ASCO: Studies show advances in treatment and understanding of
BRCA-associated and triple-negative breast cancer
Mutations in the BRCA 1 or 2 genes significantly increase an individual’s risk of developing breast cancer, as well as several other cancer types. Breast cancers related to a BRCA mutation are also more likely to be triple-negative breast cancer (TNBC), which can be more aggressive and difficult to treat.
Previous studies have shown that targeted drug therapies may be more effective in treating BRCA-associated breast cancers than other breast cancer types. Researchers are still determining which breast cancer patients may benefit most from these targeted therapies.
Results from four MD Anderson-led clinical trials show progress in the treatment and understanding of BRCA-associated breast cancers. These study findings will be presented at the ASCO20 Virtual Scientific Program.
Chemotherapy and PARP inhibitor combo shows improved survival and response (abstract 1001)
BRCA mutations cause tumor cells to have problems repairing DNA. PARP inhibitors target an important enzyme involved in DNA repair. Veliparib is a PARP inhibitor that kills cancer cells by blocking the PARP protein, which prevents the repair of DNA in cancer cells and possibly making them more sensitive to cancer treatments.
This randomized Phase II clinical trial tested how well the chemotherapy drug cisplatin works with or without veliparib in treating patients with advanced triple-negative and/or BRCA mutation-associated breast cancer. The study randomized 335 patients who had received no more than one prior chemotherapy.
All patients underwent central germline BRCA (gBRCA) testing. Patients were then divided into three groups: gBRCA-positive, BRCA-like and non-BRCA-like. Primary end-point was progression-free survival in the three groups, secondary end-points included objective response rate, overall survival and toxicity.
In the gBRCA positive group numerically better PFS was noted with veliparib though this difference was not statistically significant.
In the BRCA-like group, veliparib treatment resulted in a median PFS of 5.7 months, compared to 4.3 months for placebo, a statistically significant improvement. The median overall survival was 13.7 months for veliparib and 12.1 for placebo, and the objective response rate was 45% for veliparib and 35% for placebo.
The non-BRCA-like group had a lesser and non-significant benefit of veliparib for progression-free survival.
Grade 3/4 adverse events were neutropenia (46% versus 19%) and anemia (23% versus 7%) occurred at higher frequency in the veliparib arm compared to the placebo group.
“This study showed the value of adding veliparib to cisplatin for BRCA-positive and BRCA-like patients,” says senior author Gabriel Hortobagyi, M.D., professor of Breast Medical Oncology. “The biomarkers used in this study also identified a subgroup of BRCA patients who may benefit from the addition of PARP inhibitors to chemotherapy treatment.”
Effects of non-BRCA mutations in PARP inhibitor response (abstract 1018)
Defects in gene coding portions of the DNA damage response pathway, particularly BRCA1/2, are associated with tumor sensitivity to PARP inhibitors. The effect of DNA repair flaws beyond BRCA mutations is unknown. This clinical trial looked at the impact of non-BRCA DDR and non-DDR mutations on the efficacy of the PARP inhibitor talazoparib.
The international Phase III clinical trial, EMBRACA, enrolled 431 patients with locally advanced or metastatic and hereditary BRCA1/2 gene mutations. Patients were allowed up to three previous chemotherapies, including platinum-based therapies. 308 patients had evaluable tumor tissue that was sequenced using the FoundationOne CDx panel. 201 patients received the PARP inhibitor talazoparib, and 107 received chemotherapy. 296 patients in the study population exhibited a non-BRCA gene mutation.
Mutations in other genes associated with DNA damage response and/or potential sensitivity to PARP inhibitors were rare, with mutations detected in BARD1, CDK12, FANCG, STAG2 ATR, BRD4, FANCC, PALB2, RAD51B, ATM, BRIP1, NBN, CHEK2, FANCA, and ARID1A. No association was observed between total number of DNA damage response mutations, including BRCA1/2, and best tumor response to talazoparib or chemotherapy
With talazoparib, there was a 69% increased risk of disease progression in patients with TP53 mutations than without. PIK3CA, PTEN, RAD21 and MYC gene mutations and/or copy number alternation status were not associated with PFS in either treatment arm.
