The 40th Annual San Antonio Breast Cancer Symposium

Presenters at the recent San Antonio Breast Cancer Symposium (SABCS; December 5–9, 2017) reported the latest findings in breast cancer research. NEJM Journal Watch Oncology and Hematology Editor-in-Chief Dr. William Gradishar was on hand to summarize results of the key studies. For more information on the meeting, please visit the SABCS website, and for access to the abstracts, please visit the abstracts portal.

Ribociclib for ER-Positive Metastatic Breast Cancer

Given that almost 20% of breast cancers are diagnosed in women 49 years of age and younger, expanding treatment options for this age group is a major objective. To that end, Tripathy and colleagues conducted a randomized, double-blind, phase III trial (MONALEESA-7 trial) to assess the benefit of the CDK4/6 inhibitor ribociclib in 672 pre- and perimenopausal menopausal women (mean age, ~44 years) with ER-positive, HER2-negative advanced breast cancer (40% with de novo metastatic disease). Patients had not received any prior endocrine therapy for advanced disease and were given endocrine therapy (tamoxifen or an aromatase inhibitor) with the GnRH agonist goserelin plus either ribociclib or placebo.

At a median of 19.2 months, progression-free survival (PFS; the primary endpoint) was significantly longer with ribociclib than with placebo (23.8 vs. 13.0 months), regardless of whether patients received tamoxifen or an aromatase inhibitor. The overall response rate and clinical benefit rate also favored ribociclib. The adverse events associated with ribociclib were largely hematologic and similar to those observed in other trials of CDK4/6 inhibitors. These data support the use of ribociclib with endocrine therapy in patients with ER-positive, metastatic disease.

Adjuvant Trastuzumab for HER2-Negative Breast Cancer

The potential benefit of adjuvant trastuzumab in patients with HER2-poor disease has been debated for years, ever since data from large pivotal adjuvant trials of trastuzumab suggested it might improve clinical outcomes.

To examine this issue further, Joensuu and colleagues conducted an international, randomized, phase III study (SOLD) involving 2176 patients with confirmed node-negative or node-positive HER2-positive early-stage breast cancer. Patients received initial chemotherapy with docetaxel plus trastuzumab followed by fluorouracil, epirubicin, and cyclophosphamide, after which they received trastuzumab for 1 year or no trastuzumab.

At median follow-up of 5.2 years, disease-free survival (DFS; the primary endpoint) and overall survival (OS) were identical with or without adjuvant trastuzumab. The benefit of adjuvant trastuzumab found previously in HER2-low patients in two major retrospective trials, which used local testing for eligibility, are not readily explained and not confirmed in this study.

Duration of Adjuvant Endocrine Therapy for ER-Positive, Early Breast Cancer

The duration of extended adjuvant endocrine therapy for ER-positive breast cancer has been the subject of many trials in recent years. The prior ATLAS trial (NEJM JW Oncol Hematol Jan 2013, and Lancet 2013; 381:805) and the aTTom trial (J Clin Oncol 2013; 31 suppl 5:5), identified a clinical benefit to extending tamoxifen therapy for these patients that manifested itself beyond 10 years. These data suggested that, particularly for higher-risk patients, durations of tamoxifen to 10 years should be considered.

Another issue that has recently been addressed by a series of clinical trials is whether durations of adjuvant aromatase inhibitor (AI) therapy beyond 5 years offers any significant improvement in outcome in postmenopausal women. The MA.17R trial (N Engl J Med 2016; 375:209) was an extension of the MA.17 trial (J Clin Oncol 2008; 26:1948), which showed that 5 years of AI therapy following 5 years of tamoxifen therapy was associated with fewer recurrences than 5 years of tamoxifen therapy only. Most of the benefit appeared to be associated with a decrease in new breast cancers (a prevention effect).

Three additional trials addressing the duration of adjuvant AI therapy were presented at the prior 2016 San Antonio Breast Cancer Symposium, and all came to a similar conclusion: Longer durations of adjuvant AI therapy were not associated with a significant improvement in DFS. One of the consequences of longer durations of AI therapy is the potential for more adverse events such as bone health issues, including loss of bone density and increase in fractures. Additionally, only patients who were symptomatically tolerating AI therapy (with minimal arthralgias) were likely to consider longer durations of AI therapy beyond 5 years, and even with the best-intentioned patients, compliance and adherence has been shown to decline as the duration of therapy is prolonged.

The most recent addition to the body of evidence evaluating the duration of adjuvant AI therapy is the prospective, multicenter, randomized, phase III trial by Gnant and colleagues (ABCSG-16), which involve 3484 postmenopausal patients with ER-positive breast cancer who had received 4 to 6 years of endocrine therapy. Patients were randomized to an additional 2 or 5 years of anastrozole.

After a median follow-up of more than 9 years, DFS and OS were each similar between patients receiving 2 or 5 years of anastrozole. No subset of patients, based on clinical or pathologic features, benefited with longer duration of anastrozole. As observed in prior trials evaluating longer durations of treatment with an AI, the ABCSG-16 trial identified an increase fracture rate with longer duration therapy. But, unlike in other trials, no noticeable reduction in contralateral breast cancer was found.

Preserving Fertility in Early Breast Cancer

Ovarian suppression has been evaluated as both a component of adjuvant treatment for early-stage breast cancer as well as means to preserve ovarian function for patients undergoing chemotherapy who may wish to get pregnant in the future.

Lambertini and colleagues conducted a pooled analysis of five randomized trials evaluating the use of temporary ovarian suppression with gonadotropin-releasing hormone analogs to preserve ovarian function and fertility in premenopausal patients with early-stage disease. The primary endpoints were rates of primary ovarian insufficiency and posttreatment pregnancy rate; secondary endpoints were amenorrhea rates at 1 and 2 years, DFS, and OS.

Patients who received ovarian suppression, compared with those who did not, had a lower premature-ovarian suppression rate (14.1% vs. 30.9%) and a higher posttreatment pregnancy rate (10.3% vs. 5.5%). DFS and OS were each similar between treatment groups; the primary amenorrhea rates were also similar between groups at 1 year but were lower at 2 years in patients receiving ovarian suppression.

Although there were differences between the trials included in the analysis, these data support consideration of ovarian suppression as a means to decrease the risk for premature ovarian insufficiency and to potentially increase the rate of posttreatment pregnancy, without compromising overall outcome.

Talazoparib for Advanced BRCA-mutated Breast Cancer

The OlympiAD trial (NEJM JW Oncol Hematol Oct 2017, and N Engl J Med 2017; 377:523) demonstrated activity of the PARP inhibitor olaparib in patients with BRCA-associated, metastatic breast cancer patients.

Now, Litton and colleagues have conducted a randomized, open-label, phase III trial (EMBRACA) to evaluate another PARP inhibitor, talazoparib, in 431 patients with HER2-negative, advanced breast cancer and a BRCA1 or BRCA2 germline mutation. Approximately 45% of patients had triple-negative breast cancer, and 55% had ER-positive disease; 60% of patients had received 1 or more prior cytotoxic regimens for metastatic disease. Patients were randomized 2:1 to receive talazoparib or treatment of physician's choice (TPC) with capecitabine, eribulin, gemcitabine, or vinorelbine.

Median PFS was improved with talazoparib versus TPC (8.6 vs. 5.6 months; P<0.0001), as were objective response rate (63% vs. 27%), quality-of-life measures, and time to clinically meaningful deterioration. Talazoparib was well tolerated, and few patients discontinued therapy.