is possible associated with increased BC risk before menopause.

Obesity, diet, and physical activity, together is described as energy balance, and is associated with risk and outcomes in breast cancer.

In early stage breast, cancer, obesity, poor quality, diet, and inactivity are associated with increased risk for recurrence, and cancer related mortality. 

Increased physical activity, and weight loss, improve fitness, physical function and quality of life.

There is a strong association between obesity in both risk and prognosis in early stage breast cancer.

In a large meta-analysis of 210,000 women with early stage breast cancer, the rate of breast cancer specific mortality was 35% higher in women with obesity at the time of diagnosis, than in women with normal weight.

Adjuvant trials have shown a higher BMI at the time of diagnosis predicts a worse disease free overall survival after correction for confounding variables.

Higher rates of weight change after diagnosis of breast, cancer is associated with higher rates of recurrence and all-cause mortality.

A meta-analysis study showed a 37% lower rate of specific breast cancer mortality, and a 42% lower all cause mortality in patients with a higher versus lower levels of physical activity after diagnosis of breast cancer.

Meta-analyses show about 35% increase in breast cancer specific mortality and a 41% increase in overall mortality among women who had obesity before the diagnosis of breast cancer.

Higher risk of BC in obese women partially related to role of adipose tissue in controlling metabolism of sex steroids.

Insulin levels found to be positively associated with breast cancer risk, recurrence and mortality.

A high BMI is associated with a decreased risk of premenopausal breast cancer but an increased risk for postmenopausal breast cancer (Chang S et al).

Postmenopausal women with obesity, BMI>30 kg/m2 at increase risk of ER positive BC.

Overweight and obesity are not associated with poorer outcomes in women with metastatic disease, while underweight appears as an independent adverse prognostic factor.

Having diabetes up to 4 years before a cancer of the breast is diagnosed is associated with a 37% increase in the risk of developing BC.

Women with diabetes are more likely to present with stage II breast cancer, 21% more likely to present with stage III breast cancer, and 16% more likely tp present with stage IV breast cancer than they were stage I breast cancer (Lipscombe LI et al).

Diabetes associated with a greater risk for breast cancer, advanced stage breast cancer and decreased 5 year survival.

Low levels of lipids associated with increased risk of BC, and high levels associated with lowered risk of BC.

Meta-analysis concluded that in women with breast cancer a low-fat diet. reduces the risk of breast cancer recurrence by 23% and all-cause mortality by 17%. (Xing MY).

Adoption of a low-fat dietary patterns associated with increased vegetable, fruit, and grain intake significantly reduces the risk of death from breast cancer in postmenopausal women (WHI).

 

Consuming a diet with a high glycemic index or glycemic load may increase the risk of breast cancer (NutriNet-Sant� study).

In 2004 approximately 2.4 million women with a history of breast cancer.

Of the approximately 2.5 million breast cancer survivors, a substantial number have metastatic breast cancer.

Most women with a new diagnosis of breast cancer will be cured.

Second most common cancer in the world and most common cancer in the U.S.

More than 1.6 million new cases each year worldwide with approximately 500,000 deaths.

Accounts for 23% of wall cancers in women globally, and 14% of cancer deaths.

Estimated 233,840 new cases of breast-cancer will occur in 2015 and am estimated 40000 deaths.

Estimated 2,350 men will be diagnosed with BC in 2015.

Represents about 14% of all new cancer diagnoses.

Incidence steadily increasing, but breast cancer mortality declining.

Estimated that 232,670 women will be diagnosed with breast cancer in 2014,

In 2011 approximately 78% of new cases and 87% of deaths that will occur among women 50 years of age and older.

Leading cause of cancer death in women aged 20-59 in the US (Jemal A et al).

Long-term survival in metastatic breast cancer associated with pre-menopausal status, ER positive status, HER2 positive status, whereas triple negative status, brain metastases, visceral with bone metastasis are inversely associated with long-term survival.

Breast cancer is the most common malignant tumor in adolescents and young adult women15 to 39 years of age and accounts for 14% of all cancers in individuals in that age group.

When assessed in 2008, the risk of a woman developing breast cancer in United States was one in 173 at the age of 40 years.

Young women with breast cancer tend to have more aggressive disease than older women and have lower survival rates.

Young women have a higher risk of developing more aggressive subtypes of breast cancer.

Young women with early-stage cancer have a higher rate of recurrence and death compared to older women.

The 5-year survival rate for women 40 and under is less than 85%, but 90% for older women.

Among women 40 years of age or younger, breast cancer is the leading cause of cancer-related death.

SEER Data from 1976-2009 for women age 25-39 years there was it small but statistically significant increase in the incidence of breast cancer with distant involvement (Johnson RH et al).

1 in 8 women have a chance of developing invasive breast cancer during their lifetime.

Black women die disproportionately from aggressive forms of breast cancer.

Black women have a twofold higher rate of advanced stage breast cancer, than white women among regular breast cancer screenings.

Black women are 40% more likely to die of breast cancer compared with their white counterparts.

Black women have a higher prevalence of poor prognostic characteristics: distant stage, high grade,  hormone receptor, negative tumors.

Black women are more likely than any other race group to be diagnosed with triple negative breast cancer.

2/3 of black women are diagnosed with hormonal responsive breast cancer, with an incidence that is increasing overall.

Black women with early hormone receptor positive breast cancer experience shorter relapse free intervals and overall survival compared with white women independent of insurance and neighborhood deprivation.

Central obesity and higher adiposity are associated with higher all-cause and  breast cancer specific mortality among black breast cancer survivors.

Approximately 2140 men will be diagnosed with breast cancer and 450 will die as a result in 2011.

Approximately 35% of BCs occur during the reproductive and perimenopausal years (NCI)

In the last decade breast cancer mortality declining in most Western countries at approximately 2.2% per year.

This decline in BC mortality due to advances in adjuvant therapy and to inceased use in screening mammography, in approximately equal share.

The annual incidence ranges from 11.8 per 100,000 women in eastern China to 86.3 per hundred thousand in North America (Parkin DM et al).

About 2.5 million breast cancer survivors in the US.

Approximately 25% of women diagnosed with breast cancer in the United States are younger than 50 years of age.

Mortality has decreased by 24% since 1990 and the annual hazard rates for breast cancer deaths have decreased with ER positive and ER negative tumors, but the decline is greater for patients with ER + tumors.

Approximately 75% of patients with postmenopausal breast cancer are ER positive.

ER positive tumors are associated with better survival than those with ER low or no ER expression.

5-year survival is approximately 10 to 15% better for women with ER positive breast cancer than those ER negative.

Decline in relative hazard rates greater with ER+ tumors than in patients with ER negative tumors, 38% vs. 19%, respectively.

Breast cancer specific mortality has decreased 4.23% per year in women with ER+ tumors and 2.12% per year in women in ER- tumors.

Approximately 6% of the newly diagnosed breast cancer cases present with metastatic disease and recurrence from early stage to distant sites occurs in 20 to 50% of cases.

STAT5 is an independent marker of outcome in patients with lymph node negative breast cancer, reduced expression associated with a 2.5 fold increase in the risk of recurrence and 2.4 fold risk of dying of breast cancer (Peck AR et al).

STAT5 nuclear levels decreases as the disease progresses from normal to in-siyu, to invasive and then to nodal metastases (Peck AR et al).

STAT5 in tumors of patients treated with anti-estrogen therapy is associated with poor breast cancer survival and nearly a seven fold increase in risk of dying from breast cancer despite anti-estrogen therapy But(Peck AR et al).

25-40% of patients eventually develop metastases and die.

Accounts for 1 of 3 cancers diagnosed in women in the U.S.

Incidence 5 times higher in Western societies than in developing countries.

Women with a personal history of breast cancer are at risk of developing a second breast cancer, which can be ipsilateral or contralateral.

Women with personal history of breast cancer have a risk of a second breast cancer estimated between 5.4 and 6.6 per 1000 woman-years (Buist DS et al).

Case burden in Western countries is mostly in postmenopausal women and in resource poor countries the reverse is true.

Higher local recurrence rates after breast conservation in young patients.

One half of breast cancers occur in patients older than 65 years and one quarter in patients older than 75 years.

3-4 fold variation in breast cancer mortality worldwide.

Most common cancer in women in older than 70 years.

Two thirds of all newly diagnosed female breast cancer patients are older than 55 years.

In the U.S. incidence rates highest among white and African-American women with intermediate rates among Asian-American and Pacific Islander women, and lowest among American Indian/Alaska Native and Hispanic women.

Incidence is lower for African-Americans compared to Caucasian women but the breast cancer mortality is higher for black women.

Black women are 14% more likely to die from breast cancer.

Black women are more likely to be diagnosed with breast cancer before age 50 years or with estrogen receptor negative and triple negative breast cancer than white women.

Age adjusted incidence for breast cancer in white women is 128/100K and 123/100K in African-American women.

African American women have a younger age distribution than white women.

Presents a decade earlier in women of Mexican decent.

Lifetime exposure to estrogens is an established underlying major determinant for breast cancer.

Exposure from endogenous and exogenous hormonal exposure is associated with breast cancer risk.

Duration of estrogen replacement correlates with development of estrogen receptor positive breast cancer.

There is a discordance of receptor status between primary and metastatic lesions in approximately 25% of patients, therefore biopsy of metastatic lesions is recommended, if feasible for establishing estrogen receptor status.

Estrogen and progestin combination enhances breast carcinogenesis.

Tall stature associated with an increase risk of breast cancer.

Increased risk with earlier menarche and late menopause and reduced risk with earlier menopause.

Alcohol intake associated with increased for developing breast cancer, as alcohol intake increases estrogen levels among postmenopausal women.

