Metastatic Breast Cancer

Metastatic breast cancer

What every physician needs to know:

Breast cancer is a significant cause of morbidity and mortality among women. In the United States it is the most common malignancy in women, accounting for more than 30% of all female cancers. Breast cancer is also responsible for 15% of cancer deaths in women, making it the number two cause of cancer death. It is estimated that in the United States, 232,340 new cases of invasive breast cancer were diagnosed and nearly 39,620 resulted in death in 2013. It has been estimated that there are approximately 2 million breast cancer survivors in the United States.

In recent decades, advances in the treatment of breast cancer have significantly improved clinical outcomes. However, despite these advances, approximately 10-60% of patients will experience a relapse. Furthermore, metastatic disease is diagnosed at the time of presentation in 3-6% of the patients, but this estimate can be as high as 12%.

The treatment for patients with stage IV disease prolongs survival and enhances quality of life, but in principle the treatment is not considered curative. As is true with cancer in general, the clinical course for patients with cancer varies individually, but as a group the median survival of patients with metastatic breast cancer is 2-3 years, and the 5-year survival rate is only 17-28%.

Breast cancer is a heterogeneous disease; therefore the prognosis and the treatment of patients with metastatic breast cancer depends on a number of factors including extent and site of disease; comorbidities and performance status; and very importantly, tumor subtype.

The most common sites of distant tumor involvement are bones, liver and lungs. However it is not uncommon for breast cancer to metastasize to the brain; unusual sites like ovaries, peritoneum, and gastrointestinal tract have been reported and are usually associated with lobular histologies. Patients with bone-only disease tend to have better prognoses than patients with visceral involvement.

Are you sure your patient has metastatic breast cancer? What should you expect to find?

Metastatic breast cancer can be manifested by a number of symptoms, depending on the location and extension of the metastases. On careful physical exam, oftentimes a breast mass will be identified.

Features of metastatic disease

Bone metastases commonly present as pain but can also present as fracture, spinal cord, or nerve root compression.
Lung involvement can present as shortness of breath, or cough due to a pleural effusion, or pulmonary nodules.
Brain metastases can present with headaches, nausea/vomiting, seizures, and focal neurologic deficits.
Liver metastases can cause a variety of symptoms ranging from anorexia and weight loss to jaundice and abdominal pain.
Rarely, patients can have symptoms arising from paraneoplastic syndromes (including cerebellar degeneration, opsoclonus-myoclonus with or without ataxia, and retinal degeneration; endocrine paraneoplastic syndromes occur less commonly than neurologic syndromes).

In many instances, patients with systemic disease are asymptomatic at the time of diagnosis. It is not uncommon that the metastases are identified after abnormalities are found on laboratory or radiologic evaluations.

Many patients present initially with a breast mass as part of the initial work-up when distant disease is identified.

Confirmation of diagnosis

A complete assessment of the extent of disease should be performed once metastatic breast cancer is diagnosed. A confirmatory biopsy of the suspected lesions is recommended to confirm histology and reassessment of molecular markers, particularly hormone receptors (HR) and HER2. Recent evidence suggests a significant discordance in hormone receptor status and HER2/neu status between the primary tumor and metastases. These discrepancies can affect treatment selection in up to 20% of the patients.

When a patient is diagnosed with metastatic disease after a long disease-free interval, it is important to verify tumor markers and individualize the treatment accordingly. For example, if a patient has a prior history of a hormone receptor-positive breast cancer and develops a biopsy-proven hormone-receptor negative metastases (which can occur in up to 20% of cases), the clinician may consider avoiding hormone therapy and treat with chemotherapy.

Pathological confirmation is also essential in patients with suspected clinical metastases if the clinical course is not apparent, especially in those patients with a long disease-free interval (several years) and those with unusual metastatic sites. Retrospective studies have demonstrated that up to 15% of apparent metastases can be either a benign process or a second primary tumor.

Which individuals are most at risk for developing metastatic breast cancer:

Despite advances in adjuvant therapy for breast cancer, a significant number of patients relapse and develop metastatic disease. The risk of recurrence and the prognosis of patients with stage I, II, and III depends on a number of factors including clinical and pathological information. Patients with poor prognosis features are at higher risk of developing metastatic disease.

Pathology

Patients presenting with tumors with high histopathological grade, characterized by high proliferative activity (represented as an elevated Ki-67), have a worse prognosis than patients with well-differentiated tumors.
Grade 3 tumors (poorly differentiated) have higher proliferation rates and are associated with worse prognosis. While different cut-off levels of Ki-67 have been associated with poor prognosis, there is general agreement that levels higher than 20-30 predict poor clinical outcomes.
Tumors with lymphovascular invasion (LVI) tend to have worse prognosis.
Probably one of the most important makers of poor prognosis is lymph node involvement; the number of involved lymph nodes correlates not only with risk of recurrence but also with survival.
Patients with uncommon histologies such as metaplastic or sarcomatoid breast cancer have a poor prognosis due to lack of effective therapies.

