Breast cancer is the most common type of cancer in women in the United States and the second leading cause of cancer-related death.1 HER2-positive, hormone receptor–positive breast cancer comprises 11% of breast cancer cases diagnosed every year.2 Although most patients present with localized breast cancer and are declared clinically disease-free following local therapy, distant recurrence is common without additional systemic therapy and is the primary cause of death from the disease. Therefore, it is essential that adjuvant treatment—designed to treat micrometastatic disease, or cancer cells that have escaped the breast and regional lymph nodes but have not yet established an identifiable metastasis—be initiated promptly following surgery to reduce rates of both metastatic and local recurrence.
Adjuvant systemic chemotherapy and endocrine therapy have been used for decades to reduce the risk of recurrence and improve overall survival when added to local therapy for early HER2-positive/hormone receptor–positive breast cancer.3 The introduction of the recombinant monoclonal antibody trastuzumab further transformed the treatment of HER2-positive breast cancer; however, approximately 25% of patients with early-stage disease will experience relapse within 10 years of a curative-intent, trastuzumab-based chemotherapy regimen.4 Novel HER2-targeted therapies such as pertuzumab, ado-trastuzumab emtansine (T-DM1), and neratinib have been developed to combat the aggressive nature of HER2-positive disease.
Systemic chemotherapy in combination with trastuzumab is the foundation of adjuvant treatment for early HER2-positive breast cancer, dramatically improving survival rates. Although anthracycline-taxane–based chemotherapy is still considered a preferred regimen in the American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) Guidelines, research indicates that nonanthracycline-based regimens should be considered a preferred approach, according to Sara A. Hurvitz, MD, Director of the Breast Cancer Clinical Research Program, Co-Director of the Santa Monica University of California Los Angeles (UCLA) Outpatient Hematology/Oncology Practice, and Professor of Medicine at UCLA.
“Of the randomized studies conducted that include a nonanthracycline and anthracycline arm, none have shown that adding an anthracycline to trastuzumab and taxane-based therapy benefits patients in terms of pathologic response or disease-related outcomes,” she explained. “By routinely adding an anthracycline to taxane-based therapy, it appears that we are only adding the risk of cardiac toxicity and leukemia/myelodysplasia.” Dr. Hurvitz cited results from landmark studies, including TRAIN-2 and BCIRG-006, that validated the concept that anthracyclines increase toxicity without improving survival compared with nonanthracycline regimens.5,6 “We now have multiple options in the curative setting—trastuzumab, pertuzumab, T-DM1, endocrine therapy, neratinib—that are safer and very effective,” she said.
We now have multiple options in the curative setting—trastuzumab, pertuzumab, T-DM1, endocrine therapy, neratinib—that are safer [than anthracycline therapy] and very effective.Sara A. Hurvitz, MD
Trastuzumab is recommended in combination with chemotherapy for all patients with HER2-positive, node-positive breast cancer, as well as for patients with HER2-positive, node-negative breast cancer > 1 cm.7,8 For tumors ≤ 1 cm and T1a and T1b tumors that are node-negative, adjuvant endocrine therapy with or without adjuvant chemotherapy and trastuzumab may be considered, weighing the balance of toxicity vs uncertain benefits.7,8 Patients who are eligible for adjuvant trastuzumab should be treated for a total of 1 year, with regular assessment of cardiac function throughout treatment.8
The most common side effects with adjuvant trastuzumab include headache, diarrhea, nausea, and chills. Infusion reactions are also common and consist of a symptom complex characterized by fever and chills.9 The manufacturer recommends that permanent discontinuation be “strongly considered” in patients with a severe infusion reaction.