“Germline BRCA mutation status is appropriate to identify patients who may derive benefit from talazoparib treatment,” says lead author Jennifer Litton, M.D., professor of Breast Medical Oncology. “This study also provides valuable evidence on the survival impact for patients with TP53 mutations.”
Profiling of androgen receptor-positive triple-negative breast cancer (Abstract 517)
The ARTEMIS clinical trial identifies triple-negative breast cancer patients that do not respond to standard chemotherapy and selects a targeted therapy based on their personalized molecular characterization. Patients in the study underwent biopsy before treatment, and then began the neoadjuvant chemotherapy Adriamycin-cyclophosphamide (AC) while their TNBC subtype analysis and other assessments are conducted in parallel.
The luminal androgen receptor (LAR) TNBC subtype has the lowest pathologic complete response (pCR) rate after neoadjuvant therapy. Androgens can cause the growth of triple-negative breast cancer. Anti-androgen therapy, such as enzalutamide, prevents androgen from binding to the androgen receptor, which reduces cell growth and causes tumor cell death. Thus, patients in the clinical trial were given enzalutamide and the chemotherapy drug paclitaxel before surgery to see if additional inhibition of this androgen receptor (AR) could reduce tumor size and decrease the amount of normal breast tissue that needs to be removed during surgery. This study evaluated the association between the LAR subtype by molecular profiling performed by microarray and RNA sequencing compared to immunostained cells.
The ARTEMIS trial enrolled 267 patient who had tumors profiled by immunohistochemistry, 220 by Affymetrix, 187 by RNA sequencing and 197 by whole exome sequencing. 96 patients also had after AC treatment RNA sequencing profiling. LAR scores from both RNA sequencing and microarray profiling were highly consistent and about 10% of TNBCs tested as LAR-positive. Unlike other subtypes, luminal androgen receptor-positive TNBCs did not change subtype markers after AC treatment. Immunohistochemistry measurement of nuclear AR staining started to match with LAR-positive subtypes around 70%.
Luminal androgen receptor-positive TNBCs had low rates of pCR (23%). Seventeen patients with AC-insensitive TNBC received enzalutamide and paclitaxel, and 7 out of these 17 patients had good clinical response measured as either pCR or residual cancer burden class 1 (RCB1).
Immunohistochemistry and LAR subtype scores did not statistically associate with response to paclitaxel. However, all responders to paclitaxel had an upregulated androgen response pathway as measured by RNA analysis in pre-treatment biopsies examination.
“The LAR triple-negative breast cancer subtype has been known to have a low response rate to neoadjuvant treatment and seems to remain stable throughout chemotherapy,” said lead author Bora Lim, M.D., assistant professor of Breast Medical Oncology. “Patients with AC-resistant triple-negative breast cancer, upregulated androgen response pathways and LAR subtype may see benefit from this AR inhibitor therapy and yet more work is needed to detect patients who would gain benefit, and also possible new way to improve the response for this subgroup of TNBC.”
Deep immune profiling in patients receiving neoadjuvant systemic therapy for triple-negative breast cancer (abstract 509)
In patients with triple-negative breast cancer receiving neoadjuvant therapy, increasing tumor infiltrating lymphocytes (TILs) is associated with higher rates of pathologic complete response. Since the presence of TIL does not always reliably predict pCR, this study’s goal was to better understand the anti-tumor immune response and its association with pCR.
T-cell receptor sequencing, PD-L1 immunohistochemistry and multiplex immunofluorescence were performed on biopsies collected prior to neoadjuvant therapy from 105 patients with stage I-III TNBC enrolled in the ARTEMIS trial.
The pCR rate was 40%. pCR was associated with a more clonal T-cell population (higher TCR clonality). The link between pCR and higher TCR clonality was observed in patients with ≥10% TIL but not in patients with < 10% TIL. Additionally, higher TCR clonality was also associated with higher CD3+ and CD3+CD8+ infiltration but lower expression of PD-1 on CD3+ and CD3+CD8+ cells. Physical proximity of the T cells to the cancer cells also showed an association with pCR in patients receiving neoadjuvant therapy for TNBC.
“This study improves our understanding of the anti-tumor immune response in patients with triple-negative breast cancer who receive neoadjuvant treatment, said lead author Clinton Yam, M.D., assistant professor of Breast Medical Oncology. “These results suggest the value of deep immune profiling in further refining the predictive value of TILs.”