Molecular markers

Hormone receptors (HR): The presence of estrogen receptor (ER) and progesterone receptor (PR) is usually associated with a better prognosis. These tumors, known as HR positive, are more likely to be low grade and less likely to be associated with poor risk molecular features, including mutations, deletions, or amplifications of specific oncogenes. The presence of HRs is also predictive of response to endocrine therapy.
Human epidermal growth factor receptor 2 (HER2): HER2 is assessed by immunohistochemistry (IHC) or by in situ hybridization (ISH). It is estimated that 20-25% of invasive breast cancers have overexpression or gene amplification of HER2. These tumors are more likely to be poorly differentiated and to have lymph node involvement and in general, this tumor subtype is associated with a poor prognosis. However, HER2-targeted treatment, including monoclonal antibodies and small molecule kinase, has decreased the magnitude of the risk, improving the outcomes of these patients.
Triple negative breast cancer: Tumors that are HR negative and HER2 negative are known as triple negative (TN). These tumors are associated with a poor prognosis, tend to be diagnosed in younger patients, are poorly differentiated, are usually associated with LVI and very frequently are associated with lymph node involvement. No targeted therapies are available for these tumors.
Other molecular markers: There are a number of markers associated with invasion and metastases; however, most of them are not performed routinely and have failed to demonstrate clinical utility. Examples include S-phase; catepsin D; p53 mutations; E-cadherin and cyclin E expression; urokinase-type plasminogen activator and plasminogen activator inhibitor type-1 expression; PIK3CA mutations; CCND1 amplification; and PTEN and INPP4B loss, amongst others.
The use of multi-gene assays to evaluate genomic aberrations including mutations, copy number variants, and loss of heterozygosity are now available. However, there is no evidence of their predictive role to targeted therapies, nor have they yet demonstrated clinical utility. These type of assays should be used to direct patients to specific clinical trials in the metastatic setting.

Prior therapy

Response to chemotherapy is a prognostic indicator. Patients with locally advanced breast cancer who achieve a pathological complete response (pCR) after preoperative (neoadjuvant) chemotherapy have better prognosis than patients with residual disease. There is a strong correlation between pCR and long-term outcome regardless of the initial clinical stage. Those patients with refractory disease despite adequate treatment have a very high risk of developing metastatic disease especially if they have poor-risk pathologic features such as high grade, triple negative receptor status, or HER2 positivity.

Unique clinical scenarios

A special group of patients at high risk for recurrence are those patients with inflammatory breast cancer (IBC). IBC is a rare and aggressive form of breast cancer. These tumors are usually poorly differentiated and tend to have a high-proliferative rate. Additionally, they have features of increased angiogenesis and have increased invasive and metastatic capability compared to non-IBCs. Currently they are treated as any metastatic breast cancer according to their histology, but they tend to be more resistant to standard therapies.

What laboratory and imaging studies should you order to characterize this patient's tumor (i.e., stage, grade, Ct/MRI vs PET/CT, cellular and molecular markers, immunophenotyping, etc.) How should you interpret the results and use them to establish prognosis and plan initial therapy?

Once metastatic disease is suspected and confirmed, a careful evaluation should take place. This should include:

Comprehensive history and physical exam, noting important comorbidities and performance status.
Detailed oncologic history with information about stage at presentation, other malignancies, and information on prior treatment including duration, tolerance, response, and toxicities (this will help in making future treatment decisions). Information on prior oncologic surgeries or prior radiation therapy is also important.
Pathology reports should be reviewed and should include histology; grade; and ER, PR, and HER2 status. As mentioned previously, one should strongly consider performing a biopsy of the metastatic site to confirm recurrence and to determine the tumor subtype in the new specimen.

Laboratory evaluation

Laboratory evaluation should include:

Basic blood work (complete cell count, complete blood chemistries including calcium and liver and renal function tests).
Serum tumor markers such as CA 15.3 or CA 27.29, and CEA. These markers can be potentially helpful in monitoring response to therapy. Currently data is insufficient to recommend the use of tumor markers as a single strategy to assess response or to change therapy. If used, they should be interpreted in conjunction with history, physical examination, and diagnostic imaging.
Circulating tumor cells (CTCs) have been correlated with survival and response to treatment; nevertheless, current recommendations do not support the measurement of CTCs to establish diagnosis, or to influence treatment decisions.
In general, isolated changes in tumor markers or CTCs in the absence of radiographic progression should not prompt a change in management.

Radiology evaluation

Radiological evaluation at the time of diagnosis should include evaluation of the lung parenchyma, liver, and bones. Usually the evaluation includes:

Chest-X ray (CXR) ± computed tomography (CT) of the chest.
Abdominal ultrasound or an abdominal CT.
Nuclear bone scan. If the bone scan shows areas of abnormal uptake, plain radiographs of the affected sites may be necessary to exclude benign etiology. In addition, impending fractures in weight-bearing bones must be ruled out.
Radiological evaluation (preferably MRI) of the brain and/or spinal cord are recommended if the patient is symptomatic or has neurological findings.
The use of PET or PET/CT in recent recommendations is only indicated in those situations where other staging studies are equivocal or suspicious. Use of these modalities should probably be limited to highly proliferative disease.

Radiographic assessment of response is performed frequently in patients with metastatic disease to evaluate response in patients receiving treatment. Studies are usually performed every 2-3 cycles of treatment (approximately every 6-12 weeks). Evaluation is also indicated when there is worsening of symptoms.

