Chemotherapy and HER2-Directed Therapy for Metastatic Breast Cancer

Introduction

Despite significant advances and the introduction of new therapeutics for patients with metastatic breast cancer (MBC), based on estimates from the World Health Organization there were approximately 685,000 deaths globally in 2020 from breast cancer, which remains incurable in the vast majority of patients. In recent years, continued progress has been made in the development of new human epidermal growth factor receptor (HER2)-targeted therapies as well as new therapeutic approaches for triple-negative breast cancer (TNBC). There have also been improvements in disease management and clinical trial design to include more patients with involvement of the central nervous system (CNS), which is often a life-limiting complication of MBC. New agents such as ADCs and immunotherapy have been approved for the treatment HER2-positive disease and triple-negative disease, and many novel agents are in development. Despite major efforts in the development of smarter, less toxic, targeted therapies, in 2022 cytotoxic chemotherapy remains a central component of treatment for most women with advanced breast cancer. Current research strives not only to develop new therapies but also to identify populations in whom existing agents will be most effective and to optimize the activity of newer therapeutic modalities such as targeted and immune-based therapy by combining them with a chemotherapy backbone. Overall, women living with MBC have far more options than in the past, and there has been a modest prolongation in overall survival (OS) over the last few decades. A meta-analysis published in 2018 found that median OS increased from 21 months to 38 months from 1990 to 2010. For estrogen receptor (ER)-positive MBC patients, median survival increased during 1990 to 2010 from 32 to 57 months, and for ER-negative MBC patients from 14 to 33 months. Among eight studies of de novo stage IV MBC, median survival increased during 1990 to 2010 from 20 to 31 months. Thus the goal continues to be prolongation of survival with palliation of cancer-related symptoms, and cure remains unattainable except in anecdotal cases.

Epidemiology

Breast cancer remains the most common noncutaneous malignancy and the second leading cause of cancer death after lung cancer among women in the United States. In 2020 it was estimated that more than 268,000 new breast cancer diagnoses were made, and that MBC was responsible for about 42,000 deaths. For women aged 20 to 59 years, MBC remains the leading cause of cancer death and is therefore an important public health concern. Although only approximately 6% of women with breast cancer initially present with metastatic disease, many women with localized disease or locoregional spread at diagnosis go on to develop distant disease despite adjuvant therapy. Of women with MBC, an estimated three-quarters were originally diagnosed with local disease and later developed distant recurrence, and an estimated one-quarter were de novo stage IV or metastatic disease at the time of diagnoses. For de novo metastatic disease, survival has increased from an estimate of 19 months in 1980 to 31 months in 2010 of all tumor types. Despite this improvement over time, there is an urgent need for better therapies.

Therapeutic Goals

Although there are rare anecdotes reporting cure or long-term remission in patients with MBC, in the overwhelming majority of cases the goal of therapy is symptom control and prolongation of survival. Unfortunately, the vast majority of women with MBC will experience disease progression. A systematic review of population changes in breast cancer survival since 1995 by Lord and colleagues found that the median probability of OS of at least 5 years for de novo MBC in 1995 to 1999 was 16%. This increased to 23% for patients diagnosed between 2005 and 2009, a median gain of 7%. In addition, the OS and breast cancer–specific survival of patients with de novo MBC has continued to improve at a population level since 1995, with a relative reduction in the risk of all-cause death of 1% per year.

Treatments should be selected to achieve three objectives simultaneously: prolong survival, control symptoms if present, and minimize therapy-associated toxicity. These goals are usually achieved through the administration of systemic therapy (hormonal therapy, chemotherapy, and targeted agents) with judicious use of both radiation therapy, and, less frequently, surgery.

Prognostication

Prognostic and predictive factors should be used to determine the most appropriate therapy for an individual. Although breast cancer was historically classified as a single disease, it is now known to be a heterogeneous group of diseases, all of which arise in the breast. Complex differences in tumor biology produce variable responses to therapy in individual patients. For this reason, the particular characteristics of a patient’s tumor may help the clinician predict the pace of disease, likelihood of response to certain therapies, and prognosis.

In general, OS and disease-free intervals are longer for patients with ER- and/or progesterone receptor (PR)-positive disease; this is likely the result of a more indolent natural history and, even more important, the availability of a large armamentarium of active endocrine therapies that are generally used before the administration of chemotherapy. Similarly, given the development of multiple highly effective HER2-targeted therapies in recent years, more patients with HER2-positive disease are cured with a combination of neoadjuvant and adjuvant therapy, and median OS for HER2-positive MBC has improved dramatically. By contrast, patients with “triple-negative” tumors that do not express ER, PR, or HER2 typically have a shorter disease-free interval before the development of metastatic disease, as well as a shorter median OS from the time of diagnosis of metastatic disease.