Alcohol is a risk factor for breast cancer, particularly estrogen receptor positive cancer and it increases mammographic breast density in pre-menopausal and post menopausal women.

A linear increase in the risk of developing risk cancer with increasing alcohol intake has been noted for up to 60 g per day ( Smith-Warner et al).

For each 10 g increment of alcohol consumed each day ( approximately 0.5-1 drink) the risk of breast cancer increases approximately 9%.

A comprehensive analysis of 119 studies has found that it takes only 1 glass of wine or any other kind of alcoholic drink a day to increase risk of breast cancer.

Nurses’ Health Study, prospective obsrvational study of 105,986 women: increasing alcohol consumption increased breast cancer risk as low levels of 5.0-9.9 g per day, equivalent to 3-6 drinks per week, and increased risk related to cumulative alcohol intake throughout adult life.

Alcohol is a known risk factor for breast cancer, particularly estrogen receptor positive cancers and alcohol increases mammographic breast density in premenopausal and post menopausal women.

Worldwide research on how breast cancer risk included data from 12 million women and approximately 260,000 breast cancer cases: strong evidence found that risk of pre-menopausal breast cancer is increased by 5% and risk of post-menopausal breast cancer is increased by 9% with drinking the equivalent of a beer or a small glass of wine a day.

A meta-analysis indicated a 16% reduction in the odds of dying when surgery for early breast cancer in premenopausal women was performed during the luteal phase rather than the follicular phase of the menstrual cycle (Fentiman IS).

A meta-analysis of patients with early breast cancer, who were premenopausal and treated with surgery during the luteal phase was associated with a 34% increase in survival in those patients with positive lymph nodes (Lemon HM).

Surgery in the luteal phase compared to the follicular phase with early breast cancer premenopausal patients showed no difference in survival in relation to the menstrual cycle (Kroman N, Thorpe H).

In a study of 834 premenopausal women with breast cancer treated with surgery in the luteal or follicular phase of the menstrual cycle had no differences in their disease free survival or overall survival at a median follow-up of 6.6 years (Grant CS).

Increasing height of world population may be associated with increasing incidence of breast cancer.

Dietary factors with protective effects of vegetables, low fat dairy products and low intake of animal fat associated with premenopausal rather than postmenopausal breast cancer.

Late age at first full-term pregnancy associated with increased risk of breast cancer.

Women that have received chest radiation for pediatric malignancy have a significant risk of breast cancer at a young age.

Risk after chest radiation increases as early as 8 years after treatment for childhood malignancy and the median age of breast cancer diagnosis ranges from 32-35 years (Kenney L).

Risk of breast cancer is highest in women treated during childhood with radiation for Hodgkin�s disease with high dose mantle radiation.

Women exposed to moderate or high dose chest radiation, greater than or equal to 20 Gy, during childhood cancer therapy have an increased risk of breast cancer.

The magnitude of increased risk of breast cancer in women after being radiated during childhood is as great as that associated with BRCA mutations with a cumulative breast cancer incidence approaching 20% by age 45 years.

Among the female Hodgkin’s disease survivors breast cancer is the most commonly diagnosed solid tumor (Dores GM e al)

For women treated for Hodgkin’s disease before age 30, the risk of developing breast cancer is six times greater than the general population with an excess risk of 20-40 occurrences per 10,000 patients annually.

In women with a history of radiation therapy for Hodgkin’s lymphoma BC is diagnosed at an early stage, but these women are at a greater risk of bilateral disease (Elki EB et al).

About 10% of women younger than 50 years of age with breast cancer have a BRCA mutation, and 80% will have Ashkenazi Jewish ancestry or significant personal or family history of breast and/or ovarian cancer.

May be a late effect of exposure to doses of ionizing radiation as low as 0.1-0.5 Sievert (Land CE).

Increasing age at diagnosis associated with more favorable biology with greater expression of hormone receptors, lower proliferation rate, absence of HER2 neu expression, higher diploidy, and normal expression of p53.

About half the cases of newly diagnosed are early stage, lymph node negative, hormone receptor positive tumors.

Pathology assessment provides data about extent of disease and biological features essential in management.

These data help determine disease stage, estimate risk of recurrence, helps predict response to therapy.

Pathology report requires knowledge of patients history, prior breast biopsies, prior treatments, pregnancy status, characteristics of the tumor, status of lymph nodes, skin abnormalities,

Specimen should be oriented for the pathologist.

Bio markers should be acquired: ER,PR, HER2status.

ER/PR testing by immunohistochemistry should be done.

Approximately 75% of patients with breast cancer have hormone receptor positive disease, that is, estrogen receptor and/or progesterone receptor expression of one % or more.

Breast cancers with at least 1% positivity for staining should be considered ER positive.

HER2 recommended for all newly diagnosed invasive breast cancers and for first recurrences.

HER2 can be assessed by number of HER2 gene copies using in-situ hybridization techniques or a complementary IHC technique quantifying HER2 cell surface receptors.

Women with early stage breast cancer with ER negative lesions have a peak annual hazard of recurrence of 18.5% at 1-2 years after surgery that decline thereafter to rate of 1.4% in years 8-12.

The Tamoxifen Exemesane Adjuvant Multinational trial (TEAM) surprisingly showed that there was a higher incidence of distant BC recurrence with increasing age in post menopausal ER + with early BC.

From a molecular characterization point of view there is three types of breast cancer: HER2+ subtype, hormone receptor positive, and triple negative disease.

The four main molecular subtypes of BC are triple negative, HR +/HER2-, HR+/HER2+, HR-/HER2+.

Estimated that more than 2.5 million women living in the US have a past or present history of breast cancer.

It is estimated that greater than 150,000 patients are living with metastatic breast cancer.

Effects on bone from treatment common: chemotherapy may lead to premature menopause and accelerated bone loss, postmenopausal women treated with aromatase inhibitors and ovarian suppression can have decreased bone density, and three fourths of women with metastatic breast cancer will have bone involvement, with bone pain and risk for fracure.

Each molecular type has distinct biological features and clinical course: hormone receptor positive disease is characterized by a more indolent course, a long disease-free interval and tendency to relapse in bone and soft tissues; HER2+ gene amplification adds a more aggressive course to the behavior to the hormone receptor positive subgroup with a higher likelihood to develop visceral metastases.

Triple negative and hormone receptor negative HER2+ subtypes are aggressive with early visceral and CNS metastases.

Approximately 80% of breast cancers that develop in germline BRCA-1-mutation carriers are triple negative cancers.

Intrinsic subtypes-basal-like, HER2+/ER-, luminal A, luminal B and claudin-low tumors.

Most breast cancers are either luminal or basal-like.

The four main intrinsic molecular subtypes of breast cancer are luminal A, luminal B, HER2-enriched, and basal-like-these entities are associated with distant recurrence and response to endocrine and chemotherapy.

Luminal A and B tumors are largely ER positive.

Luminal subtypes expressed cellular markers consistent with presumed cellular origin, the secretory epithelial cells that line the lumen of mammary ducts.

Luminal A subtype is the most common form of breast cancer with an incidence of 54% and HER2 positive/ER negative/PR negative is the least common subtype, accounting for 6% of cases.

Luminal A is ER/PR positive, HER 2 negative and low Ki-67.

Luminal A type with more indolent features more common in older women.

Luminal B is ER/PR positive HER 2 negative and high Ki-67.

Luminal B is ER/PR positive HER2 positive and any Ki-67 level.

Basal-like triple negative is ER/PR negative, HER 2 negative.

HER2 + ER/PR negative HER 2 positive.

HER2 +, basal-like, and normal like tend to encompass more ER negative tumors than the luminal subtypes.

Microarray analysis can separate luminal A and luminal B tumors on a molecular basis.

Ki-67 levels of 13.25% is the cutoff value to determine luminal B disease.

Ki-67 score is at week two after preoperative endocrine therapy categorizes prognosis: at two weeks KI 67 positivity below 10% cut off, at five years had a recurrence rate of less than 10%, while those with a cut off greater than 10% at two weeks, had a five-year risk of recurrence greater than 20%.

In the POETIC study above, those who�s Ki 67 score was less than 10% at baseline and week two had a five-year recurrence rate less than 5%.

Basal-like breast cancer has a high expression of p53, an indication of mutations in the DNA repair protein p53.

Basal- like breast cancer, like TNBC, do not express ER, PR, or HER2.

Basal- like breast cancer has similar morhologic changes like TNBC, and includes pushing border edge, high nuclear grade, squamous metaplasia, tumor necrosis, spindled tumor cells, and central scar (Stockmans G).

Basal-like subtype is believed to arise from the basal/myoepithelial cell layer of the mammary duct.

Basal- like breast cancer is a subtype of TNBC, comprising 85% of TNBCs.

Basal- like breast cancer may occasional be positive for ER, PR and HER2.

Basal- like breast cancer and TNBC are discordant in 20-30% of cases, so that the two terms are not synonymous.

Basal- like breast cancer classification based on molecular phenotyping using microarrays.

Triple negative breast cancer based on immunochemical assays for ER, PR and HER2.

Luminal A subtype is defined as ER negative and or PR positive, HER-2/neu negative, and Ki-67 less than 14%.

Luminal B subtype is defined as ER negative and or PR positive, HER-2/neu negative, and Ki-67 greater than 14% (Cheung MC).

Survival times is the longest for luminal A subtype breast cancers.

Luminal tumors are less likely to respond to chemotherapy compared with basal-like or HER2 positive breast cancers.

Survival is lowest in the basal and HER2+ subtypes, with survival differences decreasing by 5 years and may be modest for ER- malignancies.

Cancers 1-2 cm in diameter with clinically negative nodes, 23% have 1-3 positive nodes at axillary resection, and 11% have 4 positive nodes (Carter CL).