In the majority of cases, it is recommended that the same radiological technique is used over time, to allow for better comparison. Special caution is recommended when evaluating bone disease, as the response to treatment can result in a flare (i.e. radiographic worsening) of the lesions.

Staging

Table I. TNM staging of breast cancer.

Table I.n

TNM Staging of Breast Cancer

Table II.

Drug	Class	Dose/Schedule	Associated toxicities
Tamoxifen	ER modulator	20mg PO daily	Hot flashes, rare (1%) risk of thrombosis and endometrial cancer
Goserelin (Zoladex)	LHRH agonist	3.6mg SC q 28 days or 10.8 mg q 3 months	Climacteric symptoms
Anastrozole (Arimidex)	AI (non-steroidal)	1 mg PO daily	Myalgias, artralgias, decrease in bone mineral density
Letrozole (Femara)	AI (non-steroidal)	2.5mg PO daily	Myalgias, artralgias, decrease in bone mineral density
Exemestane (Aromasin)	AI (steroidal)	25mg PO daily	Myalgias, artralgias, decrease in bone mineral density
Fulvestrant (Faslodex)	ER antagonist	500mg administered as 2 (5mL) IM injections on days 1, 15, 29 and monthly thereafter.	Injection site pain, hot flashes, bone pain.

What therapies should you initiate immediately i.e., emergently?

Most cases of metastatic breast cancer do not require urgent initiation of treatment; however, in rapidly growing tumors, therapy should be initiated promptly. Furthermore, a number of disease-related complications may need to be identified and addressed emergently.

Spinal cord compression

Treatment with corticosteroids should be started. A clear dose schedule has not been determined; one option is to administer dexamethasone 10 mg IV or 16 mg PO followed by 4 mg IV or PO every 6 hours. Radiation oncology and spine surgery (usually neurosurgery and/or orthopaedic surgery) consultations should be requested immediately.

Brain metastases

Initiate steroids as recommended for spinal dose compression. Consultation with neurosurgery and radiation oncology is mandatory to select the best treatment modality (whole brain radiation, stereotactic radiation, surgical resection, or a combination.)

Superior vena cava syndrome

Consider steroids and treat with radiation therapy. In specific cases a stent can be considered. Chemotherapy has been used in highly proliferative disease, especially if there is a history of radiotherapy resistance.

Pericardial effusion

Occurs secondary to tumor involvement and can lead to cardiac tamponade. Pericardiocentesis or a pericardial window is indicated. In patients with poor performance status, radiation therapy may provide benefit.

Hypercalcemia

Treatment with intravenous fluids should be started. Bisphosphonates are frequently used if renal function is preserved. Persistent hypercalcemia can be managed with denusumab, calcitonin, IV steroids, or gallium nitrate if refractory. Vitamin D levels should be adequate when using these agents.

Pain crisis

Usually associated with bone metastases. Aggressive pain management is recommended. Palliative radiation therapy may be indicated. In areas of impending fracture, orthopaedic surgery consultation can be helpful. The use of kyphoplasty in vertebrae collapse has been demonstrated to control pain rapidly.

Visceral crisis

In patients with important visceral involvement who can tolerate treatment, systemic chemotherapy in combination with targeted therapy if indicated should be started promptly.

What should the initial definitive therapy for the cancer be?

Treatment decisions are guided by the hormone receptor and HER2 status of the tumor, as well as the presence of symptomatic or life-threatening disease. The patient’s previous therapies, performance status, comorbid conditions, and organ function should also be taken into consideration.

As a general rule, metastatic breast cancer is not curable. Treatment has been proven to improve survival, but treatments with tolerable side effects are preferred in order to maintain quality of life. Goals of therapy should be palliation of symptoms associated with the disease and prolongation of life.

Principles of treatment

HR positive and HER2 negative tumors

These patients can be treated initially with endocrine therapy. However, responses are not immediate; therefore the clinician must know if the wait time is acceptable or not.

Wait time for a response of 3 months is not acceptable (patients with symptomatic disease or important or rapidly progressing visceral organ involvement [“visceral crisis”]): chemotherapy-based treatment should be applied.
Wait time for a response of 3 months is acceptable (patients with asymptomatic bone-only disease, soft tissue metastases, or oligomatastases): endocrine therapy-based treatment should be applied. Specific treatment selection is based on menopausal status, as well as endocrine therapies previously received in the adjuvant setting. If the tumor does not respond to endocrine therapy or becomes resistant, patients should receive treatment with chemotherapy.
Addition of the mTOR inhibitor everolimus to hormonal therapy should be considered for patients that have relapsed or progressed on a non-steroidal aromatase inhibitor.
Clinical trials looking at targeted therapies to overcome hormonal therapy resistance including CDK 4/6 inhibitors, and other PI3K pathway inhibitors can be considered in this population.

HR negative, HER2 negative (triple negative) or patients with HR positive symptomatic disease

Chemotherapy-based therapy should be applied. In certain cases in which a rapid response is needed, combination chemotherapy can be used. In the majority of the cases, sequential single agents are used until progression or unacceptable toxicity.

