Breast Cancer Treatment & Management
Routine systemic imaging is not indicated for patients with early breast cancer in the absence of signs/symptoms of metastatic disease.
CBC, metabolic panel, liver functions, alkaline, phosphatase, are considered if patients are candidates for preoperative or adjuvant systemic therapy.
Bone scan for pet/CT scan is indicated and patients with localized bone pain or elevated alkaline phosphatase.
Diagnostic CT Indicated only if pulmonary symptoms are present.
Abdominal/ pelvic imaging with CT or MRI/pet indicated only if the patient has an elevated Igo phosphatase, abnormal LFTs, abdominal symptoms or abnormal physical exam of abdomen or pelvis.
PET/CT scanning or not recommended in the staging of clinical stage I , II or operable stage III breast cancer due to high false negative rate for the detections of lesions that are smaller than 1 cm and are low-grade disease, the high rate of false positive scans in patients without locally advanced disease has low sensitivity for detection of axillary nodal metastases and a low probability of these patients having detectable metastatic disease.
Surgery is considered primary treatment for early-stage breast cancer; many patients are cured with surgery alone.
The goals of breast cancer surgery include complete resection of the primary tumor with negative margins to reduce the risk of local recurrences and pathologic staging of the tumor and axillary lymph nodes.
Pathological review provides necessary tissue prognostic information.
Patients with the early stage operable breast cancer initially undergo upfront definitive surgery, either with breast conservative surgery or mastectomy and systemic therapy, if indicated, based on primary tumor characteristics, such as tumor size, grade, lymph node, involvement, ER/PR status, HER2 receptor expression and tumor genomics.
Neoadjuvant chemotherapy is used in patients with locally advanced breast cancer to reduce tumor volume and allow for definitive surgery.
Neoadjuvant chemotherapy may allow less extensive surgery or obviate axillary lymph node dissection in patients who present with node-positive breast cancer.
In patients with triple-negative (estrogen receptor, progesterone receptor, and HER2) or HER2-positive disease, response to neoadjuvant therapy can guide the selection of adjuvant therapy.
Race may affect response to neoadjuvant therapy. In a review of Black and White women treated with neoadjuvant endocrine therapy,
Black women were more likely to benefit from neoadjuvant endocrine therapy than White women if treated at an earlier disease stage, but were less likely to benefit than White women if treated at a later disease stage.
Adjuvant treatment of breast cancer is designed to treat micrometastatic disease,
Adjuvant treatment for breast cancer involves radiation therapy and systemic therapy, including a variety of chemotherapeutic, hormonal, and biologic agents.
In early-stage breast cancer, tumor gene-expression assays can be used to determine the likelihood of recurrence and thus the potential benefit of adjuvant chemotherapy.
With the 21-gene assay, a recurrence score of 0 to 10 is prognostic for a 2% rate of distant recurrence at 10 years that is unlikely to be improved by adjuvant chemotherapy.
A high score, which has variably been defined as 26 or 31 or higher, is predictive of chemotherapy benefit.
The prospective Trial Assigning Individualized Options for Treatment (TAILORx) studied the outcome in 6711 women with hormone-receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative, axillary node–negative breast cancer who had a midrange recurrence score of 11 to 25:
At 9 years, patients treated with chemoendocrine therapy or endocrine therapy alone had similar rates of invasive disease–free survival, freedom from disease recurrence, and overall survival.
Chemotherapy offered some benefit only in women 50 years of age or younger with a recurrence score of 16 to 25, who represented 46% of this age group.
A secondary analysis of the TAILORx data confirmed that there is a cohort of these women who benefit from chemotherapy.
In women with a recurrence score of 26 to 100, who received adjuvant chemotherapy in addition to endocrine therapy, the estimated rate of freedom from recurrence of breast cancer at a distant site was 93% at 5 years; in comparison, the expected rate in this population of women, if treated with endocrine therapy alone, is 79% at 5 years.
RxPONDER trial, which included 5018 women with HR-positive, HER2-negative breast cancer, one to three positive axillary lymph nodes, and a recurrence score of 25 or lower, premenopausal women who received chemoendocrine therapy had longer invasive disease–free survival and distant relapse–free survival than those who received endocrine-only therapy: contrastingly postmenopausal women with similar characteristics did not benefit from adjuvant chemotherapy.
Surgical treatment of invasive breast cancer may consist of lumpectomy or total mastectomy.
In breast cancer patients who have clinically negative nodes, surgery typically includes sentinel lymph node (SLN) dissection for staging the axilla.
In the AMAROS trial, which involved patients with cT1-2N0 breast cancer up to 5 cm and clinically node-negative axillae who were undergoing either breast conservation or mastectomy with SLN mapping, axillary radiotherapy was found to be a better treatment option than ALN dissection (ALND) in women with a positive SLN.
In the AMAROS trial 744 of the patients with a positive SLN went on to receive ALND, and 681 received axillary radiotherapy.
After 5 years of follow-up, the axillary recurrence rate was 0.54% in the ALND group and 1.03% in the radiotherapy group, and there were no significant differences between the groups with respect to either disease-free survival (86.9% vs 82.7%) or overall survival (93.3% vs 92.5%).
The rate of lymphedema in the ALND group after 5 years, however, was twice the rate seen in the radiotherapy group (28% vs 14%).
