Metastatic breast cancer

It is estimated at 20-30% of women would earlier stages of breast cancer will develop metastatic disease.

About 6 to 10% of patients with newly diagnosed breast cancer have metastatic disease.

The five-year relative survival rate for metastatic breast cancer only 23%.

The median overall survival of patients with metastatic breast cancer is about three years.

Metastatic breast cancer after early breast cancer tends to have more aggressive tumor biology and worse outcome, compared with de novo metastatic breast cancer.

Survival is related to breast cancer subtype, with major advances seen in HER2  positive breast cancers.

In recent decades there has been an increase and liver and CNS metastasis and the decline in bone metastases suggesting treatment of early breast cancer has altered tumor biology and metastasis presentation in subsequent metastatic breast cancer, presumably from a molecular selection process.

The clinical progression pattern of metastatic breast cancer (MBC) is heterogeneous.

Presently, palliation is the primary goal in the management of metastatic breast cancer.

Treatment is to prolong survival and improve quality-of-life by relieving cancer related symptoms.

It is necessary to understand a patient’s disease status and recognize appropriate needs and timing of care according to daily oncologic practice.

Complications of MBC account for the majority of breast cancer related mortality.

The most common complications of MBC are skeletal complications, liver failure, pneumonia and respiratory failure, and side effects associated with chemotherapy and radiation.

Patients with MBC may be asymptomatic, but the use of chemotherapy has the potential to prevent cancer related complications, possibly for years, in contrast patients without chemotherapy may develop cancer related complications within months to years.

In a study of 225 consecutive patients whose primary tumor samples were compared to metastatic liver biopsies, estrogen receptor status changed in 14.5% of patients and changes in progesterone receptor status was seen in 48.6%, and changes in her two status was seen in 13.9% (Cerugliano C et al).

Management decisions are made by balancing efficacy of treatment regimens versus toxicity.

There are four clinical progression patterns of MBC: smoldering, gradual, rapid, and de novo poor condition.
The smoldering pattern of MBC involves a very slow progression of disease with long-term asymptomatic features characterized by survival duration of years, sometimes over 10 years.
The gradual pattern involves a gradual progression of disease over time with patients being usually stable and asymptomatic at the beginning, with progression of disease, symptoms and rate of progression tend to increase.
Rapid pattern involves the rapid progression of disease from the beginning of the metastatic stage with a few months prognosis and severe symptoms.
The de novo condition pattern involves patients who are already in poor health at the beginning of the metastatic stage.
Each pattern of metastatic disease has an acute phase, and a stable phase a different time points.
Acute phase metastatic breast cancer consists of rapid progressive symptomatic changes.
The stable phase occurs when symptoms do not change much.
In the acute phase the patient focus is predominately on symptom control, while in the stable phase patient’s focus more on improving their health condition by maintaining physical and emotional well-being.
Worse physical function and survival are consistently associated with higher mortality rates.
More than 90% of patients with metastatic breast cancer have more than one physical impairment: lymphedema, focal weakness, peripheral neuropathy, exertional, intolerance, and myofascial dysfunction.
More than 1/3 of patients with metastatic breast cancer, reported these for problems with activities of daily living, which is considered moderate physical disability: particularly true in minorities and low socioeconomic groups.
In addition to poor physical function, the majority of women with metastatic breast cancer have cardiorespiratory fitness that is below range and is a predictor of poor function, and increased mortality rate in the general population

Primary treatment options for MBC is chemotherapy and endocrine therapy.

Other therapies include radiation and surgery.

Tailored treatment decisions depending upon pathology, histology, and clinical characteristics of the tumor, ER receptor status, progesterone receptor status, HER-2 status, location of the primary-visceral versus osseous metastases, tumor burden, patient comorbidities and menopausal status.

Generally, single agent chemotherapy is given to patients with low burden and combination chemotherapy is given in patients with high disease burdens.

Endpoint of treatment plans is overall survival, although progression free survival is another acceptable target.

Meta-analyses of trials revealed chemotherapy versus endocrine therapy have little or no differences in overall survival (Wilcken N et al).

Chemotherapy regimens generally have a higher response rate versus endocrine therapy.

Objective clinical response correlates with symptom relief.

A meta-analysis of 37 randomized trials with 5707 patients revealed that the overall response rate and time to progression with multiple agent chemotherapy was significantly better than single agent chemotherapy (Carrick S et al).

Combination chemotherapy is associated with more toxicity than single agent treatment.

Sequential single agent therapy is associated with lower toxicity, preservation of treatment options as the disease progresses and no negative effect on survival in most cases.

Single agent chemotherapy response rates are 25-45%, and time to progression 5-8 months with first-line treatment, 15-30% and 2-5 months, respectively with second line treatment and 0-20% and 1-4 months, respectively with third line treatments.

Combination chemotherapy is usually pref2242ed in patients with visceral disease or in symptomatic patients, compared to single agent therapy.

Combination therapy generally has higher response rate and longer time to progression than single agent therapy.