HER2 positive disease

The selection of a HER2-targeted treatment regimen is determined by whether the patient was treated with trastuzumab in the adjuvant setting, and whether the patient developed progression during treatment.

As a general rule, patients receive treatment with chemotherapy combined with trastuzumab. Even if patients develop progression during trastuzumab therapy, trastuzumab often continues and chemotherapy is changed, as it has been shown that continued trastuzumab-based therapy provides ongoing benefit.

The preferred first-line therapy should include dual anti-HER2 therapy with trastuzumab, pertuzumab, and a taxane. After 6-8 cycles of taxane therapy, if there are toxicity issues, and patients continues to benefit, dual antibody therapy without chemotherapy can be continued.

The preferred second- or third-line therapy should include trastuzumab-emtansine (T-DM1). Careful monitoring of platelet count and LFTs is recommended.

For more advanced lines of treatment, patients may receive lapatinib and capecitabine in combination, double HER2 blockade with lapatinib and trastuzumab, or trastuzumab in combination with vinorelbine and everolimus. Clinical trial participation in this group of patients is strongly encouraged as other HER2-targeted drugs continue to be developed.

When patients have received more than 3-4 lines of therapy in the metastatic setting, usually a serious discussion about goals of therapy is indicated. In some cases, additional lines of therapy can be given; however, the best supportive care should be considered. In addition, clinical trial options should be offered throughout therapy.

Endocrine therapy

Principles of therapy

Patients with tumors that are both ER positive and PR positive have a 50-60% probability of receiving clinical benefit from endocrine therapy.
For patients who are ER positive only or PR positive only, the probability is about 30%.
Patients who have received endocrine therapy previously have a 30-50% probability of deriving clinical benefit using a second-line agent; however this percentage decreases in the third- and fourth-lines of therapy. Usually the median duration of the first response is 9 months and decreases with subsequent lines of therapy.
For patients with tumors extremely sensitive to hormonal manipulation, repeated treatment with a previously used agent may again produce clinical benefit.
Addition of everolimus to hormonal therapy improves survival in patients that have relapsed or progressed on non-steroidal aromatase inhibitors.
The selection of treatment is based on menopausal status.

Pre-menopausal patients

Selective estrogen receptor modulators such as tamoxifen or toremifene are effective in both pre- and post-menopausal patients. As a general rule, tamoxifen is the first-line agent used in pre-menopausal women diagnosed with metastatic breast cancer. LH-RH agonists are effective in pre-menopausal women only. The combination of tamoxifen and ovarian ablation is superior to ovarian ablation alone.

In patients who receive tamoxifen in the adjuvant setting and relapse during treatment with tamoxifen or shortly thereafter (within 12 months), surgical oophorectomy or ovarian ablation should be strongly considered. Once patients are in a post-menopausal state, endocrine therapy should be administered accordingly, and in most patients an aromatase inhibitor (AI) is the preferred second-line agent.

Tamoxifen or a steroidal AI with ovarian ablation in combination with everolimus should be considered for patients at the time of progression.

Post-menopausal patients

In patients who have not received previous endocrine therapy, or are within 12 months of antiestrogen exposure, the use of an AI is recommended as first-line therapy; however the use of tamoxifen is also an appropriate option.

AIs appear to be associated to superior outcomes compared to tamoxifen, but the differences are modest. All AIs are considered to be equivalent in efficacy and have similar side effect profiles. Non-steroidal AIs (anastrozole and letrozole) appear not to have significant cross-resistance with steroidal AI (exemestane); therefore these agents can be used sequentially.

Tamoxifen or a steroidal AI in combination with everolimus should be considered for patients at the time of progression.

Endocrine therapy used sequentially can provide disease stabilization in a number of patients. After treatment with AIs and tamoxifen, fulvestrant is a good second- or third-line option. Fulvestrant is an ER antagonist and appears to be at least as effective as anastrozole in patients who have progressed on tamoxifen.

Other agents that can be used include megestrol, ethynil estradiol, and fluoxymesterone; however response rates beyond the second-line of treatment are low, and these agents are rarely used.

Recent data suggests that the use of tamoxifen or aromatase inhibitors in combination with newer agents, such as mTOR inhibitors, restores sensitivity to hormone therapy. This data is encouraging, and confirmatory results are awaited. Additionally, in patients with HR positive and HER2 positive disease, some data suggests that the combination of trastuzumab or lapatinib + AI is beneficial.

Agents and side effects

As a general rule, endocrine therapy is well-tolerated. Side effects are usually associated with a low-estrogen state. Tamoxifen use is associated with hot flashes and mood disturbances. Rare but serious side effects include risk of thromboembolic events and endometrial cancer.

Recently, data regarding the use of certain antidepressants and tamoxifen has suggested that medications that inhibit CYP2D6 such as paroxetine and fluoxetine should be avoided if possible, as they may interfere with tamoxifen metabolism. Currently, based on retrospective analysis of large clinical trials, evaluating the CYP2D6 status of patients who will be treated with tamoxifen is not recommended.

AIs are associated with myalgias and arthralgias as well as bone loss. Progestins are associated also with thomboembolic events. Most of the endocrine agents (with exception of AIs) can cause weight gain.