A 3-week hypofractionated adjuvant radiotherapy—in which lower total doses of radiotherapy are delivered in fewer, larger doses (fractions)—is as effective and safe as the international standard 5-week regimen for women with early-stage breast cancer following primary surgery.
Hypofractionated regimen may cause less damage to surrounding normal breast tissue.
In stages I and II invasive breast cancer positive margins are associated with at least a 2-fold increase in ipsilateral breast tumor recurrence (IBTR).
Negative margins optimize IBTR; this risk is not significantly lowered by wider margin widths.
IBTR rates are reduced with the use of systemic therapy.
In patients who do not receive adjuvant systemic therapy, margins wider than no ink on tumor are not needed.
Biologic subtypes do not indicate the need for margins wider than no ink on tumor,
Margin width should not determine the choice of WBI delivery technique, fractionation, and boost dose.
Wider negative margins than no ink on tumor are not indicated for patients with invasive lobular cancer; classic lobular carcinoma in situ (LCIS) at the margin is not an indication for reexcision.
Young age is associated with an increased risk for IBTR after breast-conserving therapy, an increased risk for local relapse on the chest wall after mastectomy, and adverse biologic and pathologic features; an increased margin width does not nullify the increased risk for IBTR in young patients
An extensive intraductal component (EIC) identifies patients who may have a large residual ductal carcinoma in situ (DCIS) burden after lumpectomy.
The purpose of radiation therapy after breast-conserving surgery is to eradicate local subclinical residual disease while reducing local recurrence rates by approximately 75%.
Irradiation of the intact breast is considered standard of care, even in the lowest-risk disease with the most favorable prognostic features.
There are 2 general approaches used to deliver radiation therapy: conventional external-beam radiotherapy (EBRT) and partial-breast irradiation (PBI).
Whole-breast radiotherapy (WBRT) consists of EBRT delivered to the breast at a dose of 50-55 Gy over 5-6 weeks.
This is often followed by a boost dose specifically directed to the area in the breast where the tumor was present
Common side effects of radiation therapy include fatigue, breast pain, swelling, and skin desquamation. Late toxicity (lasting ≥6 months after treatment) may include persistent breast edema, pain, fibrosis, and skin hyperpigmentation.
Rare side effects of radiation include rib fractures, pulmonary fibrosis, cardiac disease with left breast treatment, and rarely secondary malignancies such as radiation-induced sarcoma (0.5%).
Partial breast irradiation is employed in early-stage breast cancer after breast-conserving surgery as a way of delivering larger fraction sizes while maintaining a low risk of late effects.
Such therapy includes interstitial brachytherapy where multiple catheters placed through the breast and intracavitary brachytherapy whera balloon catheter inserted into the lumpectomy site.
Treatment is typically administered twice daily for 5 days.
These techniques have shown low local recurrence rates comparable to those of EBRT.
Treatment with accelerated partial breast irradiation candidates:
Age ≥45 years for all tumor types
All invasive subtypes or DCIS
Total tumor size (invasive and DCIS) ≤ 3 cm
T stage Tis, T1, T2 (≤ 3 cm)
Margins; No tumor on ink for invasive tumors or tumors involved with DCIS; ≥2 mm for DCIS
Node negative
Multifocal acceptable if total span of tumors is ≤3 cm
Estrogen receptor positive or negative
Focal lymphovascular invasion
No genetic mutations
Potential complications of partial breast radiation catheter placement:
Inadequate skin spacing
Infection
Seroma
Fibrosis
Chronic pain
Disease recurrence
Standard EBRT is associated with a higher 5-year breast preservation rate than either lumpectomy alone or brachytherapy.
However, studies do not reflect use of the newest forms of brachytherapy.
Single-dose radiotherapy delivered during or soon after surgery for breast cancer is a viable alternative to conventional EBRT in selected patients who are at low risk for local recurrence.
In the TARGIT-A trial, more than 3400 patients with early breast cancer were randomized to either 1 intraoperative dose of 20 Gy using a spherical applicator or EBRT: Breast cancer mortality overall was similar in the TARGIT and EBRT groups (2.6% vs 1.9%), but there were significantly fewer non-breast-cancer deaths with TARGIT than with EBRT (1.4% vs 3.5%).
Overall mortality rates were 3.9% with TARGIT and 5.3% with EBRT.
ELIOT study, 1305 patients were randomized after lumpectomy to receive either intraoperative radiotherapy or EBRT.
The 5-year event rate for ipsilateral breast tumor recurrence was 4.4% with ELIOT and 0.4% with EBRT.
Overall survival at 5 years was similar in the 2 groups (34 vs 31 deaths), and there was no significant difference between groups in the rate of breast-cancer-related deaths.
Postmastectomy radiation therapy may
be performed according to the following criteria:
Positive postmastectomy margins
Primary tumors >5 cm
Involvement of ≥4 lymph nodes
Patients with more than 4 positive lymph nodes should also undergo prophylactic nodal radiation therapy at doses of 45-50 Gy to the axillary and supraclavicular regions.
For patients in whom ALND shows no node involvement, axillary radiation therapy is not recommended.
Meta-analyses indicate postmastectomy radiation therapy combined with regional nodal radiation therapy significantly decreases the rate of local relapse and breast cancer mortality.