The hazard curve for breast cancer deaths peaks between two and three years after diagnosis, and then declines sharply.

This type of hazard curve suggests that the biologic mechanisms responsible for early and late cancers specific events are different: therefore early and late effects of adjuvant therapy may vary accordingly.

SEER data for annual hazard rates shows a peak of nearly 3%. between second and third years after diagnosis and declines to 1 to 2% per year by the sixth through eighth years for all breast cancer patients.

The SEER data hazard rates for ER negative and ER positive tumors, peaked at 6.5% and 2% per year, respectively between the first and third years.

ER negative to ER positive hazard rates cross between the seventh and eighth years after diagnosis, and after which women with ER negative tumors have a lower rate of breast cancer death than those with ER positive tumors.

Much higher rate of recurrence among patients with T1abN0 breast cancers HER2 positive compared to HER2 negative tumors: increased risk 2-5 fold, at 5 years with an absolute risk of 10-23% despite small size of cancers (Curigliano, G, Gonzalez-Agulo AM).

In patients with larger tumors and or node positive with HER2 positive lesions the recurrence rate is much higher than in smaller lesions, node negative or HER2 negative tumors.

Older patients tend to have less aggressive tumor biology and normal likely to have low grade, hormone receptor positive, HER-2 negative and node negative disease than younger women: With the exception of a very old and very young, adjustments for breast cancer stage reveals differences in tumor biology have only minimal impact, and older and younger women and similar breast cancer specific survival.

Inferior outcomes exist for patients with two hormone receptor negative subgroups compared to luminal subtypes.

Basal subtype associated with African-American race, high tumor grade and high proliferation rates.

Basal-like subtype characterized by low expression of ER, PR and HER2 negative, described as triple negative breast cancer.

Basal-like breast cancers have a high expression of HER1, basal cytokeratin 5/6 and c-KIT.

Basal-like breast cancers associated with a shorter disease specific survival among individuals with basal cytokeratins 5/7 and 17, and HER1 is a significant independent negative prognostic factor (Nielson TO).

Basal-like breast-cancer is likely to be of higher grade, ductal type, associated with necrosis, border invasion and stromal lymphocytic response(Livasy CA).

Basal-like subtype clinically aggressive, unresponsive to typical endocrine therapies and poor prognosis (Vona-Davis L).

Patients with triple negative cancers had greater benefit treated with the PARP1 inhibitor BSI-201 (Iniparib) plus gemcitabine/carboplatin compared to gemcitabine/carboplatinum alone resulted in a clinical benefit rate of 62% vs. 21%, respectively and an objective response rate of 48% vs. 16%, respectively we have a significant survival benefit both the median progression free survival and median overall survival (O�Shaughnessy).

In a phase 2 study comparing the efficacy and safety of gemcitabine and carboplatin with or without iniparib, a small molecule with PARP inhibitory activity, in patients with metastatic TNBC: the addition of iniparib to gemcitabine and carboplatin improved the rate of clinical benefit from 34%-56%, and the overall response from 32%-52%, and also prolonged the median progression free survival from 3.6 months to 5.9 months and the median overall survival from 7.7 months to 12.3 months (O’Shaughnessy J et al).

Basal like subtype of breast cancer based on micro array gene expression profiling into molecularly distinct groups.

Basal like breast cancer identified by gene expression profiling, but has no accepted criteria for recognition.

Basal subtype breast cancers have morphological and immunophenotypical features that can be identified in routine practice.

Survival curves for ER positive basal and nonbasal tumors similar and higher than ER negative basal and nonbasal tumors (Rahka).

For patients with grade 3 tumors, ER status was not important in overall survival (in a study of 1800 patients) as nonbasal tumors of either receptor status were similar and higher than basal tumors of either receptor status (Rahka).

Basal subtype breast cancers associated with BRCA1 gene are sensitive to DNA damaging drugs such as platinum agents.

Claudin-low Is a subset of triple negative breast cancer that clusters near basal-like breast cancer on micro array studies.

Claudin-low breast cancers are slower growing then basal-like breast cancers and have features of mesenchymal and mammary stem cells.

Claudin-low tumors have a poor prognosis.

Enterolactone level elevations associated with reduced risk of breast cancer.

Annual hazard rate of recurrence for women with early stage breast cancer that is ER positive peaks at 11.0% in years 2-3, and a risk of approximately 5% through year 12.

Mammary gland is most vulnerable to carcinogenic influences before the first delivery.

Breast cancer excess greatest in atomic bomb survivors when exposure occurred before age 10 years.

High birth weight, rapid growth at the time of mammary gland development, tall stature and low-body mass during adolescence are risk factors for the later development of breast cancer.

Soy consumption inversely related to risk of breast cancer.

In a study of 5042 patients breast cancer patients in a Shangai Breast Cancer Survival Study indicated that soy consumption was significantly associated with decreased risk of death and recurrence with adjusted 4 year mortality rates of 10.3% and 7.4% and 4 year recurrence rates os 11.2% and 8%, respectively, for women in the lowest and highest quartiles of soy protein intake(Shu XO).

There is an observed inverse association with aspirin or other nonsteroidal anti-inflammatory drugs with breast cancer risk.

1 (IGF-1) levels are associated with breast cancer risk in premenopausal women.

Leptin levels associated with risk of breast cancer risk in postmenopausal women.

Physical activity has a protective role in breast cancer.

Regular use of aspirin associated with a significant reduction in the risk of breast cancer, especially the hormone positive cancers.

Among women living at least 1 year after the diagnosis of breast cancer aspirin use associated with decreased risk of distant recurrence and death (Holmes MD).

Nurses’ Health Study by Holmes consising of 4164 female nurses diagnosed with breast cancer and suvived at least one year: aspirin use associated with a 74% reduction in risk of breast cancer death, compared to never users (Holmes MD.

Nurses’ Health Study by Holmes indicated that a distant recurrence risk reduction of 43% for 6-7 day a week aspirin users, and a 60% reduction in risk for 2-5 day per week aspirin users compared to nonusers (Holmes, MD).

Use of NSAIDs for more than 6 years associated with lowered risk of breast cancer.

Increased risk for women consuming flame broiled food more than twice a month. (CLUE 2 study).

 

 

 

Women who use permanent hair dye and chemical straighteners are at higher risk for breast cancer compared to women who did not use these products.

 

 

 

The association of permanent hair dye and breast cancer is significantly higher among black women compared to white women.

Active smoking, especially smoking before the first birth, may be associated with a modest increase in the risk of breast cancer is suggested by the Nurses’ Health Study of 111,140 participants from 1976- 2006 for active smoking and 36,017 women from 1982 to 2006 for passive smoking (Xue F et al).

The peak incidence occur in women 70-74 years (461 per 100,00), 75-79 years (482 per 100,000), and 80-84 years (472 per 100,000).

Women aged 85 years and older have an incidence rate of 401 per 100,000.

Women below the age of 65 years have a breast cancer incidence of the 82 per 100,000 women, while those 65 years and older have a rate 404 per 100,00.

Approximately 1% decrease in breast cancer mortality per year.

Risk of contralateral breast cancer among breast cancer survivors is two to five times the risk of patients without a history of breast cancer.

In a women with a history of breast cancer the absolute incidence of a contralateral breast cancer is approximately 0.5-1% per year.

Death rates are similar for women who took estrogen compared to those who did not.

Fewer than 5% survive 20 years after a diagnosis of metastatic breast cancer.

Over the last 25 years the median survival has increased from 15 to 51 months and 5 year survival has increased from 10-40%.

5 year survival rates for metastatic breast cancer has improved from 22% in the year 2000-27% in the year 2008 (Jemal A).

In 1975 the rate of death for women 30-79 years of age was 48.3 deaths per 100,000 women and by 2000 fell to 38 per 100,000, likely explained by screening mammography and improved treatment.

Prognosis of tumor grade is very pronounced in women with tumors less than or equal to 2.0 cm.

While 40% of patients will have positive axillary lymph nodes only 20% of patients will develop axillary relapse after 10 years even those who receive no treatment.

Metastatic disease occurs in 40% of patients with early stage breast cancer including those who receive adequate locoregional treatment and adjuvant chemotherapy at the time of diagnosis.

Patients with tumors greater than 4 cm or at least four involved nodes experience locoregional recurrence rates in excess of 20% and should be offered adjuvant irradiation.

Patients with one to three involved nodes and large tumors, extranodal extension equal or greater than 2 mm, or inadequate axillary dissections experience high rates of locoregional recurrence and may benefit from postmastectomy irradiation.

Older patients have a lower rate of ipsilateral recurrence of breast cancer, with or without radiation, especially with small hormone receptor positive tumors (Merchant TE, Hughes, KS).

In a large randomized trial of older females with small hormone receptor positive tumors treated with lumpectomy and radiation revealed that the addition of breast radiation did not improve survival and 94% of deaths in both groups were from non-breast cancer causes. (Hughes KS).

Meta-analysis-the addition of breast radiation to lumpectomy did not improve 15 year survival rates in patients with breast cancer in patients with breast cancer at low risk for local or regional recurrence (Clarke M).

While radiotherapy in breast conservation does not improve survival, local recurrence rates are found to be unacceptably high.

Local regional recurrence rate increases with increasing tumor size and the number of lymph nodes involved.

About one third of patients with metastatic disease present with local or regional recurrence involving lymph nodes and or chest wall- over time 75% of these patients develop distant metastases.

Tumor size is a good prognostic marker for distant relapse in lymph node negative patients.