Everolimus is associated with early-onset mucositis, hyperglycemia, hyperlipidemia, cytopenias, rash, and fatigue. Patient education including early reporting of adverse events should be provided at the time of prescription.

Chemotherapy

Chemotherapy is usually administered to patients with triple negative tumors, as well as those with HER2-positive tumors in combination with HER2-targeted therapies. It is also administered to patients with HR positive tumors who need a rapid response or who have become resistant to endocrine therapy.

For chemotherapy-naive patients, the clinical benefit rate varies from 30-70%. Predictors of positive chemotherapy response include:

Soft tissue metastases.
No prior chemotherapy.
Prolonged disease-free interval after adjuvant chemotherapy.
Low tumor burden.
Good performance status.
Normal organ function.

The selection of treatment should take into account previous therapies (including responses and toxicities). For instance, patients with significant residual neuropathy should avoid agents known to cause neuropathy such as taxanes, vinorelbine, eribulin, and ixabepilone.

Compared to single-agent chemotherapy, combination chemotherapy has been shown to provide higher response rates and longer time to progression. However, combination chemotherapy is associated with more toxicities and the survival benefit is minimal compared to sequential single agents.

Combination chemotherapy can be used in cases of rapid clinical progression, life threatening visceral metastasis, or when rapid symptom control is needed. However, in the majority of cases, single agents should be used and continued until progression or unacceptable toxicity.

Anthracyclines and taxanes are some of the most active cytotoxics against breast cancer. However, antimetabolites and microtubule inhibitors are also frequently used as single agents or in combination.

In recent years a number of new agents have been approved. Ixabepilone is an epothilone that is administered alone or in combination with capecitabine for the treatment of metastatic breast cancer resistant to anthracyclines and taxanes. Side effects include neuropathy, stomatitis, fatigue, and neutropenia.

Recently, eribulin, a microtubule inhibitor, was approved for use in patients with previously treated metastatic breast cancer. Its use has been associated with a two-month improvement in overall survival.

Single agents

Anthracyclines

Doxorubicin 60-75 mg/m² IV (3-week cycles) or 20mg/m² IV weekly.
Epirubicin 60-90 mg/m²I V (3-week cycles).
Doxil (liposomal doxorubicin) 50 mg/m² IV (4-week cycles).

Taxanes

Docetaxel 60-100 mg/m² IV 3-week cycles) or 40 mg/m² IV weekly (6 weeks on, 2 weeks off every 8 weeks).
Paclitaxel 80 mg/m² IV (weekly) or 175 mg/m² IV (q 3-week cycles).
Albumin-bound paclitaxel 100 or 150 mg/m² IV (days 1, 8, 15 of a 28 day cycle) or 260 mg/m² IV (q 3-week cycles).

Antimetabolites

Capecitabine 1000-1250 mg/m² orally twice daily (days 1-14 of a 21 day cycle).
Gemcitabine 800-1200 mg/m² IV days 1,8,15 of a 28 day cycle.

Other microtubule inhibitors

Vinorelbine 25 mg/m² IV (weekly).
Eribulin 1.4 mg/m² IV (days 1 and 8 of a 21 day cycle).
Ixabepilone 40 mg/m² IV (q 3-week cycles).

Combination chemotherapy

Anthracycline-based combinations

FAC (5FU 500 mg/m²IV, doxorubicin 50 mg/m² IV, cyclophosphamide 500 mg/m² IV) (3-week cycles).
FEC (5FU 500 mg/m² IV, epirubicin 100 mg/m² IV, cyclophosphamide 500mg/m² IV) (3-week cycles).
AC (doxorubicin 60mg/m² IV, cyclophosphamide 600 mg/m² IV) (3-week cycles).
EC (epirubicin 75mg/m² IV, cyclophosphamide 600 mg/m² IV) (3-week cycles).

Taxane-based combinations

Docetaxel 75 mg/m² IV day 1 plus capecitabine 2000 mg/m² orally divided BID for 14 days (3-week cycles).
Gemcitabine 1000 mg/m²IV days 1 and 8 plus paclitaxel 175 mg/m² IV day 1 (3-week cycles).
Paclitaxel 80 mg/m² IV days 1 and 8 plus carboplatin AUC 2 IV on days 1 and 8 (3-week cycles)

Anthracycline and taxane-based combinations

Doxorubicin 50 mg/m² IV plus docetaxel 75 mg/m² (3-week cycles).
Doxorubicin 50 mg/m² IV plus paclitaxel 175 mg/m² IV (paclitaxel can also be administered 80 mg/m² IV weekly) (3-week cycles).

Other combinations

Ixabepilone 40 mg/m² IV day 1 plus capecitabine 2000 mg/m² orally divided BID days 1-14 (3-week cycles).
CMF (cyclophosphamide 600 mg/m² IV, methrotrexate 40 mg/m² IV, 5FU 600 mg/m² IV) (3-week cycles).
Gemcitabine 1000 mg/m²on days 1 and 8 plus carboplatin AUC 2 on days 1 and 8 (3-week cycles).

A number of other single agents and combinations are occasionally used. For example, combinations of gemcitabine and platinum agents have shown activity in triple receptor negative tumors. However the previously listed regimens and agents are the most commonly used and those recommended by current guidelines.