The benefit of radiation therapy for women with 1-3 positive ALNs has been uncertain.
Nonetheless, a meta-analysis of 22 clinical studies found that among women with 1-3 positive nodes following mastectomy and axillary dissection for early breast cancer, postmastectomy radiotherapy reduced the breast cancer mortality rate by 20% and reduced the recurrence rate by 32%: These benefits were similar among women with 1, 2, or 3 positive nodes.
Radiotherapy also benefits patients with 4 or more positive nodes, while no benefit was seen for those with node-negative disease.
Among women with 4 or more positive nodes, radiotherapy reduced breast cancer mortality by 13% and overall recurrence by 21%.
Adjuvant treatment of breast cancer is designed to treat micrometastatic disease which have not yet had an established identifiable metastasis.
Treatment is aimed at reducing the risk of future recurrence, thereby reducing breast cancer-related morbidity and mortality.
Adjuvant therapy has been estimated to be responsible for 35-72% of the reduction in mortality.
Adjuvant therapy with bisphosphonates may prevent disease recurrence and prolong survival.
In the Early Breast Cancer Trialists’ Collaborative Group postmenopausal women with early breast cancer, adjuvant bisphosphonate therapy produced highly significant reductions in recurrence, distant recurrence and breast cancer mortality.
However, premenopausal women, bisphosphonate treatment had no apparent effect on any outcome.
Adjuvant treatment of breast cancer is designed to treat micrometastatic disease but which have not yet had an established identifiable metastasis.
Treatment is aimed at reducing the risk of future recurrence, thereby reducing breast cancer-related morbidity and mortality.
Locally advanced disease has now broadened to include patients who are technically operable but who have large primary tumors (> 5 cm).
Using neoadjuvant therapy in women with large primary tumors, in whom the goal is to increase the possibility of breast-conserving surgery, are different from the reasons in women with disease that meets the original criteria of LABC or inflammatory breast cancer for whom the administration of systemic treatment is essential to make definitive local treatment possible with the intent of cure.
FDA approved pertuzumab for neoadjuvant treatment in combination with trastuzumab and docetaxel for patients with HER2-positive, locally advanced, inflammatory or early-stage breast cancer (either greater than 2 cm in diameter or node positive).
39.3% of patients treated with pertuzumab, trastuzumab, and docetaxel achieved a pathologic complete response (pCR) compared with 21.5% of patients treated with trastuzumab and docetaxel (n = 107) at the time of surgery.
Adjuvant olaparib (Lynparza) for BRCA-mutated HER2-negative high-risk early breast cancer in adults who have undergone treatment with chemotherapy before or following surgery.
Phase 3 OlympiA trial which patients treated with olaparib showed improvement in invasive disease-free survival (DFS), reducing the risk of breast cancer recurrence by 42% compared with the placebo group.
The 3-year distant DFS was 87.5% in the olaparib group and 80.4% in the placebo group.
Recommend HER2-targeted therapy for patients with HER2-positive advanced breast cancer trastuzumab, pertuzumab, and a taxane for first-line treatment and trastuzumab emtansine for second-line treatment.
For third-line treatment, the guidelines recommend offering other HER2-targeted therapy combinations or trastuzumab emtansine, if not previously administered, and pertuzumab if the patient has not previously received it.
The prognosis is better with T3N0 (stage IIB) and T3N1 (stage IIIA) breast cancer is better than it is for those with classically defined LABC (IIIB, IIIC) or IBC (IIIB, T4d).
Disease-free survival (DFS) and overall survival are typically better for stage IIB and IIIA patients; however, the likelihood of achieving a pathologic complete response (pCR) from neoadjuvant treatment, a well-recognized surrogate for long-term outcome, is inversely related to tumor size.
Inflammatory breast cancer (IBC) is a clinical diagnosis that implies presentation with the cardinal signs of inflammation involving the breast, although the warmth may be subtle and the mass may not be appreciated as something discrete.
The true extent of the disease is usually greater than is apparent on physical examination.
The frequency of IBC is low—1-2% of all breast cancers.
In northern Africa IBC it is much higher, for reasons that are not known.
IBC tends to occur at a younger age than LABC does.
Pathologically, IBC has findings of involvement of subdermal lymphatic vessels, though this finding is not in itself diagnostic of IBC.
IBC tumors are more likely to stain negatively by IHC for ER and PR and somewhat more likely to be positive for HER2 overexpression.
Angiogenesis and lymphangiogenesis appear to be increased by microvessel density or RNA-based gene expression arrays in IBC.
Locally advanced breast cancer (LABC) is more common in the US than IBC is; bmay account for 10-15% of patients.
LABC is associated with lower socioeconomic class and, probably for that reason, with black race in the United States.
LABC encompasses both relatively indolent neglected tumors and those that have grown rapidly.
In most case series, LABC has a better long-term outcome than IBC does,even when only inoperable cases are considered.
Patients with LABC or IBC with clinically positive nodes should undergo a core biopsy before initiating chemotherapy, and aThose with clinically negative nodes may undergo sentinel lymph node biopsy before they start treatment, or else sentinel node determination may be delayed until after treatment is completed.
It is preferable to perform sentinel node sampling up front, because chemotherapy might eradicate preexistent disease in the sentinel lymph node and result in a false-negative result.
