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Treatment of HER2-Negative EBC

CE / CME

Expert Review of Treatment for HER2-Negative Early Breast Cancer

Pharmacists: 1.00 contact hour (0.1 CEUs)

Nurses: 1.00 Nursing contact hour

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™

Released: August 31, 2023

Expiration: August 30, 2024

Kevin Kalinsky
Kevin Kalinsky, MD, MS
CME/CE Information

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Incidence of BRCA Mutations

Now we will discuss germline BRCA testing and targeting with adjuvant olaparib in the context of HER2-negative EBC.

BRCA mutations are the most common genetic variant in hereditary breast and ovarian cancer and are associated with other types of cancer including male breast cancer, prostate cancer, pancreatic cancer, and melanoma.10 Approximately 10% of patients with HR-positive/HER2-negative EBC have germline BRCA mutations.11 Incidence of BRCA mutation may be a little higher (10%-24%) in patients with TNBC,12-15 and differs by ethnicity, race, and age.14,16 For example, Ashkenazi Jewish populations are considered to have a higher rate of BRCA mutations compared with other cohorts.17

PARP Inhibition for BRCA-Mutated Cancer

PARP is an enzyme that helps maintain DNA integrity during replication via repair of single-stranded DNA breaks. Dysfunction of BRCA1 or BRCA2 sensitizes cells to PARP inhibition, leading to synthetic lethality (cell death resulting from simultaneous disruption of 2 genes).18,19 PARP inhibitors have demonstrated efficacy in BRCA-mutated cancers including breast cancer.

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OlympiA: Study Design

The practice-changing phase III OlympiA trial looked at the efficacy of adjuvant PARP inhibition with olaparib vs placebo in 1836 patients with BRCA1/2-mutated, high-risk, HER2-negative EBC.20

In the TNBC subgroup (n = 1509), patients who had received neoadjuvant therapy could not have achieved pCR, and those who went straight to surgery needed to have some nodal involvement or ≥pT2 tumor.

In the HR-positive/HER2-negative subgroup (n = 325), patients who had received prior neoadjuvant therapy could not have achieved pCR and their clinical and pathologic stage and estrogen receptor status and histologic grade scores needed to be ≥3. Patients who went straight to surgery needed to have ≥N2 disease.

Patients were randomized 1:1 to olaparib 300 mg twice daily or placebo for 1 year. The primary endpoint was iDFS, and secondary endpoints were DDFS, OS, and safety.

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Olympia: Baseline Characteristics

Most patients had TNBC (82.2%), 72.2% of patients had BRCA1 mutations, and 61.5% of women patients were premenopausal.20

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OlympiA: iDFS in ITT (Second Interim Analysis)

The iDFS was compared at the second interim analysis (median follow-up: 3.5 years) in the intention-to-treat population.20 It is worth noting that there was a separation of the curves very early on, showing a benefit even within the first 6 months. Comparison of 4-year iDFS showed a meaningful difference of 7.3% in favor of adjuvant olaparib vs placebo (82.7% vs 75.4%, respectively; hazard ratio: 0.63; 95% CI: 0.50-0.78).

Based on the results of the OlympiA trial, the FDA approved olaparib for the adjuvant treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated, HER2-negative high-risk EBC who have been treated with neoadjuvant or adjuvant CT.21 Patients should be selected for therapy based on an FDA-approved companion diagnostic.

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OlympiA: Subgroup Analysis of iDFS

Subgroup analysis of iDFS showed a similar degree of benefit for olaparib in patients with HR-positive/HER2-negative disease (hazard ratio: 0.680; 95% CI: 0.402-1.134) or TNBC (hazard ratio: 0.620; 95% CI: 0.487-0.787) and for the BRCA1-mutated (hazard ratio: 0.533; 95% CI: 0.406-0.695) or BRCA2-mutated (hazard ratio: 0.693l; 95% CI: 0.440-1.082) subgroups.20 Larger population sizes in the BRCA1-mutated or TNBC subgroups caused a relative narrowing of CIs compared with the BRCA2-mutated or HR-positive/HER2-negative subgroups, respectively. However, the P values for heterogeneity were negative (.754 and .615 for HR status and BRCA status, respectively), so we should think about giving both of these groups olaparib.