Patients with large tumors (6.1 cm -8.0 cm) have decreased breast cancer specific mortality compared with moderate to large (4.1 cm-5.0 mm) tumors but have survival comparable with small (2.1-3.0 mm) tumors in the context of LN negative disease: suggesting large tumors with LN negative disease may a surrogate for biologically indolent disease of dissemination (Yu K-D et al).

Local regional recurrence rate for patients with tumors 5 cm or smaller and with fewer than 4 involved lymph nodes is estimated to be less than 15% with a potential reduction to less than 5% with the addition of postmastectomy radiation therapy and an overall 3-4% benefit in overall survival.

In patients with four or more involved lymph nodes risk of local recurrence is nearly 30% and there is a two-third reduction in the rate of loco-regional recurrence with the use of postmastectomy radiation with a 9-10% benefit in overall survival.

Excess mortality from heart disease in women administered radiation (Clarke M et al).

Increase in cardiac deaths in early BC adjuvant radiation trials, and left sided BC associated with higher mortality resulting from ischemic heart disease compared with right sided BC.

Increase of stenosis of mid and distal LAD plus distal diagonal disease in irradiated left sided breast cancer patients (Nilsson G et al).

In the above study there was a 4-7 fold increase in high grade coronary artery stenosis in mid and distal LAD, including distal diagonal branch, when comparing women with irradiated left BC with those with right sided BC.

18% of patients that relapse, do so 10 or more so years after they are initially treated, despite the use of adjuvant chemotherapy (Weiss R).

The presence of greater than 25% positive lymph nodes in patients with 1-3 positive nodes identifies those with high risk of postmastectomy local, regional and distant recurrence and may benefit from adjuvant radiation and aggressive chemotherapy.

Data from the 70’s and 80’s indicate mortality at 10 years in women who have 10 or more involved lymph nodes or a large primary tumor at presentation exceeds 60%.

Three-fourths of patients with breast cancer develop their axillary recurrence within 2 years.

Over 25% of patients with recurrent disease after the initial diagnosis and treatment occurs after more than 5 years, and it may be higher in patients with ER positive tumors who receive adjuvant endocrine therapy.

Early Breast Cancer Trialists� Collaborative Group (EBCTCG) demonstrated that ovarian ablation by surgery or ovarian radiation or ovarian suppression with a luteinizing hormone releasing hormone inhibitors significantly improve disease free and long term survival menopausal women with early breast cancer.

Early Breast CancerTrialists Collaborative Group found a 20 year risk of distant recurrence after five years of endocrine therapy for women with node negative disease, ER positive, early breast cancer is likely about 1/4 lower than previously reported: The risks of distant recurrence during 5-20 years are reported to be 13% for stage T1N0 disease and 19% for those which stage T2N0 disease.

Patients less than 35 years of age with hormone positive tumors have a worse prognosis than older premenopausal and perimenopausal patients between the ages 35-50 , regardless of lymph node status or tumor size.

Population based retrospective studies show young women who do not receive adjuvant chemotherapy have a significant increased risk of dying, and the risk increased with the younger age of diagnosis.

Younger patients treated with cyclophosphamide, methotrexate and fluorouracil have an increased risk of relapse and death then older patients, especially if their tumors are estrogen receptor positive.

Ovarian ablation by surgery or pelvic irradiation compared to CMF (cyclophoshamide, methotrexate, 5 FU) chemotherapy in premenstrual patients with estrogen receptor positive, node positive cancer have no difference in event free or overall survival.

Metastatic disease treatment aimed at prolonging survival, relieving symptoms, improvement in quality of life and delaying disease progression.

CRP and serum amyloid A levels were followed in 734 women with disease-free breast cancer and the elevation of these two tests were associated with poor survival.

Endocrine treatment is the therapy of choice for patients with hormone positive with the exception of significant visceral involvement requiring rapid tumor shrinkage.

Chemotherapy treatment of choice for patients with metastatic breast cancer with hormone insensitive disease, or those that are hormone positive and have failed hormonal management.

Only 10% of patients with metastatic disease survive 10 year after diagnosis.

P53 mutations are seen in up to 50% of invasive breast cancers.

In women with lymph node-negative breast cancer survival is the same among women who had greater than 20 lymph nodes examined compared with women with fewer lymph nodes examined at 5 years.

Approximately 5% of patients have clinical metastases at the time of diagnosis.

It is recommended that a newly diagnosed patient had a chest x-ray as part of the staging procedure, although published rates of actual detection of metastases are between 0.93% and 1.2% (Puglisi F).

30-40% of patients at diagnosis that appear to be tumor free harbor metastases that are occult and many will relapse and die from recurrent disease despite adjuvant therapy.

Lymph node is tumor burden is a continuous variable and occult metastases are an independent prognostic factor with hazard ratios greater than 1.0 for, any outcome event, and distant disease in whom occcult metastases are detected in sentinel lymph nodes compared with patients with no occult metastases (Weaver DL et al).

In the above study women with breast cancer were randomly assigned sentinel lymph node biopsy plus axillary dissection with sentinel lymph node biopsy alone, and patients lymph nodes were evaluated for occult metastases-occult metastases were detected in 15.9% of 3887 patients: The hazard ratio for death, any outcome event, and distant disease were 1.40 and 1.30, respectively (Weaver DL et al).

In the above study the magnitude of difference in the outcome at five years was only 1.2%, suggesting that in patients with occult metastases no clinical benefit is noted from additional evaluation, and the risk associated with isolated tumor cell clusters is lower than the risk associated with micrometastatic disease.

The American College of Surgeons Oncology Group Z0010 trial involving 5210 patients who underwent breast conserving surgery for invasive breast cancer clinically stage T-1-T2 N0M0: Sentinel lymph node specimens were examined for hematoxylin-eosin or immunohistochemistry tests- patients with evidence of immunohistochemical positive SLN metastases did not have a different overall survival than women with hematoxylin-eosin negative lymph nodes (Guiliano A et al).

In the above study bone marrow patients whose specimens contained metastases was associated with a decreased overall survival, but only 3% of patients were positive for bone marrow metastases among patients with early stage invasive breast cancer.

Identification of occult metastases does not appear to be clinically useful for patients with newly diagnosed disease in whom systemic therapy is planned based on the characteristics of the primary lesion (Weaver DL et al).

AMAROS trial of women with early sentinel lymph node positive breast cancer comparing axillary radiation to axillary lymph node dissection: rates of axillary recurrence 1% vs 0.5% after 5 years, with no differences in 5 year disease free or overall survival (Rutgers EJ et al).

In the above study axillary resection associated with more lymphedema than axillary radiotherapy.

 

For patients with clinically node negative disease, evidence supports the use of sentinel lymph node biopsy is the standard of care.

In early breast cancer SLNB alone  is standard of care in patients with clinically nodal negative disease based on a low axillary recurrence rate: 0.4% with SLNB and  0.2% with SLNB plus  axillary node dissection.

Adjuvant trials reveal that short-term disease free survival benefit translates into long-term survival gain.

A combination of breast cancer screening with mammography and adjuvant therapy with chemotherapy/hormonal treatment have helped reduce the death rate of breast cancer in the U.S.

Patients with node-negative, estrogen receptor positive have a 10-year recurrence rate of 15% when treated with tamoxifen and with the addition of chemotherapy the recurrence rate of 10-11%.

Risk of relapse at 5 and 10 years approximately 20% and 30%, respectively, for patients with node-negative operable breast cancer.

Approximately 40-50% of patients who relapse after tamoxifen may achieve clinical benefits from second line endocrine therapy.

16-48% of operable patients with breast cancer have micrometastases in iliac crest bone marrow aspirates.

Risk not associated with caffeine intake.

About 3% of patients with breast cancer will have a solitary pulmonary lesion seen on chest x-ray and in as many as 40% of these cases it will be a breast cancer metastasis.

Survival after resection of a single breast cancer metastasis to the lung ranges from 42-79 months with an average survival of 53 months and average 5 year and 10 year survival of 52% and 26%, respectively.

Average survival times for patients with a single lung metastasis from a breast cancer treated medically is 8-33 months.

At 19 months after primary surgical treatment 28% of patients without evidence of recurrence have evidence of minimal residual disease in their bone marrow examinations. Furthermore, the presence of occult metastatic cells in the bone marrow predict a worse prognosis compared to patients with persistently negative bone marrow findings.

More than half of patients who develop metastases will have hepatic metastases as a component.

Approximately 10% of patents with liver metastases will have disease confined to the liver with no other signs of systemic disease.

Median survival for patients with breast cancer pre-taxanes was less than 20 months and with taxanes containing treatment it is 22-26 months.

Two-fold risk of relapse and breast cancer death associated with high-risk medial breast tumors may be due occult spread to internal mammary nodes.

The 5-year relative survival for node-negative breast cancer is 96% compared with 75% for node-positive disease.

Annual risk for the development of a second breast cancer is approximately 0.5-0.7%.

Lymphoscintograms demonstrate mapping to the internal mammary lymph nodes in 0-35% of patients with breast cancer.

20%-30% of women who develop breast cancer report a positive family history, not all of these women have hereditary susceptibility the disease.

Women, with a first degree relative with breast cancer, have twice the risk of developing breast cancer, on average, compared with other women.

Estimated that hereditary factors play a causative role in more than 25% of breast cancer cases.

Hereditary breast cancer genes account for 8-10% of ER positive breast cancers: such genes include CHEK2 ,1%, and genes associated with homologous recombination deficiency such as BRCA,12%, BRCA 2, 2%, ATM 0.5-1%, and PALB, 0.5 to 1%.

In women with a family history of breast cancer without a proven gene mutation the cumulative life-time risk of breast cancer ranges from 15-50%.

Image detected breast cancers may constitute more than 50% of all newly diagnosed breast cancers in facilities using mammographic and other image-related screening techniques.