NSABP B-27 trial suggest that the false-negative rate for sentinel lymph node biopsies performed after neoadjuvant chemotherapy is about 11%, comparable to the false-negative rate for patients undergoing initial resection.
The best single test for evaluating the status of measurable axilary tumor is ultrasonography.
A mass often appears larger on physical examination than on ultrasonography, which can more effectively discriminate hypoechoic masses from surrounding stroma or hematoma.
In IBC, no current imaging technique appears to be highly accurate for the prediction of pCR.
Despite marked advances in the treatment of early-stage breast cancer, many women develop recurrence and metastasis.
In addition, 5-10% of breast cancer patients have metastatic disease at presentation.
There remains no cure once distant metastases develop.
Furthermore, although occasional patients with metastatic breast cancer benefit from surgical resection for an isolated recurrence and many require radiation therapy for palliation at a specific site (or definitive treatment of brain metastasis),
In general, recurrent or metastatic breast cancer must be approached systemically so that the therapeutic effect reaches all sites of disease.
There are two main interventions: hormone therapy and chemotherapy.
For patients who have hormone receptor (ER and/or PR)–positive disease without a life-threatening component or systemic symptoms.
In general, hormone manipulation is the initial treatment of choice.
Response rates are higher with chemotherapy, but so is the incidence of toxicity, and there is no evidence that patients live longer as a result of receiving initial chemotherapy.
For ER–positive metastatic breast cancer endocrine therapy rather than chemotherapy is recommended as first-line treatment, except in patients with immediately life-threatening disease or if there are concerns about endocrine resistance.
The benefit of second-line hormone manipulation is nearly 50%, and failure to benefit from an initial trial with endocrine therapy correlates with second-line failure.
Common hormone therapies and dosages
Menopausal
Tamoxifen
20 mg PO every day
Elacestrant 345 mg PO every day
Anastrozole
1 mg PO every day
Letrozole
2.5 mg PO every day
Exemestane
25 mg PO every day
Fulvestrant
500 mg IM on days 1, 15, 29, and once monthly thereafter
Megestrol
40 mg PO 4 times a day
Premenopausal
Tamoxifen
20 mg PO every day
Aromatase inhibitor + LHRH*
Leuprolide
7.5 mg IM depot q28d
22.5 mg IM q3mo
30 mg IM q4mo
Goserelin
3.6 mg SC depot q28d
10.8 mg SC q3mo
Megestrol
40 mg PO 4 times a day
LHRH = luteinizing hormone–releasing hormone.
A combination treatment with anastrozole and fulvestrant was superior to either anastrozole alone or sequential anastrozole and fulvestrant treatment in patients with hormone-receptor-positive metastatic breast cancer.
Fulvestrant approved by the FDA for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)–negative locally advanced or metastatic breast cancer in postmenopausal women not previously treated with endocrine therapy.
Fulvestrant extended median progression-free survival (PFS) by 2.8 months compared with the aromatase inhibitor anastrozole, and fulvestrant resulted in a median duration of response of 20 months as compared with 13.2 months with anastrozole.
Median duration of clinical benefit was 22.1 months with fulvestrant and 19.1 months with anastrozole.
Overall response rate and clinical benefit rate did not differ significantly between the drugs.
Elacestrant (Orserdu), the first oral selective ER degrader, was approved for men or postmenopausal women with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least 1 line of endocrine therapy.
Alpelisib is a phosphatidylinositol-3-kinase (PI3K) inhibitor approved indicated in combination with fulvestrant for treatment of men and postmenopausal women with HR-positive, HER2-negative, PIK3CA-mutated, advanced or metastatic breast cancer following progression on or after an endocrine-based regimen.
Adding alpelisib to fulvestrant significantly prolonged median PFS (11 months) compared with fulvestrant alone (5.7 months) in patients whose tumors had a PIK3CA mutation.
Palbociclib and ribociclib are cyclin-dependent kinases (CDK) 4, 6 inhibitors indicated in combination with an aromatase inhibitor as initial endocrine-based therapy for postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer.
Approval of palbociclib for initial endocrine-based therapy in postmenopausal women was based on the phase II PALOMA-1 trial, in which mean PFS was 10.2 months in the letrozole group and 20.2 months for palbociclib plus letrozole group.
Approval of palbociclib for ER+/HER2- advanced breast cancer in combination with fulvestrant in women (regardless of menopausal status) with disease progression following endocrine therapy was based on the PALOMA-3 trial in which PFS was prolonged with palbociclib plus fulvestrant compared with fulvestrant alone (9.2 mo. vs 3.8 mo.).
Approval of ribociclib was based on interim analysis results from the pivotal phase III MONALEESA-2 trial in postmenopausal women who had received no prior systemic therapy for their advanced breast cancer, which demonstrated that ribociclib plus letrozole reduced the risk for progression or death compared with letrozole alone:
PFS was 63% with a duration of 19.3 months in the ribociclib group and 42.2% with a duration of 14.7 months in the letrozole-alone group.
In patients with measurable disease the overall response rate was 52.7% and 37.1%, respectively.
A subsequent analysis with an additional 11 months of follow-up showed that the median PFS was 25.3 months with the ribociclib combination vs 16 months with letrozole alone, according to a company statement.