Individualized adjuvant therapy is now informed by the response to treatment in the neoadjuvant setting. Examples of this include tailoring HER2-directed therapy based on response to neoadjuvant therapy for women with early-stage HER2-positive breast cancer based on the KATHERINE trial, which found that among patients with HER2-positive early breast cancer who had residual invasive disease after completion of neoadjuvant therapy, the risk of recurrence of invasive breast cancer or death was 50% lower with adjuvant T-DM1 than with trastuzumab alone. Another example of decreasing risk of metastatic disease is demonstrated by the CREATE-X trial. This trial demonstrated the addition of adjuvant capecitabine therapy after standard neoadjuvant chemotherapy containing anthracycline, taxane, or both prolonged disease-free survival (DFS) and OS among patients with HER2-negative breast cancer who had residual invasive disease on pathological testing. Since curing metastatic disease is not yet possible for most patients, prevention of the development of metastatic disease with intensifying treatment for patients at high risk for recurrence provides an important opportunity to decrease breast cancer–related mortality.

Other disease-specific characteristics that may help predict prognosis include disease-free interval before the development of metastatic disease, number of disease sites, visceral versus bone-only metastases, and disease volume. Patients with a prolonged relapse-free survival of more than 24 months before diagnosis with MBC have a more favorable prognosis, particularly for patients with ER-positive breast cancer. On the basis of data assembled more than two decades ago from the MD Anderson Cancer Center, the 5-year survival for patients with isolated bone metastases is 23%, compared with only 13% for MBC patients with visceral metastases. An additional study from Insa and colleagues showed that the location of the recurrence was also associated with prognosis, with visceral spread being associated with a significantly shorter median survival of 13 months compared to 28 months with metastasis to bone and 36 months with metastatic to the soft tissues. The number of locations involved at the time of recurrence was also significantly associated with shorter survival of 11 months in patients with three or more locations versus 22 and 30 months in those with one or two involved sites. CNS metastases are associated with shorter survival and impaired quality of life compared with extracranial metastases. Despite the use of neurosurgery and radiotherapy, only the minority of patients survive longer than 1 year. In a retrospective study by Niikura and colleagues of 1256 patients diagnosed with brain metastases, the median OS of HER2-positive patients with TNBC and CNS metastasis was 4.9 months and 11.2 months, respectively.

The other component to prognosis rests in individual patient characteristics. Younger age, better performance status, fewer comorbidities, and lower burden of disease all predict a better prognosis. This may be partially a result of a patient’s ability to tolerate toxic therapy and may also reflect differences in treatment approaches used for younger and older patients. Based on data from the Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2015, Lv and colleagues analyzed metastasis patterns and prognosis of octogenarians with breast MBC and found that patients 80 years or older had the shortest median OS and breast cancer–specific survival of 13 months compared to more than 22 months in all other age groups. The proportion of elderly MBC patients (≥80 years) was 9.9% in this dataset, which was consistent with previously published studies, implying that octogenarians represent approximately one in ten breast cancer patients. Thus the inclusion of early-stage patients in clinical trials is critical to better further understand the pathology, prognosis, and optimal treatment for this patient population.

In addition, past response to therapy, or lack thereof, may predict future response to therapy with new agents. Although mechanisms of chemotherapy resistance have not been fully elucidated, historical information suggests that tumor resistance to one agent is associated with an increased likelihood of resistance to other chemotherapy agents. For example, response to second- and third-line hormonal therapy is less robust compared to response to first-line endocrine therapy in the metastatic setting, and patients who develop MBC on endocrine therapy, or within 2 years of completing adjuvant endocrine therapy, have shorter duration of response to subsequent endocrine therapy in the metastatic setting.

Importantly, there are racial differences in the incidence and outcomes of patients with MBC. Non-Hispanic Black women exhibit substantially higher morbidity and mortality than women of other races/ethnicities with the greatest excess mortality risk for non-Hispanic Black women in the youngest onset age group. Both socioeconomic factors and contribution from higher risk tumor characteristics contribute to this excess risk. Social and health system determinants including poor access to care and health education, lack of financial resources, patient-provider interactions, and health system structural barriers have been cited as potential factors contributing to inequality in health outcomes for patients with breast cancer. Hispanic women with breast cancer also experience worse outcomes compared to non-Hispanic White women. A study of non-Hispanic White and Hispanic women in the California SEER database showed that Hispanic women were more likely to have TNBC or HER2-positive breast cancer, and in adjusted models Hispanic women had a higher risk of breast cancer mortality than non-Hispanic Whites. Recognizing the impact of racial, social, and economic disparities on breast cancer prognosis is needed to provide ideal care to all patients with breast cancer.

