Antonio Marra, MD, on Metastatic Breast Cancer: Patterns of Genomic Instability and Their Effect on Treatment
ESMO Congress 2022
Antonio Marra, MD, of Memorial Sloan Kettering Cancer Center, discusses a mutational signature analysis that reveals patterns of genomic instability linked to resistance to endocrine therapy with or without CDK4/6 inhibition in patients with estrogen receptor–positive/HER2-negative metastatic breast cancer (Abstract 210O).
Disclaimer: This video transcript has not been proofread or edited and may contain errors.
The study we presented at this meeting was focused on the mutational signature analysis of breast cancers. We used the genomic data collected from a clinical sequencing program at Memorial Sloan Kettering, and we studied over 4,000 breast cancer, studying mutational signatures, that are mutational processes that shape the genomes of this cancer. In breast cancer, we have three main mutational processes and mutational signatures that are HRD, APOBEC, and clock. Our work will mainly focus on APOBEC and HRD that are the two main mutational signatures that cause genomic instability.
We firstly try to identify which are the main settings where these signatures are rich, and we find that both HRD and APOBEC are rich in the metastatic samples of the ER-positive HER2-negative subtype. We then evaluated the clinical and pathologic features of these tumors, and we found the enrichment for specific pattern including lobular phenotype and tumor with high tumor mutational burden.
From a treatment perspective, we then evaluated the role of the signature on the response to specific treatments and we found something really interesting, because these two signature were both associated with a lower progression-free survival for patient treated on first-line with endocrine therapy with or without CDK4/6 inhibitor, suggesting that genomic instability caused by these two mutation processes is associated with the reduced benefit from standard treatments.
We then focus the last part of our work on studying the genomic mechanism of APOBEC mutagenesis in breast cancer and we found some very strong genetic association including enrichment for variant-specific genes like CDH1, PIK3CA, and most importantly also, some genes are associated with endocrine-resistance like NF1 or PTEN.
We finally did a very strong analysis on the association within PIK3CA variants and APOBEC mutagenesis found a specific region in tumors that have multiple PIK3CA mutations and this may have some clinical indication considering that breast cancer with multiple PIK3CA mutations seems to have a better response to PIK3C-alpha-selective inhibition.
In conclusion, our study shows that genomic stability is a marker of lower benefit on endocrine therapy and CDK4/6 inhibition, and most importantly, we may have in the future new treatment targeting this mutational process that can open to advancement in treatments and open new opportunities for our patients.
Axel Bex, MD, PhD, of the Netherlands Cancer Institute, discusses phase III findings from the IMmotion010 study, which evaluated the efficacy and safety of atezolizumab vs placebo in patients with renal cell cancer who are at high risk of disease recurrence following nephrectomy (Abstract LBA66).
Toni K. Choueiri, MD, of the Dana-Farber Cancer Institute, and Laurence Albiges, MD, PhD, of France’s Gustave Roussy Cancer Centre, discuss results from two important trials presented at ESMO 2022: Cohort 1 of the LITESPARK-003 study of belzutifan plus cabozantinib as first-line treatment of advanced renal cell carcinoma (RCC), and the KEYNOTE-B61 study of pembrolizumab plus lenvatinib as first-line treatment for non–clear cell RCC (Abstracts 1447O and 1448O).
Toni K. Choueiri, MD, of the Dana-Farber Cancer Institute, and Laurence Albiges, MD, PhD, of France’s Gustave Roussy Cancer Centre, discuss phase III findings showing that cabozantinib in combination with nivolumab and ipilimumab reduced the risk of disease progression or death compared with the combination of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma of IMDC (the International Metastatic RCC Database Consortium) intermediate or poor risk. However, the combination of cabozantinib, nivolumab, and ipilimumab vs nivolumab plus ipilimumab did not demonstrate an overall survival benefit to patients (Abstract LBA8).
Ana Oaknin, MD, PhD, of Barcelona’s Vall d’Hebron University Hospital, discusses an analysis of long-term survival from the EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 trial. Cemiplimab-rwlc is the first immunotherapy to demonstrate an overall survival benefit as a second-line monotherapy for patients with recurrent or metastatic cervical cancer previously treated with platinum-based chemotherapy but not immunotherapy. The benefit was sustained in this population (Abstract 519MO).
Neil D. Gross, MD, of The University of Texas MD Anderson Cancer Center, discusses data from a phase II study, which showed that neoadjuvant cemiplimab-rwlc in patients with stage II–IV (M0) resectable cutaneous squamous cell carcinoma is active and may enable function-preserving surgery in some cases (Abstract 789O).