The Monarch 1 trial demonstrated the safety and efficacy of abemaciclib as a stand-alone treatment.
In MONARCH 2, which included women whose cancer had progressed after endocrine therapy, median PFS was 16.4 months with fulvestrant plus abemaciclib versus 9.3 months with fulvestrant alone.
The overall response rates in patients with measurable disease were 48.1% and 21.3% in the abemaciclib and control arms, respectively.
Abemaciclib is approved for use in combination with an aromatase inhibitor for first-line treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer.
The MONARCH 3 trial, in which the addition of abemaciclib to anastrozole or letrozole reduced the risk of progression or death by 46%.
Median PFS was 28.2 months in the abemaciclib arm versus 14.8 months with the aromatase inhibitor alone.
The median duration of response was 27.4 months for the abemaciclib arm compared with 17.5 months in the control arm. [153
Cytotoxic chemotherapy for metastatic breast cancer: Combination therapy is currently considered up front, depending on the patient’s performance status, because of higher response rates. However, in the setting of advanced disease, the goal in determining a treatment regimen should be to prolong survival while maintaining a good quality of life.
The initial choice of chemotherapy is influenced by the patient’s history of previous drug exposure.
If 1 year or more has elapsed since completion of adjuvant therapy, a patient’s tumor is likely to respond to a previously given drug or combination as though that drug or combination had never been given.
Most patients have been exposed to both an anthracycline and a taxane in the adjuvant setting.
Treatment of breast cancer with a taxane in the metastatic setting after treatment in the adjuvant setting may be difficult because of residual toxicity.
Although taxanes are not cardiotoxic, they can produce lingering neuropathy and problems with edema (docetaxel especially), which makes further administration problematic.
If the tumor has recurred quickly after administration of adjuvant chemotherapy containing a taxane, then changing the schedule of administration can be effective.
At least one third of breast cancer patients with taxane resistance due to administration of every-3-week paclitaxel show a response when the same drug is administered on a weekly schedule at a lower dose.
(CALGB) 9840 trial reported an improved overall response rate in patients receiving weekly dosing of paclitaxel (40%) compared with every-3-week paclitaxel (28%), as well as improved median time to progression.
Capecitabine (Xeloda) is an oral agent that essentially represents a sustained-release formulation of fluorouracil (5-FU) and provides the convenience of self-administration.
Drugs such as capecitabine have very little associated myelosuppression, and they are often chosen when the patient’s bone marrow has been damaged by previous therapy or when there is a desire to coadminister a myelosuppressive agent for more rapid effect.
Capecitabine has an ORR of 25-30%, with minimal toxicity: when combined with a taxane, an ORR of 40-50% has been observed, along with a median overall survival benefit of 3-15 months.
Another antimetabolite, gemcitabine (Gemzar), is typically given in combination with paclitaxel, based on results from a phase III trial comparing paclitaxel with the combination regimen in locally advanced breast cancer (LABC) and metastatic breast cancer.
Vinorelbine (Navelbine) is a vinca alkaloid that targets tubulin in the mitotic spindle and is administered intravenously, usually on a weekly basis.
Vinorelbine is often used as a single agent following treatment with a taxane or anthracycline, yielding an ORR of 25%. However, when used as a first- or second-line agent, vinorelbine can have ORRs of up to 40%.
Palbociclib (Ibrance) is an inhibitor of cyclin-dependent kinases (CDKs) 4 and 6 used for first-line treatment for ER-positive, HER2-negative metastatic breast cancer in postmenopausal women, in combination with the aromatase inhibitor letrozole.
A phase II study in which progression-free survival (PFS) for women receiving palbociclib and letrozole was 20.2 months, versus 10.2 months for those on letrozole alone.
The CDK 4,6 inhibitor ribociclib (Kisqali) was approved for postmenopausal HR+/HER- advanced or metastatic breast cancer in combination with letrozole.
MONALEESA-2 trial in postmenopausal women who had received no prior systemic therapy for their advanced breast cancer.
Ribociclib plus letrozole yielded a PFS rate of 63% with a duration of 19.3 months, compared with a rate of 42.2% and a duration of 14.7 months with letrozole alone.
Subsequent analysis with an additional 11 months of follow-up showed that the median PFS was 25.3 months with the ribociclib combination versus 16 months with letrozole alone.
The likelihood of benefit from chemotherapy is related to the success achieved with the previous regimen.
Olaparib inhibits poly (ADP-ribose) polymerase (PARP) enzymes, is the first PARP inhibitor approved to treat breast cancer, and the first drug of any kind approved to treat certain patients with BRCA-mutated metastatic breast cancer.
OlympiAD clinical trial, which was the first phase III trial to demonstrate that PARP inhibitors are superior to chemotherapy for this class of patients.
Median progression-free survival (PFS) was significantly longer in those who received olaparib compared with standard therapy (7.0 months vs 4.2 months.
The objective response rate was 59.9% in the olaparib group and 28.8% in the standard-therapy group.
Overall survival and median time to death did not differ significantly between the 2 treatment arms after a median follow-up of 14 months.45.9% vs 47.4%; 19.3 months vs 19.6 months).
Talazoparib, another PARP inhibitor, approved for patients with deleterious or suspected deleterious germline BRCA-mutated HER2-negative locally advanced or metastatic breast cancer.