Medical Evaluation in the Metastatic Setting

Large randomized trials have shown that, in patients with early-stage breast cancer, routine surveillance testing beyond a regular physical examination and yearly mammogram does not improve timeliness of recurrence detection, survival, or health-related quality of life. As a result, the diagnosis of metastatic disease is typically made when a patient presents with new symptoms (e.g., bone pain, seizure, shortness of breath); has asymptomatic laboratory abnormalities; has a clinically detected local recurrence on the chest wall, in the regional lymph nodes, or within the breast itself; or has incidental findings on imaging performed for other purposes.

Once there is a suspicion for metastatic disease based on laboratory results, physical examination, or radiographs, it is generally important to biopsy a metastatic site to confirm that the lesion is consistent with breast cancer rather than another primary malignancy or some other benign process. Rebiopsy at the time of diagnosis with metastatic disease also provides a unique opportunity to reassess receptor status (ER, PR, and HER2) before the initiation of therapy. Biopsy can determine whether the patient’s MBC has the same receptor expression as the original lesion, because in some cases these properties have been known to change. One prospective study demonstrated discordant receptor status between primary and metastatic lesions in 16%, 40%, and 10% of cases for ER, PR, and HER2, respectively. In certain patients, the index of suspicion for MBC is high enough and/or the metastatic site is not amenable to biopsy, in which case one may choose to forgo biopsy. However, in almost all clinical scenarios, rebiopsy is feasible and recommended. Additionally, in the modern era, genomic profiling of metastatic biopsy tissue can have implications for both standard of care and clinical trial agent selection, and the utility of molecular profiling for selection of ideal therapeutics is likely to increase.

Before initiation of therapy, one should assess the extent of disease with imaging of the chest and abdomen, as well as with a bone scan, because bone involvement is quite common in MBC. The relative merits of fluorodeoxyglucose positron emission tomography (FDG-PET) scanning in this setting have been the subject of debate, and at this time PET scanning is an option but should not be considered essential. It is a sensitive imaging modality but is not specific for malignancy, often resulting in findings that are difficult to interpret. Highly metabolic foci may be seen in inflammatory conditions such as rheumatologic disease or infection; FDG avidity may therefore result in unnecessary anxiety or inaccurate assumptions about the extent of disease. In patients with documented metastases, PET often does not offer enough clinical information over CT and bone scan to warrant the cost. With improvements in technology and changes in cost structure, recommendations may well evolve over time.

Imaging of the brain with contrast-enhanced CT or ideally gadolinium-enhanced magnetic resonance imaging (MRI) should be performed in any MBC patient with focal neurologic findings or symptoms to suggest CNS involvement such as new-onset headaches, seizures, focal weakness or numbness, facial nerve deficits, or cognitive changes. Given the high rate of CNS disease in women with HER2-positive breast cancer and TNBC, there are some clinicians who advocate scanning asymptomatic patients with these disease subtypes, but there are no data to support that this approach improves survival or affects quality of life. In the absence of CNS signs and symptoms, brain imaging generally should not be performed when an asymptomatic patient is newly diagnosed with metastatic disease.

In addition to radiographic imaging, laboratory studies and a careful physical examination should also be performed. Physical examination should focus on identification of symptomatic foci such as bone tenderness, neurologic findings, chest wall disease, lymphadenopathy, pleural effusion, and ascites. These findings may guide directed therapy with bisphosphonates or radiation and offer a baseline from which response to therapy may be assessed. Baseline laboratory studies can evaluate renal and hepatic function, electrolyte status, and bone marrow reserve in preparation for treatment with chemotherapy. Finally, serum tumor markers such as carcinoembryonic antigen (CEA), cancer antigen (CA) 15-3, and CA 27-29 may be measured at the time of diagnosis and, if elevated, can be used in monitoring response to therapy. Current practice guidelines from the American Society of Clinical Oncology state that tumor markers may be used as adjunctive assessments, but not alone, to contribute to decisions regarding therapy. Tumor markers need to be used with caution because they do not always correlate with the course of the disease.

Local Therapy for Metastatic Breast Cancer

Although the general treatment paradigm for MBC is systemic therapy, there are unique clinical scenarios in which local therapy to a metastatic site may further the goals of therapy, namely symptom control and improvement in survival. Possible reasons to consider local therapy include oligometastatic disease, local symptoms that are unlikely to respond to systemic therapy, and impending local complications such as spinal cord compression, hydronephrosis, or bone fracture. Surgical interventions for metastatic disease may include resection of a CNS lesion, chest wall lesion, isolated pulmonary nodule, or isolated hepatic nodule. Longitudinal data indicate that mastectomy is becoming increasingly common in breast cancer and many other solid malignancies. However, mastectomy for reasons other than resection of a CNS lesion or other local palliation remains a nonstandard approach, and there are no prospective data demonstrating that it improves disease outcomes. Local radiation therapy is indicated in the event of cord compression or unstable bone lesions, although the need for radiation has been reduced by the widespread use of bone-modifying agents for lytic bone disease.