Of deaths due to breast cancer 77% occur in patients aged 55 years and older with the highest rate of 200 per 100,000 population, occurring in the 85-years- and-older age group.

A patients with a positive internal mammary lymph node is designated N3 and stage IIIB.

Percutaneous biopsy may spare as many as 80% of patients with histologically benign image-detected abnormalities from undergoing open biopsy procedures.

Common occurrence of weight gain during the first year after diagnosis in up to 80% of patients.

Weight gain following BC diagnosis associated with increased rates of recurrence and death.

Weight gain with BC associated with increases primarily in fat mass rather than lean mass.

Women receiving chemotherapy for BC who are of normal weight at the time of diagnosis are more likely to gain weight and body fat during the following year than overweight or obese women (Nissen MJ et al).

Women�s Healthy Eating and Living (WHEL) Study revealed that reduction in mortality related to physical activity and diet high in vegetables and fruits and low in fats was limited to patients with hormone positive disease, and that such a living style decreases circulating levels of estradiol and estrone.

The greatest risk for weight gain occurs in premenopausal women and those receiving chemotherapy.

Chemotherapy induces sarcopenic weight gain with evidence for reduced physical activity.

Women with osteoporosis have a lower incidence of breast cancer, presumably because of lower endogenous estrogen levels.

A 1.5 fold increased risk of recurrence in premenopausal women who gain more than the median weight during the first year after diagnosis. (5-year survival 55% v. 70% in those gaining less than the median.)

Obese women have a higher mortality rate for breast cancer.

In the setting, increases in the dose intensity of alkylating agents and anthracyclines have failed to improve survival over conventional doses.

Combination of adjuvant radiotherapy and chemotherapy with mitoxanthone induces a high risk of acute leukemia in patients with breast cancer.

20%-30% of women with negative axillary nodes experience recurrent disease in the 10-year post-operative period.

70% of patients with clinical stage T1 and T2, N0 breast cancers have pathologically negative nodes.

Up to 33% of patients with pathologically negative nodes have micrometastases on immunohistochemical analysis.

Women with node-negative breast cancers < 1 cm in diameter or 1 to 2 cm in diameter and histologic grade I have the same survival likelihood as age-matched women without breast cancer.

Patients with disease confined to bones have a longer survival than do patients with the subsequent development of metastases to extra skeletal sites (Coleman R).

Rates of skeletal complications higher in women with bone metastases only breast cancer, at first relapse, compared to women with bone and extraosseous metastases or without bone metastases, 81%, 60%, 21%, respectivley (Coleman R).

The Breast Cancer Detection Demonstration Project reveals survival rate for patients with a tumor size of less than 1 cm T1N0 of 96% at years of follow-up.

A good correlation exists for tumor size and tumor grade: larger tumors are generally of higher grade.

A randomized trial for T1a and T1b breast cancers showed that tamoxifen lowers recurrence risk among small ER positive tumors (Fisher B).

T1N0 20-year recurrence free survival 88% for tumors 1 cm or less and 72% for tumors measuring 1.1-3.0 cm.

Early studies of patients with micrometastases do not reflect survival disadvantages.

Over 25% of patients who recur do so more than 5 years after the initial diagnosis, and this percentage may be higher in patients with ER positive tumors.

Relative risk of developing contralateral breast cancer varies from 1.7 to 4.8 times the incidence in women who never had the disease.

One percent of breast cancer patients present with synchronous bilateral breast cancers.

The overall cumulative incidence of metachronous bilateral breast cancers is 2.7%.

There is an increase in contralateral breast cancer among patients with germline mutations in CHEK2 or PALB2.

There is a five-year risk for contralateral breast cancer of 10% in patients with PALB2 mutation carries versus 70% in BRCA1 carriers and 3% in women with neither mutation.

The annual incidence of contralateral breast cancer remains fairly constant of about 0.75%.

6-10% of breast cancer patients present with metastases at diagnosis.

Triple negative tumors refer to estrogen receptor negative, HER2 negative and progesterone receptor negative tumors.

Triple negative tumors often diagnosed in African-American women.

Triple negative tumors associated with poor prognosis.

Triple negative tumors are higher frequency in lower socioeconomic groups.

Triple negative highest in African-Americans, lower for Hispanic women and lowest among white women.

Triple negative tumors in African-American women associated with a 5 year survival of 14%.

Triple negative tumors seen more commonly in women under the age of 40 years.

Triple negative tumors associated with shorter survival regardless of the stage of the disease.

Triple negative and basal-like breast cancers tend to be larger than other subtypes and of higher grade.

Basal-like may be more likely than other breast cancer types to be a node negative (Cheang MC et al).

Estrogen positive-progesterone negative subtype has an outcome is bad or worse than triple negative breast cancer.

For bilateral breast cancer the disease specific survival is 68% when it is measured from the time of the first breast cancer diagnosis and 53% when measured from the second breast cancer diagnosis.

The median overall survival of bilateral breast cancer is 170 months after the first cancer and 87 months after the second cancer.

Younger age at the time of diagnosis of breast cancer is the most important risk factor for developing contralateral breast cancer.

Patients who develop bilateral breast cancer have tumor size and nodal status that are similar to those in unilateral breast cancer patients.

A second breast cancer increases the risk of dying from breast cancer by about 1.5 times.

The most important prognostic factors for disease specific survival in bilateral breast cancer patients are the nodal status of the first cancer and the size and nodal status of the second cancer.

Changing a traditional Oriental diet to that of a Western diet increases the risk of the development of breast cancer.

Women on low fat diets before diagnosis tend to have less aggressive cancers than do those on high fat diets.

Large numbers of patients observed for at least 6 years reveal that patients with micrometastases detected by immunohistochemistry have significantly lower survival rates compared with patients in whom no micrometastases were detected.

Chemoendocrine therapy in patients with micrometastases did not improve overall survival in patients with low 21 Gene assay score.

Leading cause of cancer-related deaths in women ages 20-59 years.

Obesity at the time of diagnosis and weight gain after diagnosis is associated with increased risk for recurrence of breast cancer and poorer prognosis.

Women with obesity had a 5 year survival rate of 55.6% compared with a rate of 79.9% in leaner women, and have larger tumors, higher rates of lymphatic invasion and nodal involvement (Abe R et al).

In a meta-analysis of 45 studies obese women at diagnosis have a 30% higher risk of breast cancer-related and overall mortlaity, compared to leaner women (Protani M et al).

Previous surgical biopsy of the breast does not increase incidence of immunohistologically detected keratin positive cells in axillary lymph nodes.

Associated with excessive body weight in postmenopausal women.

Primary chemotherapy has not been shown to prolong disease free survival.

Reproductive risk factors include early age of menarche, late age of first pregnancy, late age at any birth, low parity and late age of menopause.

Women with the highest levels of physical activity in the year before diagnosis may have better survival.

Cutaneous metastases more common in breast cancer than any other malignancy in women, accounting for 20% of all skin metastases.

Cutaneous metastases indicate the tumor has infiltrated into skin, capillaries and lymph vessels.

Skin metastases in breast cancer signifies widespread systemic disease and indicates a poor prognosis.

Invasive type develops in both the ipsilateral and contralateral breast at about 3.5%; 3.9% at 8 years after lumpectomy and radiation for DCIS.

Conservative surgery with negative margins associated with better relapse-free survival than patients with positive margins.

Adjuvant chemotherapy with anthracycline based polychemotherapy offers a survival advantage over Cytoxan/Methotrexate/5FU regimens.

French Adjuvant Study Group (FASOG) randomized weekly epirubicin compared to no postoperative chemotherapy for ER+, node positive patients over the age of 65 years, all of whom received adjuvant tamoxifen: modest but statistically improved disease free survival, but no improvement in overall survival for the epirubicin treated patients.

Docetaxel regarded as the single most active cytotoxic agent in advanced breast cancer with objective response rates in untreated patients of up to 68% in phase II trials and 30-40% response rates in anthracycline pretreated patients in phase III trials.

Cisplatin effective in BRCA1 mutations with a 72% pathologic complete remission in neoadjuvant therapy (Gronwald J).

In the Breast Internation Group (BIG) trial triple negative BC, an increased lymphocytic infiltrate was associated with a reduced relapse rate and improved survival, independent type of chemotherapy, and was not observed in hormone receptor positive tumors.

The presence of tumor associated lymphocytes in breast cancer patients is an independent predictor of response to neoadjuvant chemotherapy suggesting a pre-existing immunologic response may enhance the effects of conventional cytotoxic chemotherapy (Denkert C).

Tumor infiltrating lymphocytes are associated with good clinical outcome in many types of breast cancer (Giraldo NA).

In triple negative breast cancer tumor infiltrating lymphocytes is associated with a favorable prognosis.

Tumor infiltrating lymphocytes (TIL) associated with a higher rate of pathologic complete remission in the neoadjuvant setting.

TIL levels are associated with improved prognosis in HER2 positive breast cancer and triple negative breast cancer, with each approximately 10% increase in TIL being associated with a 15-25% decrease in the risk of relapse and death.

TIL predicts pathological response to neoadjuvant therapy.

4-20% of breast tumors are lymphocyte predominant.

Tumor infiltrating lymphocyte rates are higher in HER2 positive and triple negative breast cancers when compared with hormonal receptor positive tumors.

In pooled analysis of two adjuvant chemotherapy trials docetaxel had no significantly different effect on the risk of recurrence or death in ER positive and ER negative patients (Andre).

Randomized chemotherapy trials with adjuvant chemotherapy for breast cancer suggest that patients with ER positive disease derive less benefit from anthracycline and paclitaxel regimens than do ER negative patients.