First approved for use in metastatic HER2-positive breast cancer by the U.S. Food & Drug Administration (FDA) in 2012, pertuzumab is a recombinant monoclonal antibody that binds to HER2 on the opposite side of trastuzumab’s binding site. While trastuzumab inhibits the proliferation and survival of HER2-dependent tumors by binding to domain IV, pertuzumab binds to domain II—inhibiting ligand-induced dimerization and its downstream signaling. Consequently, these two drugs achieve antitumor activity complementarily.10
In the phase III APHINITY trial, 1 year of pertuzumab treatment significantly improved the rates of invasive disease–free survival among patients with node-positive, HER2-positive, operable breast cancer when it was added to trastuzumab and chemotherapy, triggering FDA approval for this population in late 2017.11 In a 6-year trial update, the improvement in invasive disease–free survival with pertuzumab in the node-positive arm was still present: 87.9% vs 83.4% with placebo, representing a 28% relative reduction.12 Both the NCCN Guidelines and ASCO 2020 Focused Guideline Update support pertuzumab in the node-positive, HER2-positive population.7,8 In contrast, a clinically insignificant benefit was observed among node-negative patients. Diarrhea is the most common side effect of pertuzumab; nausea, alopecia, fatigue, peripheral neuropathy, and vomiting are also frequently reported.13
The development of T-DM1 established an alternative to traditional nontargeted chemotherapy by covalently linking trastuzumab to a microtubule inhibitory drug, DM1. T-DM1 binds to the HER2 receptor and enters the cell by receptor-mediated endocytosis, allowing DM1—a potent cytotoxic agent—to inhibit microtubule function, prompting cell arrest and apoptosis.14 The HER2-targeted antibody-drug conjugate was the first drug approved by the FDA for the treatment of patients with HER2-positive breast cancer with residual disease after neoadjuvant treatment and surgery.15
“The KATHERINE trial yielded the biggest absolute improvement in invasive disease–free survival and the best hazard ratio we have seen in the curative [HER2-positive] setting since the original adjuvant trastuzumab studies,” said Dr. Hurvitz. “Although the data are only applicable to those patients who had residual disease after standard neoadjuvant therapy, the benefit was seen regardless of hormone receptor status.” In the KATHERINE trial, the risk of recurrence of invasive breast cancer or death was 50% lower with adjuvant T-DM1 than with trastuzumab alone among patients with stage I to III HER2-positive breast cancer who had residual invasive disease in the breast or axilla after completion of neoadjuvant taxane and trastuzumab-based treatment (hazard ratio = 0.50; 95% confidence interval = 0.39–0.64; P < .0001).4
The rate of adverse events with T-DM1 is higher than with trastuzumab; in the KATHERINE trial, grade 3 or higher adverse events were reported in 25.7% of patients treated with T-DM1 compared with 15.4% in the trastuzumab arm.4 The most common adverse events include fatigue, nausea, increased aspartate aminotransferase levels, and headache.16 If patients have disease recurrence or unmanageable toxicity with T-DM1, then trastuzumab with or without pertuzumab should be given to complete 1 year of HER2-directed therapy.7,8
Despite the significant benefits of HER2-targeted therapies, cardiotoxicity associated with their use poses challenges for both clinicians and patients. There is a four- to sixfold increase in the incidence of symptomatic myocardial dysfunction among patients receiving trastuzumab as a single agent or in combination therapy compared with those not receiving trastuzumab.9
Data from large adjuvant trastuzumab trials suggest that the proportion of patients who suffer asymptomatic declines in left ventricular ejection fraction during or after trastuzumab therapy in the curative-intent setting ranges from 4.1% to 30.1%, but rates of symptomatic congestive heart failure are more infrequent—as low as 0.4% if a nonanthracycline-based regimen is used.6,17 Although data are limited on pertuzumab and T-DM1, it is suggested that these agents may be less cardiotoxic than trastuzumab.17
An irreversible pan-HER tyrosine kinase inhibitor, neratinib is the most recent novel agent approved for adjuvant treatment of early-stage breast cancer. In the phase III ExteNET trial, 1 year of treatment with neratinib (initiated within 1 year of completing trastuzumab-based adjuvant therapy) significantly reduced the risk of invasive and distant disease recurrence in patients with stage II–III, HER2-positive, hormone receptor–positive breast cancer.18 Neratinib also achieved a numerical overall survival benefit: the estimated 8-year overall survival rates were 91.5% in the neratinib group and 89.4% in the placebo group of the hormone receptor–positive population who initiated neratinib within 1 year of completing trastuzumab, translating to an absolute between-group difference of 2.1%.19
The benefit of neratinib therapy extended to patients who did not achieve a pathologic complete response after neoadjuvant therapy. The absolute benefit of neratinib in this setting was a 7.4% improvement in 5-year invasive disease–free survival and a significant absolute benefit of 9.1% in 8-year overall survival (P = .031).19,20 Neratinib also appears to decrease the risk of central nervous system (CNS) recurrence; at 5 years, the cumulative incidence of CNS recurrence was significantly lower in the neratinib group compared with placebo (0.7% vs 2.1%).19
Subgroup analyses revealed that patients with hormone receptor–positive disease derived greater benefit with neratinib than did patients with hormone receptor–negative disease, possibly due to the “effective inhibition of cross-talk” between HER2 and estrogen receptors.19,18 The benefit of neratinib was also significantly more pronounced in patients who initiated treatment within 1 year of completing trastuzumab compared with those who started treatment later, emphasizing the value of starting therapy promptly after completion of trastuzumab.18,20
“We do know adjuvant neratinib is particularly beneficial in hormone receptor–positive, HER2-positive breast cancer, but the added benefit of neratinib in patients who received newer HER2-targeted agents has not been demonstrated yet,” said Dr. Hurvitz. She explained that patients enrolled in ExteNET had not received prior pertuzumab or T-DM1, a concern echoed in a retrospective analysis of neratinib use in a Colorado health system.21 “For patients with very high-risk disease—such as stage III, multiple nodes involved, residual disease—who have already received trastuzumab plus pertuzumab and T-DM1, neratinib should be considered, especially given its potential neuroprotective features, but at this point it is not a data-driven choice.”
