Dr. Gradishar reviewed the data related to the potential risks/benefits of using anti-HER2 therapy for patients with small breast tumors (<1 cm), for which existing evidence is uncertain and randomized clinical trial data are not available.
Potential benefits of anti-HER2 therapy for breast tumors less than 1 cm in size should be evaluated in the context of available outcomes data. Variable risk of recurrence rates have been observed among patients with HER2-positive, T1a,bN0M0 breast tumors who have not received treatment, according to a number of registry data sets (77%-99% 5-year relapse-free survival [RFS], disease-free survival [DFS], or distant-relapse-free survival).1-3 Data from a prospective cohort study within the National Comprehensive Cancer Network (NCCN) Database indicate 5-year relapse rates for patients with untreated T1a tumors of 2% to 7% and for untreated T1b tumors of 4% to 10%.4
Experts feel that there is a potential benefit to giving anti-HER2 therapy to patients with small breast tumors. Current NCCN guidelines for HER2-positive disease recommend5:
Results from a meta-analysis of randomized adjuvant trastuzumab trials (FinHER, PACS-04, NSABP B31, N9831, and HERA) support the use of trastuzumab for tumors 2 cm or less, regardless of hormone receptor status.6 However, application of these data to tumors less than 1 cm is limited by the fact that a very small number of patients within these trials were T1a or T1b; nearly all had T1c disease and positive axillary lymph nodes. In a phase II, single-arm trial of 3 months of paclitaxel/trastuzumab followed by 9-months of trastuzumab monotherapy (N = 406), 99% 3-year DFS was observed for patients with HER2-positive breast tumors 3 cm or less in size (T1a, 19%; T1b, 31%; T1c 42%; T2, 9%).7 Notably, very low rates of cardiac problems were reported in this trial (symptomatic congestive heart failure, <1%; asymptomatic decline in left ventricular ejection fraction, 3%). Looking forward, enrollment is under way for the phase II ATEMPT trial, which will randomize patients with stage 1 disease to trastuzumab-DM1 versus paclitaxel/trastuzumab followed by trastuzumab.8
In conclusion, Dr. Gradishar noted the variable outcomes among patients with small, HER2-positive tumors across data sets, with some populations experiencing significant risk of recurrence. He emphasized the need to individualize treatment decisions and commented on the limited data available for T1a tumors. Based on available data, he would consider discussing HER2-directed therapy for most patients with T1b or greater disease.
The multidisciplinary Miami Breast Cancer Conference® has been bringing together surgical, medical, and radiation oncologists for 32 years, with the aim of fostering awareness of the state-of-the-art treatments in each therapeutic area and encouraging cross-team cooperation in the clinic. This second of 3 PER Pulse™ Recaps that is focused on the 32nd Annual Miami Breast Cancer Conference® examines adjuvant endocrine therapy for premenopausal women with hormone receptor (HR)-positive breast cancer, as discussed by Dr. Hope Rugo.
After reviewing established and emerging data on adjuvant therapy for premenopausal women with early-stage, HR-positive breast cancer, Dr. Rugo proposed a new algorithm for therapeutic selection in this setting, based largely on data from the SOFT, TEXT, and ABCSG-12 trials.1-3
Low-risk disease: ≥5 years of tamoxifen
In the SOFT/TEXT analyses, 5-year breast cancer-free interval (BCFI) rates of approximately 97% were reported among women with low-risk clinicopathologic features (ie, smaller tumors, node-negative, grade 1, age ≥40 years) who did not receive chemotherapy.
Intermediate-risk disease: Chemotherapy, followed by ovarian function suppression (OFS) plus tamoxifen or exemestane, or OFS plus endocrine therapy.
There is some evidence suggesting that a subgroup of women with intermediate-risk disease (low-grade disease with larger tumor or low-grade, node-positive disease) benefit as much from OFS and exemestane or tamoxifen as they do from chemotherapy. More guidance on how to treat these patients will come from the TAILORx, RxPONDER (S1007), and MINDACT trials.4-6
High-risk disease: Chemotherapy should be given to women with high-risk disease (larger tumor, node-positive, grade 3, age <35 years), followed by OFS plus exemestane or tamoxifen.
