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HER2-Negative EBC With gBRCA PV
Key Takeaways in the Management of HER2-Negative Early Breast Cancer: Focus on Treating Patients With Pathogenic Variants in Germline BRCA

Released: May 17, 2024

Expiration: May 16, 2025

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Key Takeaways
  • There has been an expansion of the treatment armamentarium for patients with HER2-negative early breast cancer in recent years.
  • For patients with a pathogenic variant in germline BRCA1/2, targeted therapy with olaparib has demonstrated both an invasive disease-free survival and an overall survival benefit in the adjuvant setting.

PARP inhibitors have demonstrated efficacy in patients with breast cancer and pathogenic variants (PV) in germline (g) BRCA due to synthetic lethality, which results from an inability to repair breaks in DNA.

In the phase III OlympiA trial in high-risk patients with HER2-negative early breast cancer (EBC) and a PV in gBRCA, 1 year of adjuvant olaparib significantly improved invasive disease-free survival (iDFS) and overall survival (OS) compared to placebo. This trial led to the FDA approval of olaparib in the adjuvant setting following receipt of (neo)adjuvant chemotherapy (CT) for high-risk patients with EBC in March 2022. Subsequently, this also expanded guideline recommendations for gBRCA testing in the early-stage setting, which now include patients with high-risk HER2-negative EBC to aid in adjuvant therapy decisions using olaparib. Given the OS benefit with adjuvant olaparib, it is important that we identify patients who meet the high-risk criteria from the OlympiA trial and ensure gBRCA testing is completed. The OlympiA trial defined high-risk EBC as:

  • HR-positive/HER2-negative: prior neoadjuvant CT and no pathologic complete response (pCR) plus a clinical and pathological stage plus estrogen receptor and nuclear grade (CPS + EG) score of 3 or more; prior adjuvant CT and at least 4 positive lymph nodes
  • Triple-negative: prior neoadjuvant CT and no pCR; prior adjuvant CT and either node-positive or with a T2-T4 primary tumor at surgery

Adverse events (AEs) with adjuvant olaparib were as expected with PARP inhibition, with nausea, fatigue, and anemia reported most frequently in the OlympiA trial.

  • The potential for nausea is an important counseling point, as is how to take the antiemetic. When patients are prescribed olaparib, they should be provided with an antiemetic—typically ondansetron is recommended—to take as needed. In our experience, nausea is mild and manageable with as-needed antiemetics; however, some patients require routine premedication.
  • Fatigue is a larger issue, because although these patients may not be as heavily pretreated as those in the metastatic setting, they are still coming out of (neo)adjuvant therapy, surgery, and potentially radiation. It is critical to address the potential for fatigue and manage expectations with patients.
  • A less common but serious potential AE with PARP inhibitors, including olaparib, is the risk of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Fortunately, at 3.5 years of follow-up, the rates of MDS and AML were exceedingly low (0.2%) with olaparib and similar between the olaparib and placebo arms. It is important to recognize that if patients experience prolonged hematologic toxicity that does not resolve to less than grade 1 within 4 weeks, they should be evaluated for MDS and AML. 

Since the development of the OlympiA study, the CREATE-X, monarchE, and KEYNOTE-522 trials have led to the use of capecitabine, abemaciclib, and pembrolizumab, respectively, in the adjuvant setting for HER2-negative EBC. Though not currently FDA approved or guideline recommended, adjuvant ribociclib may be considered in specific cases for patients with HR+/HER2- EBC based on data from the phase III NATALEE trial demonstrating an iDFS benefit. Currently, there is a lack of data and guidance on therapy selection, concurrent administration, and/or sequencing of these therapies for patients eligible for more than one option in the adjuvant setting, which may lead to provider-specific practices and extrapolation of safety data on combining agents from other disease states or the metastatic setting. We have observed the following practices for our patients with HER2-negative EBC with a PV in gBRCA:

  • For patients with HR-positive/HER2-negative EBC who are eligible for both abemaciclib and olaparib, we have preferentially been using olaparib given the OS benefit. This results in 1 year of adjuvant therapy with olaparib, which has a proven OS benefit, vs 2 (abemaciclib) or 3 (ribociclib) years of therapy with a CDK4/6 inhibitor and an unclear OS benefit at present. It is not recommended to administer olaparib concurrently with a CDK4/6 inhibitor due to toxicity concerns.
  • For patients with triple-negative EBC who are candidates for both olaparib and capecitabine and/or receiving the KEYNOTE-522 regimen of (neo)adjuvant pembrolizumab, we are typically selecting olaparib over capecitabine, although this decision seems to be less clear as both drugs have demonstrated an OS benefit. For patients at very high risk of recurrence, healthcare professionals can consider sequencing both oral therapies—administering capecitabine for 6 to 8 cycles and then initiating olaparib; however, data supporting this strategy are lacking at this time. For both capecitabine and olaparib, we are administering these concurrently with pembrolizumab, for patients continuing immunotherapy in the adjuvant setting.

Ultimately, assessing each individual patient for recurrence risk is critical to designing an optimal treatment plan for EBC. Educating patients and caregivers on potential AEs, as well as prophylaxis and management strategies, can impact adherence and outcomes.

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