Analyses of HER2 status among 5200 patients participating in a large randomized adjuvant trials comparing anthracycline with non-anthracycline chemotherapy regimens showed that only women withHER2 positive breast cancer derived an incremental benefit from anthracycline use.

In a phase III study of albumin bound paclitaxel compared to solvent based paclitaxel in taxane naive metastatic breast cancer patients resulted in a 33% vs. 19% response rate with a longer time to tumor progression of 23 weeks vs. 16.9 weeks (Gradishar).

Anthracycline therapy may be beneficial only for patients who over express HER2.

Eastern Cooperative Oncology Group (ECOG) E2100 study of 722 patients with recurrent or metastatic breast cancer receiving paclitaxel vs paclitaxel and bevacizumab resulted: in overall response rate of 20.9% with paclitaxel alone vs 35% for the combination of drugs, and an improvement in progression free survival from 6.1 months with paclitaxel alone to 11.4 months for the combination but no difference in median overall survival 24.8 months vs 26.7 months for the combination treatment.

MINDACT study using MammaPrint 70 gene assay identified women with clinically high risk early stage disease for who adjuvant chemotherapy was unlikely to produce a benefit.

Addition of bevacizumab to chemotherapy agents paclitaxel, nab-paclitaxel, docetaxel, gemcitabine capecitabine or vinorelbine in seoond line breast cancer vs the addition of placebo: 684 patients progresion free survival with the bevacizumab group was 7.2 months vs 5.1 months for placeebo group, overall response rate 39.5% vs 29.6%, median overall survival 18 months vs 16.4 months in the placebo plus chemotherapy group (Brufsky A).

Addition of bevacizumab to Docetaxel improves response rates as well as time to progression in metastatic disease (AVAVO Trial).

AVEREL phase III trial the addition of Bevacizumab in combination with Herceptin/Docetaxel in patients with HER-2 positive metastatic breast cancer did not improve PFS.

In a randomized study of 1206 patients to receive neoadjuvant therapy consisting of docetaxel, docetaxel plus capecitabine or docetaxel plus gemcitabine for 4 cycles, with all regimens followed by treatment with doxorubicin-cyclophosphamide for 4 cycles: patients were randomly assigned to receive or not receive bevacizumab for the 1st 6 cycles of chemotherapy.-The addition of bevacizumab significantly increased the rate of pathological complete response from 28.2% without the drug and 34.5% with it (Bear HD et al).

Capecitabine with or without bevacizumab (phase 2 trial) doubled response rates in metastatic breast cancer patients in patients treated with bevacizumab, but no difference in progression free or overall survival (Miller KD et al).

Bevacizumab improved progression free survival in a phase 3 study of 424 patients with HER2 positive locally recurring/metastatic breast cancer randomized to receive trastuzumab and docetaxel or trastuzumab and docetaxel plus bevacizumab as first-line therapy.

Bevacizumab and anti-metabolites capecitabine and gemcitabine improve the outcomes when added to taxanes in patients with metastatic breast cancer.

Bevacizumab and chemotherapy increases progression free survival, response rates, but not overall survival, and prospective, randomized trials for metastatic breast cancer.

Paclitaxel with bevacizumab increased response rates and doubled time to progression (Miller K et al).

Treatment in patients with early breast cancer and adjuvant breast cancer revealed that the presence of chromosome 17 polysomy predicts improved response to anthracycline agents.

The national epirubicin trial indicated that amplification of HER2 or topoisomerase 2A were only moderately predictive for response to anthracycline as adjuvant therapy in breast cancer.

In a trial of 1286 postmenopausal, hormone receptor positive women with metastatic disease treated with Letrozole vs. Lapatinib plus Letrozole for frontline management (EGFEG30008 trial):HER2 positive population had a median progression free survival of 8.2 months in the combination group and only 3 month in the Letrozole group, overall response rate in the combination drug treatment was 27.9% vs. 14.6% in the Letrozole only group, and there was not difference in response rate of clinical benefit in either group for patients that were HER2 negative (Johnston).

Combination of lapatinib plus trastuzumab compared to lapatinib alone in women with HER2+ metastatic breast cancer that had progressed on multiple lines of treatment: combination superior in progression free survival compared to lapatinib alone, median overall survival in the combination arm 60.7 weeks compared to lapatinib alone at 41.4 weeks (Blackwell KL).

The combination of trastuzumab and lapatinib increases the pathologic complete response rate is superior to monotherapy in adjuvant trials.

In a phase II study CHER-LOB trial stage II orII breast cancer patients HER2+ who received chemotherapy prior to surgery for stage II or III BC responded better to treatment with a combination of trastuzumab and tyrosine kinase inhibitor lapatinib then with treatment with either lapatinib or trastuzumab alone with chemotherapy: A complete pathological response was noted in 28% of patients in the trastuzumab only arm, 32% in the lapatinib only arm and 48% in the combination arm (Guarneri V et al).

In a phase 3 study randomized Clinical Evaluating of Pertuzumab and Trastuzumab (CLEOPATRA) trial of 800 meet patients with metastatic HER2 positive breast cancer adding pertuzumab to a combination of trastuzumab and docetaxel chemotherapy stated progression free survival by a median of 6.1 months compared to the combination therapy plus placebo.

In the phase II NeoSphere trial 417 patients with newly diagnosed HER-2 positive early stage breast cancer were randomized to one of for treatment arms: Trastuzumab plus docetaxel, pertuzamab plus trastuzumab plus docetaxel, pertuzumab plus trastuzumab or pertuzumab plus docetaxel-Patient’s had locally advanced for early breast cancer and were treated neo-adjuvantly-patient who received docetaxel, pertuzumab plus trastuzumab Had a significant improvement in pathological complete response of 45.8% impaired with 16.8-29% for the other groups.

Adding zoledronic acid to endocrine therapy significantly prolongs disease-free survival and recurrence with survival versus endocrine treatment alone in premenopausal women with endocrine responsive breast cancer by 36% and 35% respectively (Gnant M et al).

Australian Breast and Colorectal Cancer Study Group trial 12 indicated that adding zoledronic acid to adjuvant hormonal therapy for 3 years reduced the risk of disease progression by 36% in 1803 premenopausal women with stage I or II endocrine responsive breast cancer (Gnant M et al).

AZURE trial of 3360 women (pre and postmenopausal women) with stage II or III breast cancer 96% of whom received adjuvant chemotherapy, and only 152/3360 receiving hormonal treatment alone, study group received zoledronic acid (4mg every 3-4 weeks x 6 doses, then every 6 months for 5 additional doses) median follow-up 59 months:no difference in local recurrence or death, but postmenopausal women for more than 5 years or at least 60 years old had a 29 % reduced risk of dying of breast cancer.

Adjuvant treatment with zoledronic acid should be considered to improve the standard of care in premenopausal women with breast cancer.

In a open labeled study, phase 3, randomly assigning 3360 patients to receive standard adjuvant systemic therapy with or without zoledronic acid with zoledronic acid dispute every 3-4 weeks for six doses and then every 3-6 months to complete five years of treatment: at a median follow-up of 59 months no significant difference in the rate of disease free survival was noted-findings would not support the routine use of zoledronic as an adjuvant management of breast cancer (Coleman RE et al).

In the SUCCESS-A trial there was no significant difference in point of disease free survival for women receiving five years or two years of adjuvant zoledronate (Friedl).

Median diameter of invasive breast cancers is only 1.5 cm.

30% of breast cancer patients have + lymph nodes at diagnosis.

2% of T1a and T1b cancers will recur in the axilla in the absence of axillary dissection.

10% of T1c cancers will recur in the axilla in the absence of axillary dissection.

18% of T2 cancers will recur in the axilla in the absence of axillary dissection.

Extranodal extension has a higher association with recurrence, breast cancer mortality and a higher rate of positive lymph nodes.

Patients with ipsilateral isolated supraclavicular lymph node involvement have the same prognosis associated with patients with stage III disease.

Only a limited number of microembolic axillary metastases become clinically evident.

Virtually all patients with recurrence die of breast carcinoma.

New carcinomas arise in contralateral breast at an average of nearly 1% per year.

Bone marrow metastases associated with increasing primary tumor size detected in 30%, 42%, 62% and 75% of T1, T2, T3, and T4 carcinomas, respectively.

Bone marrow metastases more common in higher-grade tumors: 52% of grade III tumors compared with 39% of grade I and II tumors.

Locally advanced constitute 10-29% of all breast carcinomas.

Premenopausal adult white women treated for well differentiated thyroid cancer are more likely than other women to develop breast cancer.

Breast reduction operations decrease risk of breast cancer by 30-50%.

Adjuvant hormonal therapy in elderly patients with ER+ tumors the risk of recurrence is reduced by 50%.

Prognostic value of tumor size depends on the size of the invasive component.

The size of the entire lesion including the ductal in situ is useful in making decisions about breast conservation surgery.

The presence of mammographic calcification associated with higher rates of local recurrence.

Local recurrence is more frequent with cancers with extensive intraductal carcinoma manifesting as calcifications.

Tubular carcinoma of the breast is a well-differentiated form of infiltrating ductal carcinoma with a prevalence of from 0.7-10.3% of all breast cancers.

Local failure treated with local excision and radiotherapy occurs in about 13% of patients.

Current standard of care of axillary management in patients with invasive breast cancer is to perform a level I and II axillary lymph node dissection.

There is no benefit to removing noninvolved lymph nodes from the axilla.

Two-thirds of women with early breast cancer will not benefit from nodal dissection.

Survival after mastectomy and breast conserving therapy is equal for stage I and stage II breast cancer.

