Clinical trial results presented at the American Society of Clinical Oncology’s (ASCO) annual meeting, held virtually this year, highlighted advances in precision medicine for both early- and advanced-stage breast cancers.
The most impactful study reported at the ASCO meeting was the phase III OlympiA trial, which tested the addition of PARP inhibitor olaparib (Lynparza®) versus a placebo, following standard therapy for early-stage, HER2-negative breast cancer in patients with an inherited mutation in the BRCA1 or BRCA2 genes. Olaparib was previously approved to treat metastatic HER2-negative breast cancer in this population in 2017 based on results of the OlympiAD study conducted by several BCRF investigators.
After a median follow-up of two and a half years, the OlympiA study investigators reported that patients receiving olaparib had a 42 percent reduction in local recurrence, metastatic recurrence, and death when compared to the placebo. The first report on overall survival will occur after 10 years of follow-up.
“These finding are extremely exciting and impactful,” BCRF investigator Dr. Nadine Tung noted when commenting on the study at the meeting. “One of the key challenges is going to be identifying patients with BRCA mutations.”
She referenced studies citing underutilization of genetic testing in patients who meet the criteria and offered thoughts on whether all early-stage breast cancer patients should be offered genetic testing for BRCA mutations.
“In the past, we used genetic testing for inherited BRCA mutations to identify patients at risk of recurrence or a new cancer so that preventive surgery or intense monitoring could be utilized. The OlympiA results highlight the importance of identifying BRCA mutation carriers at their diagnosis,” she said.
BCRF Scientific Director Dr. Judy Garber and BCRF investigator Dr. Susan Domchek were co-authors of the study, and Dr. Garber also served as the study’s co-chair.
Read on for other notable updates from this year’s ASCO annual meeting.
Some women with HER-positive breast cancer may be able to forgo chemotherapy
The ADAPT study compared neoadjuvant (prior to breast surgery) dual HER2-targeting therapy (pertuzumab plus trastuzumab) alone and in combination with chemotherapy (paclitaxel) in patients with hormone receptor (HR)–negative/HER2-positive breast cancer. Study investigators previously reported that patients receiving paclitaxel were more likely to have significant reduction of their tumor at the time of surgery (called pathological complete response/pCR) compared to patients receiving HER2-targeted therapy alone. These results prompted the study’s discontinuation; however, the trial investigators continued to follow patients.
Reporting on the five-year follow-up, Dr. Nadia Harbeck from Germany’s Ludwig Maximilian University of Munich reported no difference in the rate of invasive disease recurrence with paclitaxel compared to dual HER2-targeted therapy alone. Patients whose tumors did not respond to HER2-targeted therapy did worse overall regardless of chemotherapy than those whose tumors responded to HER2-targeted therapy. Investigators found that the non-responding tumors tended to have low amounts of HER2 and be basal-like—an aggressive characteristic—suggesting that women whose breast cancers have high HER2 levels and pCR after neoadjuvant HER2-directed therapy may be able to forego chemotherapy. Read more about the study here.
CDK4/6 inhibitors maintain long-term benefit in metastatic breast cancer
After a median follow-up of 73.3 months, investigators from the phase III PALOMA-3 study reported a five-year survival rate of 23.3 percent in patients with metastatic breast cancer who received the CDK4/6 inhibitor palbociclib (Ibrance®) with fulvestrant, compared to 16.8 percent in patients receiving a placebo plus fulvestrant.
The analysis included 521 patients with metastatic, HR-positive/HER2-negative breast cancer who had progressed on previous endocrine therapy. This was the first study of CDK4/6 inhibitors to include patients who had received one or more chemotherapy treatments, making it possible to compare response in patients with or without exposure to chemotherapy. The greatest benefit of palbociclib was seen in patients whose tumors were endocrine sensitive, and there was no benefit in patients with prior chemotherapy—but small sample sizes of the subgroups limit the ability to interpret these findings. Analysis of circulating tumor DNA obtained from liquid biopsy showed a palbociclib benefit despite mutations in the ESR1, TP53, or PIK3CA genes.
BCRF investigator Dr. Hope Rugo was a co-author on the study.
The phase III MONALEESA-3 trial also reported an extended overall survival benefit after 53.6 months of follow up in post-menopausal patients receiving the CDK4/6 inhibitor ribociclib (Kysqali®) plus fulvestrant compared to a placebo plus fulvestrant. Over 700 post-menopausal patients with metastatic HR-positive/HER2-negative breast cancer who had received either no previous therapy or one line of therapy were enrolled. The study investigators reported a median survival benefit of nearly 12 months (53.7 months versus 41.5 months) in patients receiving ribociclib plus fulvestrant compared to the placebo. This was the first trial of CDK 4/6 inhibitors in patients with no prior therapy for metastatic breast cancer—the group that saw the greatest benefit of ribociclib.
Discussing these results, BCRF investigator Dr. Otto Metzger commented that the studies demonstrate CDK 4/6 inhibitors are very effective at changing the natural course of advanced HR-positive/HER2-negative breast cancer. He cautioned, however, that the sub-study analyses—which compared benefit in patients with prior chemotherapy versus those without and endocrine-resistant versus endocrine-sensitive disease—are inconclusive and require further validation.
PD-L1 confirmed as biomarker for response to immunotherapy in TNBC
Results from the IMpassion130 study led to the 2019 approval of atezolizumab (Tecentriq®)—the first immunotherapy treatment for metastatic triple-negative breast cancer (TNBC)—specifically for tumors where immune cells had high amounts of the PD-L1 marker. Reporting at ASCO this year, BCRF investigator Dr. Leisha Emens provided results of further exploratory analysis identifying specific molecular characteristics of the tumor microenvironment associated with tumor response to the combination of atezolizumab and chemotherapy (nab-paclitaxel/Abraxane®).
Analysis of 836 patient samples confirmed that the presence of PD-L1 on immune cells is a critical biomarker of response. The current analysis, however, revealed a role for the tumor microenvironment in tumor response to atezolizumab. In addition to high PD-L1 levels, the activation of molecular pathways, particularly those promoting an inflamed tumor microenvironment, were associated with the best overall survival in the IMpassion130 study. These studies continue to inform a targeted approach to immunotherapy in TNBC and may ultimately lead to its application in other breast cancer subtypes.
Read the rest of BCRF’s coverage of the 2021 ASCO annual meeting here.
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