Neoadjuvant and Adjuvant Therapy for Locoregional Disease
Case Patient 1
A 56-year-old woman undergoes ultrasound-guided biopsy of a self-palpated breast lump. Pathology shows invasive ductal carcinoma that is ER-positive, PR-negative, and HER2 equivocal by IHC (2+ staining). Follow-up FISH testing shows a HER2/CEP17 ratio of 2.5. The tumor is estimated to be 2 cm in diameter by imaging and exam with no clinically palpable axillary lymphadenopathy. The patient exhibits no constitutional or localized symptoms concerning for metastases.
- What is the recommended management approach for this patient?
According to the ASCO/CAP guidelines, this patient’s tumor qualifies as HER2-positive based upon testing results showing amplification of the gene. This result has important implications for management since nearly all patients with macroscopically invasive HER2-positive tumors should be considered for adjuvant chemotherapy in combination with anti-HER2 therapy. The patient should proceed with upfront tumor resection and sentinel lymph node biopsy. Systemic staging imaging (ie, computed tomography [CT] or bone scan) is not indicated in early stage breast cancer.12,13 Systemic staging scans are indicated when (1) any anatomical stage III disease is suspected (eg, with involvement of the skin or chest wall, the presence of enlarged matted or fixed axillary lymph nodes, and involvement of nodal stations other than in the axilla), and (2) when symptoms or abnormal laboratory values raise suspicion for distant metastases (eg, unexplained bone pain, unintentional weight loss, elevated serum alkaline phosphatase, and transaminitis).
Case 1 Continued
The patient presents to discuss treatment options after undergoing a lumpectomy and sentinel node biopsy procedure. The pathology report notes a single focus of carcinoma measuring 2 cm with negative sentinel lymph nodes.
- What agents are used for adjuvant therapy in HER2-postive breast cancer?
Nearly all patients with macroscopically invasive (> 1 mm) breast carcinoma should be considered for adjuvant therapy using a regimen that contains a taxane and trastuzumab. However, the benefit may be small for patients with tumors ≤ 5 mm (T1a, N0), so it is important to carefully weigh the risk against the benefit. Among the agents that targeting HER2, only trastuzumab has been shown to improve overall survival (OS) in the adjuvant setting; long-term follow-up data are awaited for other agents.8 A trastuzumab biosimilar, trastuzumab-dkst, was recently approved by the US Food and Drug Administration (FDA) for the same indications as trastuzumab.14 The regimens most commonly used in the adjuvant and neoadjuvant settings for nonmetastatic breast cancer are summarized in Table 2.
Patients with small (≤ 3 cm), node-negative tumors can generally be considered for a reduced-intensity regimen that includes weekly paclitaxel plus trastuzumab. This combination proved efficacious in a single-group, multicenter study that enrolled 406 patients.15 Paclitaxel and trastuzumab were given once weekly for 12 weeks, followed by trastuzumab, either weekly or every 3 weeks, to complete 1 year of therapy.After a median follow-up of more than 6 years, the rates of distant and locoregional recurrence were 1% and 1.2%, respectively.16
A combination of docetaxel, carboplatin, and trastuzumab is a nonanthracycline regimen that is also appropriate in this setting, based on the results of the Breast Cancer International Research Group 006 (BCIRG-006) trial.17 This phase 3 randomized trial enrolled 3222 women with HER2-positive, invasive, high-risk adenocarcinoma. Eligible patients had a T1–3 tumor and either lymph node–negative or –positive disease and were randomly assigned to receive 1 of 3 regimens: group 1 received doxorubicin and cyclophosphamide every 3 weeks for 4 cycles followed by docetaxel every 3 weeks for 4 cycles (AC-T); group 2 received the AC-T regimen in combination with trastuzumab; and group 3 received docetaxel, carboplatin, and trastuzumab once every 3 weeks for 6 cycles (TCH). Groups 2 and 3 also received trastuzumab for an additional 34 weeks to complete 1 year of therapy. Trastuzumab-containing regimens were found to offer superior disease-free survival (DFS) and OS. When comparing the 2 trastuzumab arms after more than 10 years of follow-up, no statistically significant advantage of an anthracycline regimen over a nonanthracycline regimen was found.18 Furthermore, the anthracycline arm had a fivefold higher incidence of symptomatic congestive heart failure (grades 3 and 4), and the nonanthracycline regimen was associated with a lower incidence of treatment-related leukemia, a clinically significant finding despite not reaching statistical significance due to low overall numbers.
BCIRG-006, NSABP B-31, NCCTG N9831, and HERA are all large randomized trials with consistent results confirming trastuzumab’s role in reducing recurrence and improving survival in HER2-positive breast cancer in the adjuvant settings. The estimated overall benefit from addition of this agent was a 34% to 41% improvement in survival and a 33% to 52% improvement in DFS.8,17–20
Dual anti-HER2 therapy containing both trastuzumab and pertuzumab should be strongly considered for patients with macroscopic lymph node involvement based on the results of the APHINITY trial.21 In this study, the addition of pertuzumab to standard trastuzumab-based therapy led to a significant improvement in invasive-disease-free survival at 3 years. In subgroup analysis, the benefit was restricted to the node-positive group (3-year invasive-disease-free survival rates of 92% in the pertuzumab group versus 90.2% in the placebo group, P = 0.02). Patients with hormone receptor–negative disease derived greater benefit from the addition of pertuzumab. Regimens used in the APHINITY trial included the anti-HER2 agents trastuzumab and pertuzumab in combination with 1 of the following chemotherapy regimens: sequential cyclophosphamide plus either doxorubicin or epirubicin, followed by either 4 cycles of docetaxel or 12 weekly doses of paclitaxel; sequential fluorouracil plus either epirubicin or doxorubicin plus cyclophosphamide (3 or 4 cycles), followed by 3 or 4 cycles of docetaxel or 12 weekly cycles of paclitaxel; or 6 cycles of concurrent docetaxel plus carboplatin.
One-year therapy with neratinib, an oral tyrosine kinase inhibitor of HER2, is now approved by the FDA after completion of trastuzumab in the adjuvant setting, based on the results of the ExteNET trial.22 In this study, patients who had completed trastuzumab within the preceding 12 months, without evidence of recurrence, were randomly assigned to receive either oral neratinib or placebo daily for 1 year. The 2-year DFS rate was 93.9% and 91.6% for the neratinib and placebo groups, respectively. The most common adverse effect of neratinib was diarrhea, with approximately 40% of patients experiencing grade 3 diarrhea. In subgroup analyses, hormone receptor–positive patients derived the most benefit, while hormone receptor–negative patients derived no or marginal benefit.22 OS benefit has not yet been established.23
Trastuzumab therapy (with pertuzumab if indicated) should be offered for an optimal duration of 12 months (17 cycles, including those given with chemotherapy backbone). A shorter duration of therapy, 6 months, has been shown to be inferior,24 while a longer duration, 24 months, has been shown to provide no additional benefit.25
Finally, sequential addition of anti-estrogen endocrine therapy is indicated for hormone-positive tumors. Endocrine therapy is usually added after completion of the chemotherapy backbone of the regimen, but may be given concurrently with anti-HER2 therapy. If radiation is being administered, endocrine therapy can be given concurrently or started after radiation therapy is completed.