The National Surgical Adjuvant Breast and Bowel Project B-06 trial (NSABP b-06) 20 year follow-up showing overall survival of 46% and 47% for breast conservation therapy and mastectomy, respectively, and 20 year local recurrence rate 8.8%, and 2.3% respectively (Fisher B et al).

Despite equivalence of mastectomy and BCT for primary treatment of breast cancer the rate of mastectomy has been increasing in recent years.

Diagnosis of breast cancer not a sufficient reason to perform a genetic analysis for germ line mutations in cancer suppressor genes, such as BRCA1 and BRCA2 since the risk of carrying such a gene is less than 1% in women without a high risk of familial cancer syndromes.

Only 5-10 % of cases caused by inheritance of germline mutations in highly penetrant susceptibility genes such as BRCA1 administration BRCA2.

7 genes contribute to breast cancer susceptibility: BRCA1, BRCA2, TP53, PTEN, CHK2, ATM and STK11.

Single-nuucleotide polymorphisms(SNPs) are low risk genetic changes associated with a risk for breast cancer-16-170 SNPs associated with increased risk of BC.

Between ages 40-49 a woman has a 1.5% risk of developing breast cancer at some time during the decade.

Between ages 50 through 59 years a woman has a 2.5% risk of developing breast cancer.

Between ages 60 through 69 years a women has a risk of 3.4% of developing breast cancer.

High-dose chemotherapy with stem cell support in patients with 10 or more positive lymph nodes is not advantageous over standard adjuvant chemotherapy treatments.

30-70% of patients of patients with breast cancer develop bone metastases.

Associated with increased bone turnover and resorption even at sites distant from metastases.

Compared to a control group without breast cancer patients with breast cancer have a 20 fold increase risk of vertebral fractures in the presence of soft tissue metastases without evidence of bone metastases.

47% of patients with localized breast cancer bone metastases will be the initial site of distant metastases.

Median survival with patients with bone metastases ranges from 24-34 months.

As a third line drug for patients with ER+ disease Fulvestrant can benefit 20-30% of patients who have failed tamoxifen or other aromatase inhibitors in the metastatic setting for 6-26 months.

A phase 2 trial postmenopausal womenwith metastatic breast cancer , and acquired resistance to aromatase inhibitors demonstrated a 28 percent benefit with high-dose estradiol therapy and a 29% benefit with a low dose estradiol regimen (Ellis MJ).

Recent studies suggest median survival for patients with metastatic breast cancer and hormone responsive disease is up to 45 months, making it a chronic disease with similar survival as heart failure, myeloma, and chronic obstructive pulmonary disease with hypoxia.

Becoming a chronic disease, where the majority of recurrences, as well as two-thirds of breast cancer related deaths, occur after 5 years of initial endocrine therapy.

Patients with ER- disease or high-grade tumors consistently have greater likelihood of favorable response to chemotherapy.

Postmastectomy radiation along with adjuvant chemotherapy can improve local-regional control rates by 20% and survival rates by 10% in patients with four or more positive axillary nodes, with clinical stage III disease or T3 tumors.

Disease free survival and overall survival are shorter in patients with locally advanced, EGFR positive lesions when treated with adjuvant 5-flurouracil, adriamycin, and cyclophosphamide compared to a similarly managed EGFR negative breast cancer group.

PARP-1 inhibitors in a Phase 2 study of breast cancer of metastatic breast cancer patients increased overall survival by 50% in triple-negative patients.

A Phase 2 study of patients with BRCA deficient advanced breast cancer, PARP-1 inhibitors resulted in a progression of the survival duration of 5.7 months.

Frequently associated with increased expression of epidermal growth factor receptor tyrosine kinases that are involved in the regulation of breast tissue.

In a placebo controlled phase 2 trial utilizing sorafenib in combination with capecitabine, significantly extended progression free survival in patients with advanced breast cancer.

The combination sorafenib and capecitabine had a 74% improvement in progression free survival in advanced breast cancer compared to capecitabine alone, 6.4 vs. 4.1 months (Baselga).

Increased expression and activation of EGFR tyrosine kinases associated with increased risk of recurrence after primary treatment and with a poor prognosis.

Overexpression of HER1 (ErbB-1) occurs in approximately 27-30% of breast cancers, while HER-2 (ErbB-2) is overly expressed 20-25% of cases.

Human epidermal growth factor receptor-2 (HER-2) overexpression occurs early in breast cancer development and leads to aggressive disease with high risk of recurrence, metastases and a poor prognosis.

HER-2 positive breast cancer, when treated with surgery associated with early peak of local relapse or metastases.

Higher incidence of overt CNS metastases in the range of 25-34% for patients who have received trastuzumab based regimens for HER-2 positive disease.

The addition of adjuvant trastuzumab significantly improved disease free and overall survival among women with HER2 positive breast cancer in a study of 3222 women with early stage BC comparing doxorubicin and cyclophosphamide followed by docetaxel, the same treatment plus trastuzumab, or docetaxel plus carboplatin plus trastuzumab: Estimated disease free survival at 5 years 75%,84%, and 81%, respectively and overall survival 87%,92%, and 91%, respectively (Slamon D et al).

In the above study congestive heart failure and cardiac dysfunction higher in the group receiving AC-T plus trastuzumab, and 8 cases of anthracycline acute leukemia (Slamon D et al).

The addition of trastuzumab to chemotherapy significantly improves rates of objective response, response duration, and time to progression, 56%, 58%, and 65% improvement, respectively, as well as a 30% improvement in the rate of overall survival among patients with first line metastatic breast cancer disease.

Signaling pathways P13K and hsp90 may account for resistance in breast cancer treatment with trastuzumab.

PIK3 inhibitor apselib is effective for ER positive breast cancers with PIK3CA mutations.

The gene product of PIK3CA is phosphatidylinositol 3 kinase a tyrosine kinase and key component of the PI3K and protein kinase B (AKT) pathway that regulated cell growth.

Dysregulation of the PI 3K and AKT pathway occurs in several subtypes of breast cancer, and maybe highest in triple negative breast cancer, buddy incidence of these mutations is most common in the hormone receptor positive and HER2 breast cancer.

The risk of brain metastases in breast cancer is subtype dependent, and patients with human epidermal growth factor receptor 2 positive and triple negative subtypes experience significantly higher rates of CNS relapse than patients with hormone receptor positive and HER2 negative tumors.

Higher incidence of brain metastases may be explained by higher affinity of HER-2 overexpression breast cancer metastases for the CNS, or trastuzumab based treatment prolongs survival to such an extent that brain metastases become apparent.

Incidence of CNS metastases in the range of 14-16% and another 15% have asymptomatic lesions, and up to 30% experience brain metastases during the course of their disease.

The incidence of central nervous system metastases may be increasing year by year because of advancements in therapy for metastatic disease have resulted in patients living longer to develop such metastases, and because of advances in imaging techniques have improved the detection of such lesions.

Risk for breast CNS metastases is increased for younger patients under the age of 50 years, for hormone receptor negative patients, for patients with higher disease burden, such as with patients who have greater than 2 metastatic sites at the time of initial diagnosis and the presence of HER2 positivity.

Patients with HER2 positive disease have an increased risk of developing CNS metastases that range from 30.7 to 53%.

In a study of 83 patients with breast cancer the median overall survival for patients with HER2 positive disease from diagnosis of brain metastases was 17.1 months compared with 5.2 months for patients with HER2 negative breast cancer patients with CNS disease (Eichler AF).

After primary treatment of breast cancer and a median follow-up of 8 years 1.7% of patients HER-2 negative had brain metastases, while 8% of patients overexpressing HER-@ had brain metastases (Abdulkarim).

Single agent everolimus 10 mg/day phase II study in pretreated metastatic breast cancer patients indicated a 12% response rate (Ellard SL et al).

In a phase 3 trial Breast Cancer Trials of Oral Everolimus ( BOLERO-2) 724 postmenopausal patients with metastatic breast cancer hormonally receptive positive and with progressive disease while receiving aromatase inhibitors anastrozole or letrozole, treated with exemestane plus everolimus resulted in a median progressive free survival of 7.4 months, compared with 3.2 months among those treated with exemestane plus placebo.

BOLERO-2 trial of women with advanced hormone resistant estrogen receptor positive breast cancer treated with everolimus and the aromatase inhibitor exemestane found at increased progression free survival from a median of 2.8 months with exemestane alone to 6.9 months for the combination with a 64% reduction in risk of progression or death.

The addition of everolimus to paclitaxel and trastuzumab in patients with trastuzumab refractory, HER2 positive patients with metastatic breast cancer was associated with a high response rate and suggested m-TOR inhibition can delay or reverse trastuzumab resistance by the PI3K/AKT/m-TOR pathways.

About 40% of patients with ER positive breast cancers are PIK3CA mutated.

Adding the tyrosine kinase inhibitor dasatinib to standard aromatase inhibitor therapy with letrozole doubled progression-free survival (PFS) compared with letrozole alone in women with hormone receptor-positive, HER2-negative metastatic breast cancer.

In an evaluation of 728 patients with distant metastatic disease at the time of first diagnosis patients who received surgery for the primary survived an average of 31 months, compared to those who did not have surgery of 14 months(Ruiterkamp J).

The five year survival revealed a 24.5% survival for patients with metastatic breast cancer and who had surgery to remove the primary were alive at five years, whereas only 13.1% of those who did not have surgery were alive at five years (Ruiterkamp J).

A population based study of HER-2 negative patients had 10% CNS metastases, while HER-2 positive patients had 24% brain metastases (Abulkarim).

In 242 patients with HER 2 positive metastatic breast cancer and progressive brain metastases after brain radiation treated with Lapatinib had a 6% greater than 50% reduction in tumor volume and 17% had a 20% reduction in brain tumor volume: with tumor progression capecitabine was added and 20% of these patients had a 50% greater reduction in tumor volume and 40% had a 20% or greater volume tumor response. (Lin NU).