Molecular targeted therapy

HER2 targeted therapies

Tumors with overexpression or amplification of HER2 benefit from HER2-targeted therapy. The two methods used to test for HER2 are immunohistochemistry (IHC) and fluoresence in situ hybridization (FISH).

According to current guidelines, testing criteria define HER2-positive status if there is (1) protein overexpression (IHC) of 3+ (based on observing within an area of tumor that amounts to > 10% of contiguous and homogeneous tumor cells) or (2) gene amplification (HER2 copy number >6, or HER2/CEP17 ratio >2.0 by ISH, based on counting at least 20 cells within the area).

Trastuzumab

Trastuzumab is a humanized monoclonal antibody targeted against HER2. Trastuzumab has been shown to improve outcomes significantly in patients with HER2-positive tumors and is considered standard of care.

Trastuzumab as a single agent has limited activity; therefore, it is usually used in combination with different chemotherapeutic agents. In general, all recommended trastuzumab-based chemotherapy combinations are well-tolerated and toxicities are largely determined by the chemotherapeutic agent used.

A rare, but serious, side effect is cardiotoxicity. Accordingly, patients receiving trastuzumab should have adequate baseline cardiac function, and monitoring during treatment is necessary. Current guidelines recommend cardiac monitoring with echocardiogram or nuclear scan at baseline and every 3 months during treatment. Higher rates of cardiotoxicity have been reported when trastuzumab is combined with anthracyclines, and the simultaneous use of adriamycin and trastuzumab should be avoided.

In general, the selection of a specific regimen is determined on the prior regimens that the patients received. It is recommended to continue HER2 blockade for patients who have progressed on first-line trastuzumab-based regimens.

This approach also applies to patients who received trastuzumab in the adjuvant setting and subsequently develop metastatic disease. In clinical practice, patients usually receive at least two trastuzumab-based regimens. Beyond that, clinicians should consider the use of other HER2-targeted agents.

Selected regimens:

TPC (carboplatin AUC 6 IV day 1, paclitaxel 175 mg/m² IV day 1, trastuzumab 4 mg/kg IV day 1 followed by 2 mg/kg IV weekly) (3-week cycles).
TCH (carboplatin AUC 6 IV day 1, docetaxel 75 mg/m² IV day 1, trastuzumab 4mg/kg IV day 1 followed by 2 mg/kg IV weekly) (3-week cycles).
Paclitaxel 175 mg/m² IV day 1 every 3 weeks (or 80-90 mg/m² IV weekly) plus trastuzumab 4 mg/kg IV day 1 followed by 2 mg/kg IV weekly (or loading dose of 8 mg/kg IV on day 1 followed by 6 mg/kg IV every 3 weeks).
Docetaxel 80-100 mg/m² IV every 3 weeks (or 35 mg/m² IV weekly) plus trastuzumab 4 mg/kg IV day 1 followed by 2 mg/kg weekly (or loading dose of 8 mg/kg IV on day 1 followed by 6 mg/kg IV every 3 weeks).
Vinorelbine 25 mg/m² IV weekly plus trastuzumab 4 mg/kg IV day 1 followed by 2 mg/kg IV weekly (or loading dose of 8 mg/kg IV on day 1 followed by 6 mg/kg IV every 3 weeks).
Capecitabine 1000-1250 mg/m² orally twice daily days 1-14 (3 week cycle) plus trastuzumab 4 mg/kg IV day 1 followed by 2 mg/kg IV weekly (or loading dose of 8 mg/kg IV on Day 1 followed by 6 mg/kg IV every 3 weeks).

Lapatinib

Lapatinib is a selective dual EGFR-HER2 inhibitor. As a single agent, it has shown little activity; however its use has been approved in combination with capecitabine for patients previously treated with an anthracycline, taxane, and trastuzumab. Patients treated with capecitabine and lapatinib had a longer time to progression compared to patients treated with capecitabine alone.

Recently, data on dual HER2 blockage has demonstrated benefit from using two different agents targeting HER2. In a heavily pretreated group of patients, there was a survival advantage in the patients treated with trastuzumab in combination with lapatinib compared to patients treated with lapatinib alone. Among patients with HER2 and HR+ tumors, the use of lapatinib in combination with letrozole has shown a reduction in the risk of progression.

Selected regimens:

Capecitabine 1000 mg/m² orally twice daily days 1-14 (3-week cycle) plus lapatinib 1250 mg orally daily.
Lapatinib 1000 mg orally daily plus trastuzumab 4mg/kg IV day 1 followed by 2mg/kg IV weekly (or loading dose of 8mg/kg on day 1 followed by 6mg/kg every 3 weeks).

Pertuzumab

Pertuzumab is a humanized monoclonal antibody that binds HER2 at a different epitope of the HER2 extracellular domain (subdomain II) than trastuzumab. Pertuzumab prevents HER2 from dimerizing with other ligand-activated HER receptors, most notably HER3. Like trastuzumab, pertuzumab stimulates antibody-dependent, cell-mediated cytotoxicity. Because pertuzumab and trastuzumab bind to different HER2 epitopes and have complementary mechanisms of action, these two agents, when given together, provide a more comprehensive blockade of HER2 signaling and result in greater antitumor activity than either agent alone in HER2-positive tumor models.

