Study Decodes Deescalation: Impact of BRCA Pathogenic Variants on Neoadjuvant Treatment in Triple-Negative Breast Cancer

Recent investigation focuses on the effects of BRCA1 and BRCA2 tumor pathogenic variants (tPVs) within the parameters of two deescalated neoadjuvant chemotherapy regimens—nab-paclitaxel combined with either carboplatin or gemcitabine—on key outcomes, specifically pathologic complete response (pCR), invasive disease-free survival (IDFS), and overall survival (OS) in early-stage triple-negative breast cancer (TNBC) patients. This analysis is centered on a phase 2 randomized clinical trial, ADAPT-TN, conducted across 45 sites in Germany.

DNA Sample Analysis

Out of 307 available DNA samples collected from pretreatment biopsies, successful sequencing was achieved for 266 patients due to low DNA amounts and quality control failures in some samples. The cohort comprised entirely of female patients with a median age of 51 years. Investigators found that the association between pCR rates and survival outcomes, particularly IDFS, was crucial. While TP53 tPVs did not markedly impact pCR, there was a trend indicating that PIK3CA tPVs could be deleterious, although results were not statistically significant.

Challenges in TNBC Treatment

The study underscores the ongoing challenges in treating TNBC due to its aggression and the lack of effective therapeutic targets. The prevalence of germline pathogenic variants in BRCA1/2 ranges from 9% to 18% among unselected TNBC patients, implying a significant link between hereditary factors and treatment response. Notably, previous studies noted superiority in pCR rates and disease-free survival when carboplatin is included in therapy.

Trial Methods and Outcomes

In the ADAPT-TN trial, patients were randomly assigned to receive either nab-paclitaxel with carboplatin or nab-paclitaxel with gemcitabine for 12 weeks. A statistically significant improvement in pCR rates was observed in the carboplatin group (45.9%) compared to the gemcitabine group (28.7%). Importantly, the enhanced pCR rates did not translate to improved 5-year IDFS or OS, suggesting that while pCR serves as a critical marker for response, it does not automatically guarantee better long-term outcomes.

BRCA1/2 tPV Status Insights

A significant aspect of the findings is the potential role of BRCA1/2 tPV status in determining which patients may benefit from carboplatin. Within the smaller subgroup of patients with BRCA1/2 tPVs treated with carboplatin, there was a notable pCR rate of 64.3%, which is promising compared to the BRCA1/2 wild-type group (24.6%). Despite these encouraging results, the impacts on long-term survival rates for this cohort were not statistically significant and require further investigation.

Survival Outcomes and Trends

Additionally, survival outcomes indicated a concerning trend for patients with PIK3CA tPVs showing poorer survival rates compared to those with wild-type status, aligning with existing literature linking PIK3CA mutations to chemotherapy resistance. Conversely, patients without TP53 tPVs exhibited better survival outcomes, a finding echoed in previous studies.

Analysis Limitations

The exploratory nature of this secondary analysis highlights several limitations. The small sample sizes within genetic subgroups resulted in insufficient statistical power, which hinders definitive conclusions. Furthermore, survival was a secondary endpoint of the primary trial, complicating the interpretation of the survival data. In conclusion, while deescalated neoadjuvant nab-paclitaxel plus carboplatin appears effective, the role of BRCA1/2 tPVs presents a promising avenue for further research. The study advocates for larger trials that can focus on survival endpoints to better delineate the potential benefits of chemotherapy deescalation based on genetic profiling. This research heralds the necessity of precision medicine in refining treatment strategies for TNBC.

Key Points

\- \*\*Investigation Focus\*\*: The study evaluates the impact of BRCA1 and BRCA2 tumor pathogenic variants (tPVs) on outcomes of de-escalated neoadjuvant chemotherapy regimens, specifically comparing nab-paclitaxel combined with carboplatin versus gemcitabine, in early-stage triple-negative breast cancer (TNBC) patients. Key outcomes assessed include pathologic complete response (pCR), invasive disease-free survival (IDFS), and overall survival (OS).

- \*\*DNA Sample Insights\*\*: Out of 307 collected DNA samples from pretreatment biopsies, 266 were successfully sequenced. The patient cohort, consisting entirely of women with a median age of 51 years, showed a crucial relationship between pCR rates and survival outcomes, particularly IDFS. While TP53 tPVs had minimal effects on pCR, there was a suggestive trend toward deleterious implications of PIK3CA tPVs, although not statistically significant.

- \*\*Challenges and Prevalence\*\*: The investigation emphasizes the treatment challenges posed by TNBC's aggressiveness and the dearth of effective therapeutic targets. It notes that 9% to 18% of unselected TNBC patients carry germline pathogenic variants in BRCA1/2, highlighting the hereditary link to treatment responses. Prior studies have suggested improved pCR rates and disease-free survival with carboplatin inclusion in therapy.

- \*\*Trial Design and Results\*\*: In the ADAPT-TN trial, patients were randomly assigned to nab-paclitaxel with either carboplatin or gemcitabine for 12 weeks. Results indicated a significant improvement in pCR rates within the carboplatin group (45.9%) compared to the gemcitabine group (28.7%). However, this increase did not correlate with improved 5-year IDFS or OS, indicating that pCR alone does not ensure better long-term outcomes.

- \*\*BRCA1/2 tPV Impact\*\*: The analysis suggests that the BRCA1/2 tPV status may identify patients who would particularly benefit from carboplatin, as evidenced by a pCR rate of 64.3% in the BRCA1/2 tPV subgroup compared to 24.6% in the wild-type group. However, differences in long-term survival rates for this group were not statistically significant and warranted further exploration.

- \*\*Limitations and Future Directions\*\*: The exploratory nature of the analysis identifies limitations such as small genetic subgroup sample sizes affecting statistical power and the secondary endpoint nature of survival data. It calls for larger trials focusing on survival outcomes to better understand the implications of chemotherapy deescalation based on genetic profiles, emphasizing the need for precision medicine in TNBC treatment strategies.

Reference –

Lisa Richters et al. (2025). Genetic Alterations, Therapy Response, And Survival Among Patients With Triple-Negative Breast Cancer. *JAMA Network Open*, 8. https://doi.org/10.1001/jamanetworkopen.2024.61639.