EMBRACA trial (n=431), which talazoparib reduced the risk of disease progression or death by 46% compared with chemotherapy in patients with germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer.
The ORR was 62.6% in the talazoparib group and 27.2% in the control chemo group.
The median OS was 22.3 months with the PARP inhibitor compared with 19.5 months with chemotherapy.
Unresectable metastatic triple-negative breast cancer is aggressive and carries a poor prognosis.
The combination therapy with the programmed cell death ligand–1 (PDL1) inhibitor atezolizumab plus nanoparticle albumin-bound (nab)–paclitaxel has been shown to prolong PFS in these patients.
Azolizumab in combination with nab-paclitaxel for TNBC approval was based on the phase III IMpassion130 trial in patients with untreated metastatic TNBC, in which intention-to-treat analysis showed median PFS of 7.2 months with atezolizumab plus nab-paclitaxel versus 5.5 months with placebo plus nab-paclitaxel.
In patients with PDL1-positive tumors, median PFS was 7.5 months and 5.0 months, respectively.
Subsequent study found that atezolizumb plus paclitaxel is ineffective in patients with previously untreated, inoperable, locally advanced or metastatic TNBC based on findings from the phase III IMpassion131 trial showing that atezolizumab plus paclitaxel did not significantly reduce the risk of cancer progression and death, when compared with paclitaxel plus placebo, in PD-L1–positive patients.
Interim overall survival results in IMpassion131 also favored paclitaxel plus placebo over paclitaxel plus atezolizumab in both the PD-L1–positive and the total study population.
Since metastatic TNBC is aggressive, it is important to have multiple treatment options.
The FDA granted approval to the first antibody-drug conjugate, sacituzumab govitecan-hziy (Trodelvy), for metastatic TNBC in patients who have received at least two prior therapies for metastatic disease.
IMMU-132-01 trial; regular approval was based on results of the phase III ASCENT trial (n=529), in which median PFS was 4.8 months in patients receiving sacituzumab govitecan, compared with 1.7 months (95% CI: 1.5, 2.5)in those receiving chemotherapy (HR 0.43; 95%
Surgical resection of the intact primary tumor may provide a survival advantage:
Critical evaluation of whether surgically achieved local control can lead to improved survival as a part of multimodal treatment.
Two selective estrogen receptor modulators (SERMs), tamoxifen and raloxifene, are approved for reduction of breast cancer risk in high-risk women.
Two NSABP trials showed that tamoxifen reduced the risk of DCIS and invasive breast cancer by 30-50%.
In the NSABP P2 prevention trial, raloxifene was as effective as tamoxifen in reducing the risk of invasive breast cancer but was 30% less effective than tamoxifen in reducing the risk of DCIS.
Tamoxifen use for 5 years reduces risk of breast cancer for at least 10 years in premenopausal women, particularly ER-positive invasive tumors.
Women 50 years or younger have few adverse effects with tamoxifen, and vascular/vasomotor adverse effects do not persist after treatment.
With BRCA1 and 881 BRCA2 mutation carriers, adjuvant tamoxifen reduced the risk for contralateral breast cancer recurrences in women who carry these mutations.
Tamoxifen and raloxifene are equally effective in reducing the risk of ER-positive breast cancer in postmenopausal women.
Raloxifene is associated with lower rates of thromboembolic disease, benign uterine conditions, and cataracts than tamoxifen is.
However, evidence does not allow determination of whether either agent decreases mortality from breast cancer.
The aromatase inhibitors exemestane and anastrozole are used off label for breast cancer risk reduction in postmenopausal women.
The Mammary Prevention.3 (MAP.3) trial, conducted in 4560 postmenopausal women with moderately increased breast cancer risk, exemestane decreased the incidence of invasive breast cancer by 65% and that of invasive plus in situ breast cancer by 53%, compared with placebo.
In the International Breast Cancer Intervention Study II (IBIS-II), conducted in 3864 postmenopausal women at increased risk of developing breast cancer, after a median follow-up of 131 months, anastrozole was associated with a 54% decrease in ER-positive invasive breast cancer, and a 59% decrease in DCIS.
In premenopausal women who are at least 35 years old and have completed childbearing, tamoxifen (20 mg/day for 5 years) remains the standard of care for risk reduction.
Low-dose tamoxifen (5 mg/day) may be an alternative in women with intraepithelial neoplasia.
Anastrozole, exemestane, or raloxifene should not be prescribed for breast cancer risk reduction in premenopausal women.
In postmenopausal women, the choice of endocrine therapy includes anastrozole (1 mg/day) in addition to exemestane (25 mg/day), raloxifene (60 mg/day), or tamoxifen (20 mg/day).
SERMs carry warnings about risk of thromboembolic events, and aromatase inhibitors carry warnings about bone mineral density (BMD) reduction.
Hence, tamoxifen and raloxifene are not recommended for use in women with a history of deep vein thrombosis, pulmonary embolus, stroke, transient ischemic attack, or during prolonged immobilization.
Anastrozole is relatively contraindicated in women with a history of osteoporosis and/or severe bone loss, and should be used only with caution in postmenopausal women with moderate BMD loss.
If anastrozole is used, the addition of bone-protective agents such as bisphosphonates and RANKL inhibitors should be considered.