The addition of a second chemotherapy agent to a single agent provides survival advantage.

It is probable that sequential single agent therapy is as effective as combination regimens.

A meta-analysis of 21 trials with 3643 patients taxane containing regimens showed no significant or slightly improved overall survival (Ghersi D et al).

Eribulin mesylate (Halaven) is indicated for MBC for patients who have received at least to chemotherapy regimens.

Significant improvements in overall survival with the use of trastuzumab in combination with chemotherapy for HER-2 positive metastatic breast cancer as, and similar improvements in rates of tumor control for adding bevacizumab to first-line chemotherapy in HER-2 negative breast cancers.

Endocrine therapy is pref2242ed over chemotherapy, in general, in patients with estrogen receptor positive metastatic disease.

Metastatic tumors are not usually rebiopsied, however a study of 255 consecutive patients whose primary tumors were compared with subsequent liver biopsy from metastatic disease Revealed a change in ER status was present in 14.5% of patients, a change in PR status was seen in 48.6% of patients and a change in HER2 status was seen in 13.9% (Cerugliano C et al).

In patients with estrogen receptor positive disease chemotherapy is reserved for endocrine resistance, visceral tumor involvement and symptomatic disease.

The best five-year relative survival rate is only 20%, and median survival time is 2 to 3 years.

In metastatic breast cancer weekly dosing has a higher response rate then once every week treatment schedule, but there was no difference in time to progression or overall survival (V2242ill MW et al).

In a phase 3 trial of metastatic breast cancer weekly treatment was associated with a higher response rate and increased time to progression and oral survival then every three week administration of the same drug (Seidman AD et al).

nab-Paclitaxel consistently demonstrates superior efficacy compared to paclitaxel in clinical trials for metastatic breast cancer.

Capecitabine as monotherapy for taxane and anthracycline resistant cancers have a response rate of about 20%.

Capecitabine in combination with ixabepilone has a response rate of 35% for taxane and anthracycline resistant cancers.

In a trial of monotherapy with first line treatment of patients with HER-2 negative metastatic breast cancer progression free survival and time to progression were in the range of 6-7.9 months and median overall survival within the range of 18.6-29.4 months (O’Shaughnessy JA et al).

Ixabepilone as a single agent has a response rate of 11.5% in Taxane and anthracycline resistant metastatic breast cancers.

Ixabepilone in a National Cancer Institute phase 1/2 trial in 23 patients who have not received a taxine previously at a dose of 6 mg meter square days 1-5 of a 3 week cycle 57% of patients with metastatic breast cancer had a partial response to 26% and stable disease current dosage is 40 mg per meter squared every 3 weeks.

Pemetrexed as a single agent has a response rate of 8% in Taxane and anthracycline resistant metastatic breast cancers.

nab-paclitaxel in metastatic breast cancer has a significantly higher overall response rate, significant longer time to progression, significant greater overall survival in patients treated with a second line or greater therapy compared with patients who receive paclitaxel (Gradishar WJ et al).

In a randomized study in first-line treatment for metastatic breast cancer nab-paclitaxel 150 mg meter squared weekly versus docetaxel 100 mg per meter squared Q3 weeks resulted in a statistically and clinically significant prolongation of progression free survival of greater than five months (Gradishar WJ et al).

In general, treatment decisions are made for patients with hormone receptor positive metastatic breast cancer based on the HER 2 status: patients with HER 2positive disease often receive chemotherapy plus HER2 targeted therapy, while some patients will receive an aromatase inhibitor alone or in combination with anti-HER2 therapy.

Patients with hormone receptor positive, and HER2 negative disease, the most commonly utilized treatment is hormonal therapy.

In most instances with hormone receptor positive disease and HER 2 negative disease chemotherapy is withheld until it becomes clinically necessary.

Postmenopausal women can receive aromatase inhibitors or tamoxifen, and in a second line setting fulvestrant.

In patients with estrogen receptor positive breast cancer the addition of a CDK4/6 inhibitor such as palbociclib or ribociclib added to hormonal treatment dramatically increases progression free survival.

In patients with progression after endocrine therapy plus a CDK 4/6 inhibitor, determination of PIK3CA and estrogen receptor 1 mutations as well as BRCA1/2 mutations is recommended for specific new agents:possible agents include fulvestrant, alpelisib, everolimus, tamoxifen, PARP inhibitors.

For the treatment of HER2 positive metastatic breast cancer pertuzumab, docetaxel, and trastusumab agents are the treatment of choice.

For HER2 positive breast cancer adO– trastuzumab emtansine (T-DM1) was the second line therapy based on progressive free survival and overall survival data.

fam-Trastusumab deruxtecan is associated with improved progressive free survival compared with T-DM1 in patients previously treated with a taxane and trastuzumab in advanced disease setting.

Trastusumab deruxtecan Is now the new standard second line therapy.

Tucatinib a HER2 selective tyrosine kinase inhibitor in combination with Capecitabine/ trastuzumab is also consideration for select the patient with brain metastasis.



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