Capecitabine has efficacy for breast cancer brain metastases (Ekenel M).

A retrospective analysis of the early treatment of breast cancer revealed HER-2 negative patients with 2.6% CNS metastases and 7.2% among HER-2 positve patients during an 8.1 year follow-up (Ahn).

In a study of 2,685 patients never exposed to trastuzumab and HER-2 overexpression there was no association of increased brain metastases (Tham).

Majority of patients that develop CNS metastases do so subsequent to extracranial manifestations..

CNS metastases first manifestation of recurrence in 20-39% of patients.

The interval between the first diagnosis of breast cancer and brain metastases is 34 months and 16 months after the diagnosis of metastatic disease.

Comedocarcinomas associated with ER negative and HER-2 overexpression.

Patients who maintain a healthy weight and who exercise after diagnosis have a better survival than overweight or sedentary individuals.

It is found that vigorous exercise like fast bicycling or running reduces the risk of pre-menopausal as well as post-menopausal breast cancer.

Almost 1/3 of breast cancer survivors have aerobic capacity below the minimum physiologic threshold needed for functional independence.

Statistically significant benefit of recurrence risk in early stage breast cancer with the use of bisphosphonates in premenopausal women treated with medical ovarian ablation and tamoxifen or aromatase inhibitors (ABCSG-12 trial).

 

About 2% of breast cancers have mismatch repair deficient to microsatellite instability.

An analysis of 13 trials involving 6886 patient’s randomized to treatment with bisphosphonates, or either placebo or no treatment in the adjuvant chemotherapy management of breast cancer resulted in: No reduction in the overall number of deaths, bone metastases, overall disease recurrence, distant relapse, visceral recurrence, or local relapse, therefore adjuvant bisphosphonate should not be recommended routinely. (Davide M).

With bone metastases a bone modifying agent such as zoledronic acid or denosumab in addition to chemotherapy or endocrine therapy is recommended with expected survival of three months or greater.

Bisphosphonates used for 1 year in postmenopausal women resulted in fewer breast cancers compared to control group with a hazard ratio of 0.61(Breast Cancer in Northern Israel Study, Rennert G et al).

Women’s Health Initiative study indicated a 31% lower risk of invasive breast cancer among bisphosphonate users.

Bisphosphonates as adjuvant therapy reduces bone recurrence by 34% and breast cancer death by 17%, only in postmenopausal women and those women who have had chemotherapy induced menopause: Indicating bisphosphonates can exert an anticancer effect in breast cancer patients (Coleman R).

Current guidelines call for 3 to 5 years of bisphosphonate therapy on the theory that these drugs might reduce breast cancer recurrence as well as treatment-related bone problems.

Results,however, show no difference in disease-free survival, distant disease-free survival, and overall survival ― regardless of menopausal status ― between the 1540 women who received intravenous zoledronate over a 5- year period and 1447 women who received such therapy over a 2-year period.

There was a substantially higher risk for adverse events with prolonged bisphosphonate treatment, including risks for grade 3/4 events, bone pain, bone fractures, arthralgia, and jaw necrosis.

There was also no difference in rates of bone recurrence or in circulating tumor cells, which the bisphosphonates theory would have predicted. 

10.5% of women in the 5-year group had one or more circulating tumor cells on follow-up, vs 7.2% in the 2-year group.

Almost half of the women in the 5-year treatment group experienced adverse events with zoledronate ― including 7.6% with grade 3/4 events ― vs just over a quarter in the 2-year arm and only 5.1% with grade 3/4 events.

In the 5-year group, 8.3% of partients experienced bone pain and 5.1% experienced arthralgia, vs 3.7% and 3.1%, respectively, in the 2-year arm.

Fractures were reported in 14 women in the 5-year group but in only three in the 2-year arm.

Jaw necrosis, was reported in 11 women in the 5-year group and in five in the 2-year group.

Measurement of vitamin 25-OH D levels at the time of diagnosis of 512 breast cancer patients and tracked over an overage of 12 years, revealed: only 24% of women had adequate levels at the time of diagnosis, and women deficient in vitamin D has significantly worse distant disease free survival and overall survival independent of the patients age, weight, tumor stage or tumor grade (Goodwin).

Low vitamin D levels are associated with poor survival in a prospective study of women with breast cancer (Yao S et al).

It is suggested that an inverse relationship exists between total average annual sunlight energy that strikes the ground and age-adjusted breast cancer mortality.

Inverse associations have been suggested between serum 25-hydroxyvitamin D levels and breast cancer development, risk for recurrence, and mortality in women with early stage breast cancer.

Management of primary breast tumors in the presence of metastatic disease has traditionally been approached to treat with systemic therapy, with local management reserved for women who require palliation at the primary site.

The primary tumor may be a source of metastasizing cells and should be considered for treatment to prevent the development of new metastatic lesions.

A review of multiple studies showed that resection and/or radiotherapy in 30-55% of women with de novo stage for disease was associated with a consistent survival advantage for women who undergo therapy for the primary tumor in the setting of metastatic disease, and there was a reduction in the hazard of death from 40-50% (Perez CB, Khan SA).

Surgical therapy for the primary tumor in patients with metastatic disease is associated with improved survival with the National Cancer Data Base showing a three-year survival was 35 months in patients surgically resected with free margins and 17 months in a nonsurgical group (Khan SA et al).

SEER data suggest surgically treated primary breast cancers with metastases lived a median 15 months longer than those patients not treated surgically (Gnerlich J et al).

A meta-analysis of 6210 patients with adjuvant node positive will locally advanced breast cancers treated with high doses of chemotherapy And autologous stem cell support achieved a 13% reduction in the risk of recurrence, but without a significant reduction in the risk of death after a median follow-up of six years ()BerryDA et al).

A meta-analysis of 866 patients with metastatic breast cancer comparing high-dose chemotherapy with stem cell support to a standard chemotherapy control arm indicating a progression free survival with median 11 versus 8.3 months without significant improvement in overall survival (Berry DA et al).

High dose chemotherapy with stem cell support does not produce sufficient benefit to be employed as an adjuvant therapy or a palliative management approach for breast cancer.

Ovarian suppression of estrogen production reduces the recurrence rate in hormone receptor positive early breast cancer patients who are pre-menopausal.

In premenopausal women randomized to receive chemotherapy or non-chemotherapy and five years of tamoxifen or tamoxifen plus ovarian suppression or aromatase inhibitor plus ovarian suppression: heading ovarian suppression to tamoxifen does not provide a significant benefit and women who receive chemotherapy and who remained premenopausal the addition ovarian suppression improved disease outcome (SOFT Investigators).

In an Indian study there was no evidence to suggest that local regional treatment of the primary breast cancer conferred an overall survival advantage in patients with de novo metastatic breast cancer (Badwe R et al)

Hormonal receptor positive tumors are associated with lower rates of programmed cell death ligand 1 (PD-L1) positivity, lower levels of tumor infiltrating lymphocytes, and lower median tumor mutational burden.

About 5% of breast cancers have higher tumor mutation burden, with enrichment in metastatic tumors associated with a higher neoantigen burden and increased T-cell infiltration.

Pembrolizumab may be efficacious in HER2 positive breast cancer patients with PD-L1 positive tumors and resistant to trastuzumab.

Pembrolizumab is approved for patients with mismatch repair deficient or microsatellite instability high breast cancers, accounting for only 2% of breast cancers.

Pembrolizumab plus chemotherapy leads to prolonged overall survival among patients with advanced triple negative breast cancer:its success is based on PD-L1 levels.

Tailor trial demonstrated about 70% of patients with hormone receptor�positive, human epidermal growth factor receptor 2 (HER2)�negative, axillary node�negative early-stage breast cancer, who received intermediate score on the Oncotype Dx test, could be

spared chemotherapy.

The trial found no difference in the disease-free survival whether these women were treated with endocrine therapy alone or with the combination of endocrine therapy with chemotherapy.

The trial found about half of all breast cancers are hormone receptor positive, HER2 negative, and axillary node negative but up to 30% of patients have recurrences by 10 years,

CDK4/6 inhibitors combined with endocrine therapy are the standard of care for ER positive, HER2 negative metastatic breast cancer with improved progression free survival and overall survival and good toxicity profile seen in several trails.

Endocrine therapy plus CDK4/6 inhibition yield similar or better efficacy versus chemotherapy and it is associated with less toxicity.  making it the preferred treatment unless a patient has imminent organ failure.

This population can be spared an estimated 70% of patients and limit chemotherapy to the 30% who may benefit from it.

Adjuvant chemotherapy in the above patients reduced the risk for relapse, but the absolute benefit was only 3% to 5%,suggesting many women are being overtreated, because endocrine therapy would be adequate.

Alpelisib approved for the treatment of postmenopausal patients with hormone receptor (HR)-positive, HER2-negative, PIK3CA-mutated, advanced or metastatic breast cancer that has been detected by an FDA-approved test and progressed during or after an endocrine-based therapy regimen, in combination with fulvestrant.

The prognosis for many women with small, early-detected cancers receiving standard multi-disciplinary therapy has become so favorable that new, active treatments contribute only marginally to further reductions in the risk of recurrence and rarely affect overall survival. 

High dose chemotherapy with hematopoietic stem cell Produce no long-term survival benefit in patients with stage III breast cancer but did improve overall survival in patients with 10 or more axillary lymph nodes-20 year follow up Steenbruggen TG).

 

((Tucatinib)) inclusive triple regimen in patients with metastatic disease that  received  one more HER2 based regimens is very active and compelling for its used for patients with brain metastases.