Regular exercise and adequate calcium and vitamin D supplementation should be encouraged in all patients receiving aromatase inhibitor.
Prophylactic mastectomy is an option for women found to be at extremely elevated risk for breast cancer.
Either total mastectomy or subcutaneous (nipple-sparing) mastectomy may be performed.
Genetic factors that place a woman at very high risk of developing breast cancer include the following:
Strong family history of breast and/or ovarian cancer
Pathogenic mutation in BRCA1 or BRCA2
High-penetrance mutation in another gene associated with breast cancer risk (eg, TP53, PTEN)
The only women who should consider risk-reduction mastectomy are those with a genetic mutation that confers a high risk for breast cancer, a compelling family history, or possibly a personal history of receiving thoracic radiation therapy before 30 years of age.
Risk-reduction mastectomy had previously been considered for lobular carcinoma in situ (LCIS), risk-reduction therapy (ie, healthy lifestyle, endocrine therapy) is currently the preferred approach for LCIS.
With median follow-up periods of 13-14 years, bilateral risk-reduction mastectomy decreased the risk of developing breast cancer by at least 90% in women at moderate to high risk and in those with known BRCA1/2 mutations.
In women with deleterious mutations in other genes that are associated with a 2-fold or greater risk for breast cancer but without a compelling family history of breast cancer, the value of risk-reducing mastectomy is unknown.
Contralateral prophylactic mastectomy
Women with unilateral breast cancer who are at average risk should be discouraged from undergoing a contralateral prophylactic mastectomy (CPM), because most of those women, with the possible exception of BRCA carriers, will not obtain a survival benefit, and CPM doubles the risk of surgical complications.
CPM should be considered for patients with any of the following significant risk factors for contralateral breast cancer:
BRCA1/2 mutations
Strong family history
Mantle chest radiation before age 30 years
CPM can be considered for women with factors that place them at lower risk:carriers of a non-BRCA gene (eg, CHEK-2, PALB2, p53, CDH1) and those with a strong family history of breast cancer but who are themselves BRCA negative and have no family member with known BRCA.
Other reasons for considering CPM:
according to the ASMBrS, include the following:
To limit contralateral breast surveillance (dense breasts, failed surveillance, recall fatigue)
To improve reconstructed breast symmetry
To manage risk aversion
To manage extreme anxiety
CPM is discouraged noin average-risk women with unilateral breast cancer.
The majority of relapses, both local and distant, occur within the first 3 years, especially in higher-risk and ER-negative patients.
ASCO guidelines do not support the use of tumor biomarkers, including CEA, CA15.3, and CA27.29, for monitoring patients for recurrence after primary breast cancer therapy.
ASCO and NCCN have both provided recommendations for surveillance in the adjuvant setting:
History and physical examination
Year 1, every 3-4 mo
Year 2, every 4 mo
Year 3-5, every 6 mo
Year 6+, annually
Year 1-3, every 3-6 mo
Year 4-5, every 6-12 mo
Year 6+, annually
Breast self-examination
Counseled to perform monthly breast self-examination
Mammography-6 mo after post-BCS radiation therapy
Annually thereafter
6 mo after definitive radiation therapy
Every 6-12 mo for surveillance of abnormalities
Annually if stability of abnormalities is achieved
Pelvic examination
Annually, for women on tamoxifen
Annual exam if uterus present
Regular gynecologic follow-up
Patients on tamoxifen should be advised to report any vaginal bleeding
Women who have had surgery for breast cancer may still require breast cancer screening with mammography.
If a woman had a total mastectomy, then the other breast requires yearly follow-up, because there is still a higher risk that cancer will develop in the remaining breast.
If the woman had a subcutaneous mastectomy, partial mastectomy, or lumpectomy, then that breast itself requires follow-up mammography.
The first mammogram is best performed 6 months postoperatively to provide a baseline for the new postoperative and postirradiation changes.
Thereafter, mammography may be performed every 6-12 months for screening and follow-up.
Measurement of tumor markers, such as CEA, CA15.3, and CA27.29, can be used in conjunction with diagnostic imaging, history, and physical examination for monitoring patients on active therapy.
CA15.3 and CA27.29 levels correlate with the course of disease in 60-70% of patients, whereas CEA levels correlate in 40% of patients.
Cautions should be used in the interpretation of rising CEA, CA15.3, or CA27.29 levels during the first 4-6 weeks of a new therapy, as spurious early rises may occur.
Computed tomography (CT) of the chest, abdomen, and pelvis; MRI; bone scanning; or PET-CT is performed when symptoms change or tumor markers rise.
Patients treated with radiotherapy to the chest for Hodgkin’s disease, or breast, lung, or esophageal cancer, should have an echocardiogram every 5 to 10 years to detect radiation-induced heart disease (RIHD).
The relative risk of RIHD is 2- to 5.9 times higher in patients treated with radiation for breast cancer.
Before initiating radiotherapy to the chest, patients should have a baseline echocardiogram to evaluate cardiac morphology and function, and identify any abnormalities.
Exercise and physical activity programs improve outcomes such as shoulder mobility, lymphedema, pain, fatigue, and quality of life.
Yoga significantly improved QoL and reduced anxiety, depression, sleep disturbance, fatigue, and gastrointestinal symptoms.
