September 17, 2024
By Catlin Nalley
There are several targeted therapy options available for patients with hormone receptor-positive (HR+), metastatic breast cancer with germline mutations (BRCA 1 and 2, PALB2), such as CDK4/6 inhibitors (CDK4/6i) and poly (ADP-ribose) polymerase inhibitors (PARPi). However, further data is needed to better understand the optimal sequence of therapy.
A recent analysis, presented at ESMO 2024 in Barcelona by study author Gerneiva Parkinson, MD, MHS, in the Department of Medical Oncology at Stanford Medicine, sought to fill this knowledge gap (Abstract 342MO).
In this investigation, Parkinson noted that “mBRCA represents somatic tumor analysis of BRCA1, BRCA2, and PALB2 suggestive of pathogenic/likely pathogenic germline mutations. Real-world overall survival information was calculated from time of first contact to last treatment time.”
A retrospective analysis was performed on 11,650 breast cancer patient samples with available genomic, subtyping, and treatment data, according to Parkinson. Of these, 628 patients were identified with HR-positive breast cancer and mBRCA (BRCA1: 19%, BRCA2: 66%, PALB2: 15%) and compared to 7,635 patients identified with HR-positive breast cancer and wild-type BRCA.
The median age was 63 years in the wild-type BRCA group and 57 years in the mBRCA group. In terms of treatment, 33 patients in the wild-type cohort received PARP inhibitors versus 156 among those with a germline mutation. Additionally, 3,571 wtBRCA patients underwent treatment with CDK4/6 inhibitors compared with 285 in the mBRCA group.
While discussing the tumor mutations associated with the two patient groups, Parkinson reported that mBRCA patients, when compared to their wild-type BRCA counterparts, were less likely to have a PIK3CA (23.9% vs. 42.5%) or TP53 (28.6% vs. 31.4%) mutation. Conversely, patients in the mBRCA cohort were more likely to have an RB1 mutation (8.5% vs. 5.2%) and high tumor mutational burden (21.2% vs. 8.9%), as well as high PD-L1 expression (18.6% vs. 11.1%).
Looking at the immune cell landscapes of mBRCA and wtBRCA, Parkinson said “there was an enrichment for mBRCA of NK cells, macrophages M2, and CD8 T cells, and also the depletion of neutrophils.”
This analysis also explored the impact order of administration of CDK4/6 inhibitors versus PARP inhibitors on overall survival in HR+ breast cancer mBRCA patients.
“Statistically there was not much difference between the two orders of administration,” Parkinson noted. The median overall survival difference was 7.76 months.
Other factors affecting outcomes were also explored in this study. Data showed that mBRCA patients with high tumor mutational burden had worse overall survival when compared to those with low tumor mutational burden.
“In conclusion, patients with HR+ breast cancer and mBRCA (vs. wild-type) are more likely to have RB1 tumor mutations and less likely to have PIK3CA and TP53 tumor mutations,” Parkinson stated. “For immune cell landscapes, mBRCA patients were more likely to have enrichments of CD8 T cells, NK cells, and macrophage M2 cells. They were also more likely to have a depletion of neutrophils.”
Summarizing her presentation, Parkinson also noted that patients in the mBRCA cohort were more likely to have high tumor mutational burden, as well as high PD-L1 expression levels, when compared to those in the wild-type BRCA group.
While acknowledging that the number of patients receiving the therapies is relatively small, she reiterated that there was no significant difference in overall survival among HR+ breast cancer mBRCA patients when comparing the order of administration of PARP inhibitors and CDK4/6 inhibitors.
“Among patients with HR+ metastatic breast cancer and mBRCA, more prospective analysis is needed to evaluate optimal targeted therapy sequencing, establish germline status of mBRCA variants, and include consideration for PIK3CA status/targeting,” noted Parkinson and colleagues.
“This work should reassure physicians that they will not harm patients by using either sequence,” said study author George W. Sledge, Jr., MD, Adjunct Clinical Professor at Stanford Medicine, while discussing the team’s findings. “As we know, no therapy works for every patient. Given the large amount of genomic data attached to the clinical data in this cohort, we’re interested to further leverage it to learn which patients derive the greatest benefit for each therapy.”
Catlin Nalley is a contributing writer.