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OlympiA: OS in ITT (Second Interim Analysis)

Of importance, the second interim analysis started to show an OS benefit for olaparib (4-year OS: 89.8% vs 86.4%; hazard ratio: 0.68; 95% CI: 0.47-0.97; P = .009) compared with placebo.20 I suspect that this will continue to improve with additional follow-up.

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OlympiA: Subgroup Analysis of OS

When looking at the subgroup analysis of OS, again the benefit with olaparib vs placebo was clearest in patients with TNBC (hazard ratio: 0.640; 95% CI: 0.459-0.884), but the total number of events in patients with HR-positive/HER2-negative disease was only 33.20 Considering this is a very small subgroup, I would not overinterpret these data, and I still consider giving adjuvant olaparib to patients with high-risk HR-positive/HER2-negative breast cancer.

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OlympiA: Safety

When we started to give adjuvant olaparib, a major question was whether we would see an increased rate of myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) or new primary malignancies.20 Thankfully, we are not seeing that to be the case. The most common adverse events (AEs) related to olaparib were nausea (any grade: 57.1%; grade ≥3: 0.8%), fatigue (any grade: 40.3%; grade ≥3: 1.8%), and anemia (any grade: 23.6%; grade ≥3: 8.7%). There was some increase in hematologic toxicity with olaparib compared with placebo, including decreased neutrophil count (any grade: 16.1%; grade ≥3: 4.9%) and decreased white blood cell count (any grade: 15.8%; grade ≥3: 3.0%). There were the same rates of MDS/AML (0.2% vs 0.3%) and pneumonitis (1.0% vs 1.3%) and a lower rate of new primary malignancies (2.3% vs 4.0%) in patients treated with olaparib compared with placebo.

There was a numerically higher rate of AEs leading to permanent treatment discontinuation in the olaparib arm vs placebo (10.8% vs 4.6%).

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Practical Management Strategies: Olaparib AEs

It is important to monitor cell counts closely, including for anemia, to dose reduce if a patient requires multiple transfusions.21,22 Treatment should be held if patients are neutropenic, and if they have persistent or significant bleeding despite dose reduction because of thrombocytopenia, olaparib treatment should be discontinued. Mitigation strategies for patients who have gastrointestinal issues include 5-HT3 receptor antagonists such as ondansetron, which may also be used as prophylaxis. I mentioned the rare AEs of MDS/AML and pneumonitis, but the rates were similar to those seen in the placebo population.

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NCCN Guidelines on Testing for BRCA1/2 Mutations

It is important that we test patients for BRCA1/2 mutations according to the NCCN guidelines for genetic and familial high-risk assessment.4 Otherwise, we do not know whether to give them adjuvant olaparib.

Criteria to keep in mind are: any patient with TNBC; Ashkenazi Jewish ancestry, multiple primary breast cancers; bilateral breast cancer; male breast cancer; strong family history of breast cancer; or a personal history of breast cancer at 50 years of age or younger.

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Testing for BRCA1/2 Mutations

We should test all patients who are eligible for treatment with PARP inhibitors, both in the metastatic breast cancer and high-risk EBC settings.4 Those with a personal history of breast cancer with no immediate therapeutic implication should be tested if they are ≤60-65 years of age.23 Point-of-care testing should be considered if treatment decisions are time sensitive. Something that we commonly see when running these large platform panels testing multiple genes is the identification of variants of unknown significance, which we as medical oncologists sometimes need genetic counselors to help interpret.

For the actual test, you can use either blood or saliva, with a median turnaround of 3-4 weeks. Some of the assays prioritize BRCA testing, and you may be able to receive those results before you get the results of the other alterations. Most insurance covers this testing if the patient meets eligibility criteria.

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