Adjuvant treatment for breast cancer involves radiation therapy and a variety of chemotherapeutic and biologic agents.
It is designed to treat micrometastatic disease
Adjuvant treatment is aimed at reducing the risk of future recurrence, thereby reducing breast cancer−related morbidity and mortality.
In patients with metastatic breast cancer, interventions include hormone therapy; chemotherapy; and biologic therapy targeted to the histologic and mutational characteristics of the tumor.
In patients receiving adjuvant aromatase inhibitor therapy for breast cancer who are at high risk for fracture, the monoclonal antibody denosumab or either of the bisphosphonates zoledronic acid and pamidronate may be added to the treatment regimen to increase bone mass.
These agents are given along with calcium and vitamin D supplementation.
Carboplatin is an analogue of cisplatin.
It exerts its cytotoxic effect by platination of DNA, a mechanism analogous to alkylation, leading to interstrand and intrastrand DNA cross-links and inhibition of DNA replication.
It binds to protein and other compounds containing the SH group.
Cytotoxicity can occur at any stage of the cell cycle, but the cell is most vulnerable to the action of these drugs in the G1 and S phases.
Carboplatin has the same efficacy as cisplatin but a better toxicity profile.
Its main advantages over cisplatin include less nephrotoxicity and ototoxicity, absence of a need for extensive prehydration, and reduced likelihood of inducing nausea and vomiting; however, it is more likely to induce myelotoxicity.
Cyclophosphamide is chemically related to nitrogen mustards.
It can be used as a single agent or in various combination chemotherapy regimens for recurrent or metastatic breast cancer.
Cyclophosphamide is activated in the liver to its active metabolite, 4-hydroxycyclophosphamide, which alkylates the target sites in susceptible cells in an all-or-none type of reaction.
The mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with the growth of normal and neoplastic cells.
Anthracyclines work in multiple ways, including intercalation between DNA base pairs and inhibition of type II topoisomerase function, resulting in inhibition of cell replication and transcription.
They also work by inhibition of DNA helicase, resulting in DNA cleavage.
Doxorubicin is a cytotoxic anthracycline that inhibits topoisomerase II and produces free radicals, which may cause destruction of DNA.
It blocks DNA and RNA synthesis by inserting between adjacent base pairs and binding to the sugar-phosphate backbone of DNA, which causes DNA polymerase inhibition.
It binds to nucleic acids, presumably by specific intercalation of the anthracycline nucleus with the DNA double helix.
Tis also a powerful iron chelator.
The iron-doxorubicin complex induces production of free radicals that can destroy DNA and cancer cells.
Maximum toxicity occurs during the S phase of the cell cycle.
Epirubicin is indicated as a part of adjuvant therapy in patients with evidence of axillary-node tumor involvement after resection of primary breast cancer.
It can be used as a single agent, but such use is much less common in the setting of recurrent or metastatic disease.
Epirubicin is a cell cycle phase inhibitor–nonspecific anthracycline derivative of doxorubicin with maximum cytotoxic effects on the S and G2 phases of the cell cycle.
Bisphosphonates are complementary to chemotherapy and hormone therapy because they may lessen the damage to bone from metastatic disease, by
inhibiting osteoclast function and reduce the resorption of bone.
An intravenous bisphosphonate should be used in combination with oral calcium citrate and vitamin D supplementation in bone metastasis.
Pamidronate disodium is a bone resorption inhibitor that absorbs calcium phosphate crystals and prevents the dissolution of this mineral.
It also inhibits osteoclast activity in the bone.
Zoledronic acid inhibits bone resorption by acting on osteoclasts or osteoclast precursors. It may be superior to pamidronate in patients with lytic bone metastases.
Antimetabolite therapy can stop cancer cell growth and cell division by interfering with DNA replication of these cells.
Capecitabine is a pyrimidine analogue that, in combination with docetaxel, is indicated for metastatic breast cancer after the failure of prior anthracycline-containing chemotherapy.
Monotherapy with capecitabine is indicated for the treatment of patients with metastatic breast cancer that are resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or is resistant to paclitaxel in a situation where further anthracycline therapy is not indicated.
It is the preferred first-line agent for human epidermal growth receptor 2 (HER2)-positive disease, along with trastuzumab.
Gemcitabine is a pyrimidine analogue that is metabolized intracellularly to an active nucleotide.
It inhibits ribonucleotide reductase and competes with deoxycytidine triphosphate for incorporation into DNA.
It is cell-cycle specific for the S phase.
Gemcitabine, in combination with paclitaxel, is indicated as a first-line treatment for metastatic breast cancer after the failure of prior anthracycline-containing adjuvant chemotherapy.
Methotrexate is an antimetabolite that inhibits dihydrofolate reductase, thereby hindering DNA synthesis and cell reproduction in malignant cells.
Methotrexate is indicated alone or in combination with other anticancer agents for the treatment of breast cancer.
Data demonstrate the beneficial effects outcomes, such as physical functioning, physical fitness, body composition, bone health, sleep and quality of life in addition to reductions in fatigue, depression/anxiety, pain, and physiological biomarkers of inflammation and insulin metabolism in early stage breast cancer.
In early stage breast cancer, the rate of breast cancer specific mortality is 35% higher in women with obesity at the time of diagnosis in women of normal weight.