Haematology+Oncology_News

8 CONFERENCE COVERAGE

H aematology & O ncology N ews • Vol. 9 • No. 1 • 2016

BRCA mutation predicts neoadjuvant therapy benefit but is not strongly prognostic

San Antonio Breast Cancer Symposium 2015 8–12 December 2015 • San Antonio, Texas The 38th Annual San Antonio important clinical information, including notable results in trials of adjuvant and neoadjuvant therapies, promising advances in immune therapies, and new findings on predictive factors such as circulating free DNA and tumour cells. Go to www.practiceupdate.com for more reports from SABCS. Breast Cancer Symposium presented clinicians with

be somewhat weaker in patients with a BRCAmutation, compared to wild- type patients, but you have to keep in mind the test for interaction in this ex- ploratory analysis was not significant,” Dr Fasching commented. The investigators also performed exploratory analyses looking at the impact of achieving a pCR in each treatment arm. As far as a rationale, hypoxia is known to cause DNA damage, and synthetic lethality has been described in BRCA mutation carri- ers, Dr Fasching explained. “There are some data that show that angio- genic factors are as a matter of fact increased in tumours with a BRCA mutation, compared to wild-type patients,” he added.

extend the exploratory analysis to that subpoint.” Giving some background to the analysis, he commented, “Neoadju- vant studies may serve as a very good research ground to look for answers to both questions: whether BRCA mutation status predicts response to a chemotherapy and, furthermore, whether this translates into a prog- nostic effect.” All patients with triple-negative disease in the GeparQuinto ran- domised phase III trial received neo- adjuvant chemotherapy (epirubicin, cyclophosphamide, and docetaxel), with or without the antiangiogenic antibody bevacizumab. Additional findings showed that among BRCA mutation carriers, a pCR was not significantly associated with better disease-free survival. In contrast, among patients with wild- type genes, it was associated with a sharply reduced risk of events (HR, 0.21; P < 0.0001). However, the inter- action was not statistically significant. “The prognostic information of pCR with regard to prognosis appeared to

30.8% in those with wild-type genes (P = 0.001). The patients with a mutation also had better disease-free survival than their wild-type peers (hazard ratio, 0.64), but this difference missed statistical significance (P = 0.06). “BRCA mutation carriers had a significantly higher pathologic complete response rate after neo- adjuvant chemotherapy,” com- mented Dr Fasching, an oncologist the University Hospital Erlangen (Germany), Comprehensive Can- cer Centre Erlangen-EMN. “And BRCA mutation carriers had a better prognosis.” Attendee Dr George Somlo of City of Hope, Duarte, California, wondered if surgical management played a role in the findings. “Can you clarify…whether mastectomies on the ipsilateral side or contralateral side had any effect on the disease- free survival, since I assume once the mutations were known, other in- terventions might have taken place?” “Unfortunately, I cannot,” Dr Fasching replied. “We did not

BY SUSAN LONDON Frontline Medical News

I n patients with triple-negative breast cancer, the presence of a mutation in the breast cancer susceptibility genes BRCA1 and BRCA2 appears helpful for iden- tifying those who will benefit from neoadjuvant chemotherapy but not very helpful for estimating progno- sis, finds a subgroup analysis from the GeparQuinto trial. Dr Peter A. Fasching and col- leagues studied 471 patients with triple-negative disease who were treated with neoadjuvant therapy in the trial, underwent surgery, and did not receive any postoperative therapy. Prospectively specified genome- wide association studies showed that 17.4% of the patients had a BRCA1/2 mutation, he reported at the San Antonio Breast Cancer Symposium. The rate of pathologic complete response (pCR), defined as ypT0/ ypN0 stage, was 50% in the patients with a mutation, compared with

Results here showed that ad- dition of bevacizumab improved pCR rate among both BRCA1/2 mutation carriers (65.7% vs 38.3%, P = 0.025) and patients with wild- type (35.8% vs 26.2%, P =  0.048). But addition of bevacizumab did not significantly improve disease- free survival in either group. T-DM1 trial points way to de-escalation of breast cancer therapy

not postmenopausal women. “Single-agent T-DM1 therapy warrants fur- ther evaluation in early breast cancer, not just because of the efficacy, which I think is very impressive, but also because of the favourable safety profile,” she said. Mild to moderate constipation, thrombocy- topenia, dry mouth, fatigue, arthralgia, head- ache, and hot flushes were roughly twice as common in the combined T-DMI and T-DMI plus endocrine therapy arms, compared with the trastuzumab plus endocrine therapy arm. But the only grade 3 adverse event that was more frequent in the two T-DMI study arms was an elevation in liver enzymes, which oc- curred in 4.1% of those patients and none on trastuzumab and endocrine therapy. WSG-ADAPT is actually an umbrella trial that to date has enrolled about 4000 patients. An important goal of ADAPT is to identify and validate useful early biomarkers of clinical re- sponse. WSG-ADAPT HER2+/HR+ assessed

3.6 mg/kg every 3 weeks, 41.5% with T-DM1 plus endocrine therapy, and just 15.1% with tamoxifen plus endocrine therapy. Adding in those patients with a near-pCR – that is, patients who were ypT1a, with very little remaining tumour burden of dubious clinical significance – the results looked even stronger: a pCR/near-pCR rate of 53% with neoadjuvant T-DM1 alone and 52.9% with T-DM1 and en- docrine therapy, versus 19.3%with trastuzumab plus endocrine therapy, Dr Harbeck said at the San Antonio Breast Cancer Symposium. Thus, adding endocrine therapy to T-DM1 didn’t improve upon the effectiveness of T-DM1 alone in this updated and final WSG- ADAPT analysis. That’s an important differ- ence from an earlier 130-patient prespecified interim analysis Dr Harbeck presented at the 2015 ASCO meeting. At that point it seemed – incorrectly, as it turned out – that concurrent endocrine therapy and T-DM1 provided added benefit in premenopausal but

two: a drop in Ki67 of 30% or greater or low cellularity as defined by fewer than 500 tumour cells in the biopsy taken at the 3-week point in neoadjuvant therapy, after one cycle of treat- ment had been completed. Patients with either marker of early response proved to be 2.2-fold more likely to have a pCR than women in whom the early biomarkers were absent. Dr Harbeck argued that the ADAPT find- ings make a cogent case for changing the current standard of care in treating HER2+ early breast cancer, which is chemotherapy plus anti-HER2 therapy regardless of the ma- lignancy’s hormone receptor status. “We don’t adjust for hormone receptor status in our standard treatment today, even though we know hormone receptor-positive disease is a distinct entity,” she said. The study was sponsored by Roche. The pre- senter serves as a consultant to Roche, Celgene, and Genomic Health.

BY BRUCE JANCIN Frontline Medical News

T welve weeks of trastuzumab emtasine as single-agent neoadjuvant therapy in HER2-positive/hormone receptor-positive early-stage breast cancer achieved a pathologic complete response rate of 41%, underscoring the feasibility of therapeutic de-escalation in that pa- tient subgroup, according to Dr Nadia Harbeck. Dr Harbeck, head of the breast centre at the Technical University of Munich, presented the final analysis of the phase II, 376-pa- tient WSG-ADAPT HER2+/HR+ (Women’s Healthcare Study Group – Adjuvant Dynamic Marker – Adjusted Personalised Therapy HER2+/HR+ trial). The primary finding: The pathologic complete response (pCR) rate in the breast and lymph nodes after 12 weeks of neoadjuvant therapy with no systemic chemo- therapy in this three-armed trial was 41% with trastuzumab emtasine (T-DM1) alone at

© SABCS/Todd Buchanan 2015