The CLEOPATRA study randomly assigned 808 patients with HER2-positive metastatic breast cancer to receive placebo plus trastuzumab plus docetaxel or pertuzumab plus trastuzumab plus docetaxel as first-line treatment. Primary endpoint was progression-free survival. In this study, additional pertuzumab showed improvement of both progression-free and overall survival.

Pertuzumab is in general safe. There are no reports of increase in left ventricular systolic dysfunction. However, use has been associated with increased rates of febrile neutropenia and diarrhea.

Selected regimens:

THP (docetaxel 75 mg/m² IV day 1, trastuzumab 8 mg/kg IV loading dose followed by 6 mg/kg IV on day 1 every 3 weeks, and pertuzumab 840 mg/kg IV loading dose followed by 420 mg/kg IV on day 1 every 3 weeks) (3-week cycles).
PHP (paclitaxel 80 mg/m² IV day 1 weekly (2 weeks on, one week off), trastuzumab 8mg/kg IV loading dose followed by 6 mg/kg IV on day 1 every 3 weeks, and pertuzumab 840 mg/kg IV loading dose followed by 420 mg/kg IV on day 1 every 3 weeks) (3-week cycles).

Trastuzumab-Emtansine (TDM-1)

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that combines the HER2-targeting properties of trastuzumab with the cytotoxic activity of DM1 (a tubulin targeting derivative of maytansine). Both agents are conjugated by a stable linker. T-DM1 allows intracellular drug delivery specifically to HER2-overexpressing cells, improving therapeutic index and minimizing exposure of normal tissues. Pertuzumab has no activity as a single agent.

The EMILIA study was a phase III trial to assess the efficacy and safety of T-DM1, as compared with lapatinib plus capecitabine, in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane. Primary endpoints were progression-free and overall survival. T-DM1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine in patients with HER2-positive advanced breast cancer.

The most common toxicities of TDM-1 are thrombocytopenia and elevated liver function tests. These tend to occur early and require dose reductions to maintain therapy.

Selected regimens:

T-DM1 3.6 mg/kg IV every 21 days (3-week cycles).

Everolimus

Everolimus is an mTOR (mammalian target of rapamycin) inhibitor that binds allosterically to mTORC1. In preclinical models, the use of mTOR inhibitors in combination with hormonal therapy inhibitors results in synergistic inhibition of cell proliferation and induction of apoptosis. Studies have looked at the combination of everolimus with steroidal AIs in the phase III setting (BOLERO-2), and with tamoxifen in the phase II setting.

The BOLERO-2 study evaluated the efficacy and safety of the combination of everolimus and exemestane in patients with HR-positive breast cancer refractory to nonsteroidal aromatase inhibitors. TamRAD was a randomized phase II trial of everolimus in combination with tamoxifen in patients with HR-positive/HER2-negative metastatic breast cancer with prior exposure to aromatase inhibitors. Both studies demonstrated a progression-free survival advantage with the addition of everolimus.

On the other hand, trastuzumab resistance is often thought to be mediated via the PI3K pathway via PTEN loss and PIK3CA activating mutations leading to activation of mTOR. Inhibition of mTOR has been shown to sensitize HER2-positive/PTEN-deficient breast cancer models.

Everolimus has been studied in combination with trastuzumab and chemotherapy in HER2-positive metastatic breast cancer that has progressed on trastuzumab. A phase III randomized trial of trastuzumab/vinorelbine with or without everolimus in patients with metastatic HER2-positive breast cancer previously treated with trastuzumab demonstrated a small but significant improvement in progression-free survival; making this another therapy alternative for this patient population.

Everolimus increases the toxicity profile of other therapies. Main adverse events include early- onset mucositis, fatigue, cytopenias, pneumonitis, and metabolic changes including hyperglycemia and hyperlipidemia. Patients on everolimus should be monitored regularly, including blood counts and metabolic profiles.

Selected regimens:

Everolimus 10 mg PO daily + exemestane 25 mg PO daily
Everolimus 10 mg PO daily + tamoxifen 20 mg PO daily
Everolimus 5 mg PO daily + trastuzumab 4 mg/kg IV loading dose followed by 2 mg/kg IV weekly and vinorelbine 25mg/m² IV weekly

What other therapies are helpful for reducing complications?

A number of therapies are commonly used in patients with metastatic breast cancer to treat, prevent or reduce complications.

Supportive care

Anemia

Treatment with erythropoiesis stimulating agents (ESAs) is indicated only in patients in which treatment is administered without a curative intent. Most patients with metastatic breast cancer fall in to this category.

Caution using these agents is recommended as they are associated with an increased risk of thromboembolic events. When they are used, the target hemoglobin should never be at supranormal levels. In symptomatic patients, transfusion of leukoreduced packed red blood cells provides rapid relief of symptoms.

Neutropenia

Primary prophylaxis with growth factor support is not commonly used in patients with metastatic breast cancer. As a general rule, quality of life with close attention to the side effects of chemotherapy is a priority of treatment. However, in patients with poor bone marrow reserve after prolonged chemotherapy treatments or with history of neutropenic fever, filgastrim (G-CSF) or pegfilgrastim (long-acting G-CSF) can be used.

