Susan Domchek, MD, FASCO, executive director, the Basser Center for BRCA, director, the MacDonald Women’s Cancer Risk Evaluation Center, the Basser Professor in Oncology at Penn Medicine, discusses the importance of germline testing in breast cancer care.

Over the past decade, the importance of using genetic markers to determine the optimal treatment plan for patients with breast cancer has become more evident, Domchek begins. Additionally, using a genetic markers can have an effect at several stages of treatment. For example, data for the PARP inhibitors olaparib (Lynparza) and talazoparib (Talzenna) showed that these agents were effective in the treatment of select patients with advanced breast cancer harboring 

 mutations, Domchek continues, noting that these PARP inhibitors demonstrated improved efficacy over chemotherapy in this setting.

the FDA approved olaparib for the treatment of patients with germline

-positive, HER2-negative metastatic breast cancer

 who have previously received chemotherapy. Additionally, 

 in October 2018 for patients with deleterious or suspected deleterious germline 

-mutated, HER2-negative locally advanced or metastatic breast cancer. Olaparib was then approved by FDA in setting in March 2022 for patients with germline BRCA-mutated, HER2-negative, high-risk early breast cancer who have previously received chemotherapy either before or after surgery.

Patients with early-stage, high-risk breast cancer, including those with positive lymph nodes, triple-negative breast cancer (TNBC) that is more than 2 cm in diameter, or those with breast cancer that has not completely responded to preoperative chemotherapy, can now be candidates for olaparib following the completion of other therapy if they harbor a 

 mutation. The use of a PARP inhibitor in this setting decreases the chances that the cancer will come back outside of the breast and improve overall survival, Domchek emphasizes.

Based on this knowledge, it is important to recognize individuals who are good candidates for genetic testing, including any individual with TNBC, anyone with breast cancer under the age of 50, or anyone who has a family history of breast cancer, ovarian cancer, metastatic prostate cancer, or pancreatic cancer, Domchek explains. Although other patients are also candidates for genetic testing, these are subgroups where it is always important to have genetic testing done, Domchek concludes.

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Susan Domchek, MD, FASCO, discusses the importance of germline testing in breast cancer care.

Dr Domchek on the Importance of Germline Testing in Breast Cancer Care

Susan Domchek, MD, director, MacDonald Women’s Cancer Risk Evaluation Center, executive director, the Basser Center for BRCA, and Basser Professor in Oncology, at Penn Medicine, discusses the results of the phase II 63.36636 trial in germline 

Prior results showed a 12-week disease-control rate (DCR) of 80% with the combination of durvalumab (Imfinzi) and olaparib (Lynparza) in 30 patients with germline 

-mutated metastatic breast cancer. At 28 weeks, the DCR was 50%. Data presented at the 

 demonstrated an objective response rate of 63.3% (95% CI, 43.9-80.1) in the full analysis set. Similar responses were observed in the triple-negative and hormone receptor—positive subgroups, says Domchek.

Investigators also evaluated PD-L1, CD3, and CD8 expression as potential predictors of duration of response and overall survival; however, none of these markers showed a direct correlation, says Domchek. In terms of mechanisms of resistance, 3 patients who progressed early were found to have resistance mutations to olaparib—specifically, a reversion mutation, the absence of allele-specific loss of heterozygosity, and a 

Susan Domchek, MD, discusses the results of the phase II MEDIOLA trial in germline BRCA-mutated metastatic breast cancer.

Dr. Domchek on Results of the MEDIOLA Trial in BRCA-Mutated Metastatic Breast Cancer

Susan Domchek, MD, director, MacDonald Women’s Cancer Risk Evaluation Center, executive director, the Basser Center for BRCA, and Basser Professor in Oncology, at Penn Medicine, discusses the potential benefits of biosimilars in oncology.

If a biosimilar demonstrates similarity in efficacy to the originator product and is likely to result in cost reduction, it should be considered a valuable addition to the field. Oncology treatment is very expensive, says Domchek. More focus needs to be placed on looking for ways to decrease the cost of cancer care while maintaining efficacy. If biosimilars are the means to that end, they should be embraced, she adds.