Data from the SOFT/TEXT trials suggest that OFS plus tamoxifen or exemestane is superior to tamoxifen monotherapy (particularly in women age <35 years) for high-risk disease (absolute improvement in 5-year BFCI vs tamoxifen: OFS plus exemestane, 16%; OFS plus tamoxifen, 11%). Moreover, OFS plus exemestane is superior to OFS plus tamoxifen in terms of 5-year breast cancer-free interval (BCFI) and distant recurrence-free interval (DFCI).
Dr. Rugo noted that the follow-up for DFCI and overall survival from the SOFT and TEXT trials are relatively short at 5 years and with about 50% of clinical events reported. Clinical management will be aided by longer follow-up data. Additionally, accrual for these trials was conducted prior to the widespread clinical implementation of genomic testing.
Dr. Rugo emphasized the importance of individualizing treatment planning, with particular consideration and management of toxicity during decision making. In the SOFT trial, 22% of patients discontinued OFS therapy by 3 years; however, she noted, these patients still derived benefit. Depression and menopausal symptoms are the most marked symptoms of OFS therapy. Younger women are most likely to experience toxicity from endocrine therapy. Offering young women endocrine therapy immediately after chemotherapy, before ovarian function is restored, is generally more tolerable than initiating OFS after ovarian function has resumed post-chemotherapy.
The multidisciplinary Miami Breast Cancer Conference® has been bringing together surgical, medical, and radiation oncologists for 32 years, with the aim of fostering awareness of the state-of-the-art treatments in each therapeutic area and encouraging cross-team cooperation in the clinic. This third of 3 PER Pulse™ Recaps that is focused on the 32nd Annual Miami Breast Cancer Conference® examines sequencing of adjuvant therapies for advanced HER2-positive breast cancer, as discussed by Dr. Mark Pegram.
Dr. Mark Pegram summarized regimens currently preferred for HER2-positive metastatic breast cancer (MBC):
These recommendations are based primarily on results from the phase III CLEOPATRA,3 EMILIA,4 and MARIANNE trials.5 Dr. Pegram noted that, as always, therapeutic selection and management must be individualized. Other regimens should be considered and discussed as needed.
The benefits of dual anti-HER2 blockade with trastuzumab and pertuzumab were demonstrated in the phase III CLEOPATRA trial of trastuzumab/placebo/docetaxel or trastuzumab/pertuzumab/docetaxel for HER2-positive MBC, and established pertuzumab-based regimens as the leading choice for MBC in the front line.1,2
The pivotal EMILIA trial randomized patients with locally advanced breast cancer (LABC) or MBC to salvage therapy with T-DM1 or capecitabine plus lapatinib.4 The co-primary endpoints of progression-free survival (PFS) and overall survival were both met, and T-DM1 was clearly less toxic than capecitabine plus lapatinib. These results led to FDA approval of this regimen for patients with advanced breast cancer who had received trastuzumab and taxane therapy.6
The phase III MARIANNE trial was initiated to build on results from a phase II randomized trial, which favored T-DM1 over trastuzumab plus docetaxel (PFS: 14.2 mo vs 9.2 mo; HR = 0.59; 95% CI, 0.36-0.97; P <.035), and evaluate efficacy of first-line T-DM1 for advanced HER2-positive breast cancer.7,8 MARIANNE randomized 1095 patients to trastuzumab plus taxane, T-DM1 plus pertuzumab, or T-DM1 plus placebo. Top-line data indicate that the trial met its noninferiority endpoint, with similar PFS across the 3 trial arms. Adverse events (AEs) observed in the 2 experimental arms were consistent with previous studies of T-DM1 and/or pertuzumab.5,9
Although T-DM1 is less toxic than cytotoxic-chemotherapy–based regimens, it is associated with thrombocytopenia, minor bleeding, and transaminase elevation. Patients should be monitored for these AEs, which can be mitigated with standardized dose modifications. Nodular regenerative hyperplasia is a very rare AE that is associated with portal hypertension, and requires discontinuation of T-DM1.10
Finally, Dr. Pegram reviewed potential regimens for use beyond a CLEOPATRA-like regimen and/or T-DM1 as first- and second-line treatments. Namely, he mentioned lapatinib-based regimens, endocrine therapy (for the nearly 50% of patients with HR–positive, HER2-positive disease), or enrollment in a clinical trial.1,2