Patients who received 12 months of neratinib had significantly improved rates of invasive disease–free survival compared with patients who discontinued within 3 months of initiating neratinib,22 a finding that underscored the importance of proactively managing neratinib-related diarrhea to prevent early discontinuation of therapy.
Diarrhea is the most commonly reported adverse event and dose-limiting toxicity associated with neratinib and is prevalent in the absence of antidiarrheal strategies and proactive management.18,23 In the ExteNET trial, where antidiarrheal therapy was reactive instead of prophylactic, grade 3 diarrhea was observed in 40% of patients and 17% discontinued treatment due to diarrhea.18 Neratinib-related diarrhea may be multifactorial, involving inflammation, bile acid malabsorption, and possibly secretory mechanisms.24 Most diarrhea events occur soon after the initiation of treatment; the median onset of grade ≥ 3 diarrhea is 8 days.18 “Clinical trials show that prophylaxis reduces the rate of diarrhea, so it should be the standard of care,” said Dr. Hurvitz.
The CONTROL trial found that preemptive prophylaxis and dose escalation reduced the rate, severity, and duration of grade 3 diarrhea compared with ExteNET (Table 1).25 Several antidiarrheal strategies used in the first one to two cycles lowered diarrhea-related discontinuations and dose reductions. “The strategies that seem to work best are colestipol plus loperamide and dose escalation,” explained Dr. Hurvitz, who was involved in the phase II trial. The study authors noted that neratinib dose escalation is a “particularly promising strategy” because it significantly reduced rates of diarrhea-related discontinuation while also eliminating mandatory prophylaxis and related side-effects.25
Endocrine therapy is a critical part of adjuvant therapy in women with hormone receptor–positive breast cancer and has been shown to reduce the risk of recurrence and death. The individualization of endocrine therapy depends on multiple factors, including menopausal status, risk of recurrence, and side effect profile.
Premenopausal women have the option of:
In general, higher-risk patients should receive ovarian suppression in addition to adjuvant endocrine therapy, whereas lower-risk patients, including women with stage I breast cancers not warranting chemotherapy and those with node-negative cancers 1 cm or less, should not. Based on the results of the Suppression of Ovarian Function Trial (SOFT)27 and Tamoxifen and Exemestane Trial (TEXT)28 trials, NCCN added ovarian suppression plus an aromatase inhibitor for 5 years as an adjuvant endocrine therapy option for premenopausal women with hormone receptor–positive breast cancer at a higher risk of recurrence. High-risk patients include those at a young age, with high-grade tumors, and/or with lymph-node involvement.8
After 5 years of endocrine therapy, women who have become postmenopausal in the interim should consider extended therapy with an aromatase inhibitor for up to 5 years, while women who are still premenopausal can consider continuing tamoxifen for a total of 10 years of tamoxifen therapy.
Postmenopausal women have the option of:
Hormone receptor–positive breast cancers carry a substantial risk of late recurrence despite 5 years of adjuvant endocrine therapy.29,30 Multiple strategies of treatment extended beyond 5 years have been shown to reduce recurrence risk and offer an additional benefit in reduction of the risk of contralateral breast cancer.30 Several studies have established that postmenopausal women at greater risk of recurrence—those with high-risk prognostic factors, such as nodal involvement and larger tumors—are more likely to realize substantial clinical benefits from treatment and thus should receive extended endocrine therapy up to a total of 10 years of treatment. “For a patient with high-risk disease with nodal involvement, it is very reasonable to discuss extended endocrine therapy,” explained Dr. Hurvitz. Conversely, women with a lower risk of late recurrence, typically stage I disease with lower-risk features, may reasonably stop therapy after 5 years unless there is strong motivation for prevention of late recurrence or contralateral breast cancers.29
Despite the potential for risk reduction, extended-duration endocrine therapy is associated with ongoing adverse events, such as menopausal symptoms and arthropathy, that may affect quality of life or increase the risk of other health problems.31–33 Additionally, much less common—but potentially life-threatening—side effects of adjuvant endocrine therapy include pulmonary embolus and endometrial cancer associated with tamoxifen and osteoporotic fracture associated with aromatase inhibitors. The cumulative risk of these toxic events increases with longer treatment.8
With the addition of novel HER2-targeted agents in HER2-positive, hormone receptor–positive breast cancer, the range of treatment options with notable benefits has expanded. Dr. Hurvitz expressed optimism for the future direction of early HER2-positive, hormone receptor–positive breast cancer. “We are seeing more and more patients without disease recurrence,” she said. Risk stratification may be central to further improving outcomes. “Accurately distinguishing patients at high risk for metastatic recurrence from those who are not is the key. Work is still needed to establish who needs more therapy and who can get away with less,” Dr. Hurvitz concluded.
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