Nausea/vomiting

Some chemotherapeutic agents used in the metastatic setting are moderately to highly ematogenic. Medications for the prevention of acute nausea should be administered concurrently with chemotherapy and shortly thereafter. 5-HT3 antagonists such as ondansetron, granisetron, or palonosetron are recommended.

For severe cases, aprepitant (day 1: 125 mg PO; days 2 and 3: 80 mg PO) should be administered. Dexamethasone 4 mg orally BID for 3 days helps in the management of delayed nausea. Additionally, agents such as lorazepam, prochlorperazine, and metoclopramide can be used.

Palmar-Plantar erythrodysesthesia

Also known as hand-foot syndrome, this is a common side effect of capecitabine. Prevention is very important and involves reducing friction and heat exposure. Frequent use of emollients on the hands and feet is strongly encouraged.

Regular use of a topical petroleum-lanolin based ointment with antiseptic applied 3 times a day has been reported to alleviate symptoms. If severe pain or peeling develops, treatment needs to be interrupted until the symptoms have improved, then restarted at a reduced dose.

Bone metastases

Patients with bone metastases are at risk of developing skeletal-related events (SREs) such as bone fractures, hypercalcemia, cord compression, or bone pain that requires radiation therapy.

Patients with symptomatic bone metastases should be evaluated by a radiation oncologist as radiation therapy can provide important palliation to the symptoms and improve quality of life. Recently radioactive agents such as samarium-153 (153Sm) and strontium-89 (89Sr) have demonstrated efficacy in the management of patients with painful bone metastases.

Bisphosphonates such as pamidronate and zoledronic acid inhibit bone resorption by osteoclasts. Patients with bone metastases and a life expectancy of more than 3 months should be treated with bisphosphonates. Extensive data from randomized clinical trials supports its use. Patients with bone metastases treated with bisphosphonates have significantly fewer SREs.

Treatment is considered a palliative measure.
Treatment can be administered with antineoplastic agents or hormonal agents.
Pamidronate 90 mg IV over 2 hours or zoledronic acid 4 mg IV over 15 minutes every 3-5 weeks is recommended.
Calcium citrate and vitamin D oral supplements should be administered.
There is risk of renal toxicity; therefore, renal function monitoring is important prior to each dose.
Osteonecrosis of the jaw (ONJ) is a rare, but serious, side effect associated with bisphosphonate use. Poor baseline dental health is a risk factor and the risk seems to increase with cumulative doses. Dental examination should take place before the start of the treatment and dental procedures during treatment should be avoided if possible.
Current data supports the use of bisphosphonates for up to 2 years; there are limited long-term safety data beyond that duration.

Recently, denosumab, a fully human monoclonal antibody against RANK (receptor activator of nuclear factor kappa-B) ligand, a mediator of osteoclast functions, was proven to be at least as effective as zoledronic acid preventing SREs in patients with breast cancer and bone metastases.

Denosumab is administered as a 120 mg subcutaneous injection every 4 weeks.
Denosumab is also associated with ONJ.
In clinical trials to date, denosumab appears to cause less renal toxicity compared with zoledronic acid.

Surgery

As a general rule, the management of patients with metastatic breast cancer and an intact primary tumor is systemic therapy without surgery. However, surgery may be indicated after systemic therapy in patients who require palliation for pain, bleeding, or ulceration. Surgery should only be performed if complete local clearance can be obtained. Additionally, radiation therapy to the breast can be used.

Recent studies have suggested a potential survival benefit from breast tumor resection in selected patients with metastatic breast cancer. These retrospective studies have substantial bias. Ongoing prospective clinical trials are evaluating this approach.

What should you tell the patient and the family about prognosis?

A pivotal component of the management of patients with metastatic breast cancer is the discussion of goals of care. Despite important advances in the treatment, metastatic breast cancer remains, as a general rule, an incurable disease. Median survival is 2 years and 5-year overall survival estimates range from 17-28%.

Patients with bone-only disease tend to have better prognosis than patients with visceral disease; patients with uncontrolled brain metastases have very poor prognosis. Patients with bone-only disease can have median survival of up to 5 years or more, compared with patients with brain metastases who tend to live less than 12 months.

Without treatment, median survival ranges 9 to 12 months. Among treated patients, responses and clinical outcomes depend on a number of factors, including the breast cancer tumor subtype, the patient’s performance status, the number and extension of the metastases, the disease-free interval, and prior therapies received, among others.

In rare instances (1-3% of all patients with metastatic breast cancer), long-term remissions can be achieved. It is not possible to predict which individuals will fall into this group. They tend to be young, have good performance status and very low volume of disease. Also, in patients with solitary metastases, complete responses can be achieved and in few cases a multidisciplinary treatment approach with curative intent can be justified.

There are reports of successful resections of single lung or liver metastases that are consolidated with systemic therapy. In this very select group of patients with single or oligometastatic disease the 5-, 10- and 15-year overall survival rates can be as high as 36%, 26%, and 24% respectively after resection and administration of systemic therapy.

Unfortunately, the scenario previously described is rare and in the great majority of patients treatment for metastatic disease will be administered with a palliative intent. Special emphasis should be placed on re-evaluating quality of life and expectations.

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