It is hard to estimate the cost differential between biosimilars and biologics because many biologics have yet to come off patient. However, the cost savings are going to be more evident across health systems than in relation to individual patients, explains Domchek. Even so, it will be important to educate patients on the differences between biosimilars, biologics, and generics.

Dr. Domchek on Potential Benefits of Biosimilars in Oncology

Susan Domchek, MD, director of the Basser Center for BRCA at Penn Medicine, discusses areas of investigation in breast cancer.

Things that physicians are looking at as predictors of response to chemotherapy include how many tumor-infiltrating lymphocytes (TILs) are at baseline and what the immune cells are, says Domchek. Additionally, physicians are also looking at expression of PD-L1 in the tumor to hopefully give a clear picture of who will respond.

It might also be that certain characteristics of the tumor, including DNA damage repair and homologous recombination defects, may give physicians a clue to these questions. However, it is challenging and physicians still need to sort through all of this information, explains Domchek.

Dr. Domchek Discusses Areas of Investigation in Breast Cancer

Susan Domchek, MD, director of the Basser Center for BRCA at Penn Medicine, discusses the development of immunotherapy in breast cancer.

Both physicians and patients are hopeful that immunotherapy regimens will show more success in breast cancer, explains Domchek. Currently, there are a lot of drugs that work well for patients with breast cancer compared with the limited options in other tumors where immunotherapy has been helpful. Breast tumors shrink well with chemotherapy, which sets the bar higher for immunotherapy, says Domchek.

Breast cancer is fundamentally different than melanoma or lung cancer, where immunotherapy has shown a significant benefit. According to Domchek, it is important to understand which groups are most likely to respond to immunotherapy. For example, there is a signal for the first-line treatment of patients with triple-negative breast cancer, where immunotherapy can induce durable responses.

Dr. Domchek Discusses Immunotherapy in Breast Cancer

Susan Domchek, MD, director of the Basser Center for BRCA at Penn Medicine, discusses promising biomarkers in breast cancer.

 are currently used to determine treatment for patients with breast cancer, explains Domcheck.

Domcheck adds that if a patient is microsatellite instability-high (MSI-H), then that patient can receive pembrolizumab (Keytruda) regardless of tumor site.

Dr. Domchek on Promising Biomarkers in Breast Cancer

Susan Domchek, MD, director of the Basser Center for BRCA at Penn Medicine, discusses the MEDIOLA trial in breast cancer.

During the 2017 San Antonio Breast Cancer Symposium, the results of the first 25 patients with 

-mutated metastatic breast cancer treated with olaparib (Lynparza) and durvalumab (Imfinzi) from the MEDIOLA trial were presented.

Results showed an 80% clinical benefit rate at 12 weeks, suggesting that this is an active combination in this population. The impact of durvalumab is still unknown, says Domchek, as olaparib has shown benefit as a single-agent in this population.

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Susan Domchek, MD, director of the Basser Center for BRCA at Penn Medicine, discusses the MEDIOLA trial in breast cancer.
 

Dr. Domchek on the MEDIOLA Trial in Breast Cancer

Susan Domchek, MD, director of the Basser Center for BRCA at Penn Medicine, discusses some questions that remain after the recent phase II MEDIOLA trial.

The trial, which was presented at the 2017 San Antonio Breast Cancer Symposium, showed that the combination of olaparib (Lynparza), a PARP inhibitor, and durvalumab (Imfinzi), an immunotherapy agent, could be a promising option for patients with BRCA1- or BRCA2-mutant metastatic breast cancer who did not have a response on prior therapies. In the study, 25 women were given the combination. At 12 weeks, there was an 80% clinical benefit rate. Domchek finds these results very promising, especially since there were no additional toxicities other than what would normally be expected for both of the agents.

However, there are still unanswered questions regarding this line of therapy, Domchek says. First, olaparib is effective as a single-agent for this patient population, so it is unclear if durvalumab is enhancing efficacy by providing a prolonged response. Also, more pre-treatment predictors must be identified so that oncologists can better understand who which patients will have the best response with the combination.