Selecting Therapy for Metastatic Breast Cancer

Before initiating treatment in the metastatic setting, there are many factors to be considered. The primary objective is to select the systemic treatment that is most likely to yield a clinical response while minimizing toxicity and side effects. Tumor characteristics either from the original breast biopsy or ideally from a metastatic site determine which classes of agents are likely to be most active. Chemotherapy is used invariably in the course of treatment for MBC of all subsets, but the appropriate time and context for its use varies by subtype (ER-positive vs. HER2-positive vs. TNBC). ER-positive and/or PR-positive disease is often initially sensitive to endocrine-based therapy, and cytotoxic agents are reserved for the scenarios outlined subsequently. HER2-directed therapies will form the backbone of all systemic therapy in HER2-positive disease, sometimes in combination with chemotherapy, as discussed later in the chapter. Lastly, in women with TNBC, cytotoxic therapy continues as the mainstay of treatment, but with an important minority of patients also now eligible for treatment with poly-ADP ribose polymerase (PARP) inhibitors in BRCA -mutated disease and immunotherapy based on PDL1 expression or high mutational tumor burden (TMB).

In patients with hormone receptor–positive tumors, endocrine therapy should be the initial course of treatment unless they have extensive visceral metastases (“visceral crisis”), rapid disease progression, or symptoms that need rapid palliation ( Fig. 61.1 ). Of course, the decision to use endocrine therapy also will be influenced by prior endocrine treatment in the adjuvant setting and the timing of recurrence with respect to their adjuvant endocrine therapy. Patients with primary endocrine resistance as defined as relapse while on the first 2 years of adjuvant endocrine therapy or progressive disease within the first 6 months of first-line endocrine therapy for MBC tend to have more resistance to subsequent lines of therapy and may not benefit from additional endocrine-based therapies. Although patients whose disease displays primary resistance to upfront endocrine therapy should usually proceed directly to treatment with chemotherapy, women with an initial response to endocrine therapy may receive multiple additional lines of endocrine therapy. Treatment options for women receiving endocrine therapy include tamoxifen, aromatase inhibitors (AIs), ovarian suppression with gonadotropin-releasing hormone (GnRH) agonists, fulvestrant, progestins, high-dose estrogens, and androgens. AIs (letrozole, anastrozole, and exemestane) are often used in the first-line setting for postmenopausal women, given evidence that they offer superior time to progression (TTP) and response rates compared with first-line tamoxifen for MBC. More recently a combination of endocrine therapy with CDK 4/6 inhibitors is preferred as standard first-line therapeutic approaches for endocrine-sensitive breast cancers in the metastatic setting prior to the use of chemotherapeutic agents due to the efficacy of these regimens and also a relatively favorable toxicity profile. After first-line treatment, endocrine therapy combined with an mTOR inhibitor and PIK3CA inhibitor may be appropriate for some patients.

In patients who have previously been treated either in the adjuvant or metastatic setting, shorter disease-free interval is a predictor of more aggressive disease. The degree of symptoms, tempo of disease, and extent of disease (visceral vs. bone-only involvement) are critical criteria for drug selection and timing of therapy in the palliative setting. Response to prior treatment has also been shown to be a predictor of response to the next line of therapy, so early relapse after adjuvant therapy is suggestive of resistant disease. If there is a short disease-free interval, generally defined as less than 1 to 2 years, strong consideration should be given to the use of new non–cross-resistant agents based on the presumption that the tumor is now resistant to similar drugs administered in the past. In general, women who have received anthracyclines in the adjuvant setting are not retreated with anthracyclines in the first-line setting for MBC, largely related to concerns about cumulative cardiac toxicity.

A final dimension to individualizing the treatment plan incorporates patient preference, performance status, and comorbidities. A patient’s unique constellation of comorbidities, age, and general health status will likely predict her ability to tolerate a given treatment. The toxicity profile of a given agent may limit its use (e.g., avoiding anthracyclines in a patient with borderline cardiac function or risk factors for cardiac dysfunction or avoiding taxanes in a patient with preexisting neuropathy). In addition, patient preference regarding alopecia or concerns about toxicities (e.g., neurotoxicity), which may have an impact on occupation and quality of life, should also be considered in the decision-making process.

Chemotherapy for Metastatic Breast Cancer