Background: Germline genetic alterations are established mediators of breast carcinogenesis, often giving rise to specific forms of genomic instability. BRCA1/2 pathogenic variants (PVs) are emblematic of this phenomenon through their induction of homologous recombination deficiency. While specific patterns of genomic instability may sensitize cancers to therapies such as PARP inhibitors (PARPi) or platinum chemotherapy, their implications for lineage-directed therapies such as endocrine therapy (ET) or CDK4/6 inhibitors (CDK4/6i) are unknown. Herein, we systematically investigated the patterns of association of germline alterations with specific somatic alterations and explored the resulting effect on clinical outcomes. Methods: Patients who underwent germline and matched tumor tissue sequencing utilizing MSK-IMPACT from April 2014 to May 2021 and had available germline analysis results were included. The final analysis presented at SABCS will include 6000 tumors from 5,150 patients, anonymized according to established institutional IRB guidelines to allow for germline analysis on the full cohort. We analyzed genomic data to inform the full spectrum of somatic and germline mutations, ploidy, and allele-specific copy number to determine loss of heterozygosity (LOH). We performed gene- and pathway-level enrichment analyses between somatic variants and germline PVs. Univariable and multivariable Cox proportional hazards models were constructed to assess the association of therapy-specific progression-free survival (PFS) with select germline PVs and germline-somatic interactions. Results: The preliminary analysis includes 2,798 tumors from 2,242 patients with germline and somatic sequencing results. The most frequent germline PVs were: BRCA2 (n = 81), BRCA1 (n = 67), CHEK2 (n = 57), ATM (n = 32), PALB2 (n = 19). The cohort robustly confirmed previously established relationships such as mutual exclusivity of gATM and TP53 variants (OR 0.10, 95% CI 0.032 - 0.33, q = 0.005). Alterations of TP53 were seen in 83% (56/67) of gBRCA1 patients; however, this did not achieve significance when adjusted for receptor subtype (OR 3.90, 95% CI 1.34-11.38, q = 0.15). The size of the cohort allowed discovery of several novel relationships. For instance, gBRCA2 loss was associated with alterations in TGF-B pathway components (OR 3.58, 95% CI 1.70 - 7.56, q = 0.002), potentially relevant to metastatic disease progression. PIK3CA mutations were significantly less prevalent in both gBRCA2 (OR 0.52, 95% CI 0.31 - 0.87, q = 0.063) and gBRCA1 PVs (OR 0.21, 95% CI 0.085 - 0.51, q = 0.014). Our analysis uncovered a strong association between gBRCA2 and somatic RB1 pathogenic alterations (OR 3.58, 95% CI 1.70 - 7.56, q = 0.011), with most variants (80%) encountered in metastatic gBRCA2 tumors. Given the essential role of RB1 in CDK4/6i response, we investigated the effect of BRCA2 status on clinical efficacy of CDK4/6i-ET. Strikingly, gBRCA2 PVs were significantly associated with inferior PFS (HR 2.17, 95% CI 1.46-3.22, p < 0.001) on first line treatment with CDK4/6i-ET. We posited the enrichment of somatic RB1 loss as a potential mechanism of resistance to CDK4/6i. Given the proximity of RB1 to BRCA2 on chromosome 13, we hypothesized that co-LOH of BRCA2 and RB1 predisposes the cancer cells to bi-allelic loss under therapeutic pressure of CDK4/6i. Indeed, 18/26 gBRCA2 (69.2%) tumors evaluable for allele-specific copy number had evidence of RB1 LOH. Discussion: Analysis of germline-somatic interactions yielded novel associations relevant to breast cancer progression and treatment resistance. Among these, we demonstrated BRCA2 carriers to have inferior outcomes to first line CDK4/6i-ET with potential implications for optimal first line therapy and sequencing of CDK4/6i vs PARPi in this patient population. Citation Format: Anton Safonov, Chai Bandlamudi, Paulino Tallón de Lara, Emanuela Ferraro, Fatemeh Derakhshan, Marie Will, Mark Donoghue, Pier Selenica, Joshua Drago, Ezra Rosen, Carlos dos Anjos, Elaine Walsh, Elizabeth A Comen, Mehnaj Ahmed, Barbara Acevedo, Ahmet Zehir, Michael F Berger, David Solit, Larry Norton, Ronglai Shen, Zsofia Stadler, Simon Powell, Jorge S Reis-Filho, Sarat Chandarlapaty, Mark Robson, Pedram Razavi. Comprehensive genomic profiling of patients with breast cancer identifies germline-somatic interactions mediating therapy resistance [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS4-08.
Derzeit existiert keine etablierte Standardtherapie für Patienten mit metastasiertem cSCC. Wegen der Pathomechanismen, die bei der Karzinogenese des kutanen Plattenepithelkarzinoms eine Rolle spielen, wurde postuliert, dass diese Tumoren möglicherweise durch eine PD-1/PD-L1-Blockade beeinflussbar sind. Der vorliegende Bericht beschreibt den Fall eines Patienten, der wegen eines kutanen Plattenepithelkarzinoms mit Lymphknotenbeteiligung und Lungenmetastasen, das gegenüber 2 Therapielinien mit platinbasierten Schemata und Salvage-Operation refraktär war, eine Behandlung mit Nivolumab erhielt. Der klinische Verlauf war durch ein atypisches Ansprechmuster mit initialem Rückgang der Weichteilläsionen/viszeralen Läsionen bei gleichzeitig neu auftretenden Knochenläsionen gekennzeichnet. In den anschließenden bildgebenden Untersuchungen zeigten sich insgesamt eine Verbesserung und eine anhaltende Krankheitskontrolle unter Fortführung der Therapie. Im vorliegenden Fall erhielt der Patient mit metastasiertem therapierefraktärem cSCC eine Immuntherapie und entwickelte ein atypisches Ansprechmuster.
Background: According to several estimates, African American women are 40% more likely to die from breast cancer than white women in the United States. Proposed explanations for this disparity include differential socioeconomic factors and access to care, however some studies have raised the possibility that variation in tumor biology is a contributing factor. Methods: We prospectively sequenced primary and metastatic breast cancer tumors and their matched normal DNA using the MSK-IMPACT assay. We performed gene enrichment analyses to identify the oncogenic mutations and copy number alterations that were more frequent in patients who self-identified as African American or black (AA/B) compared with patients who self-identified as non-Hispanic white (NHW). Detailed clinicopathologic variables were collected for the full cohort. Mann-Whitney U test, Fisher’s exact test, and multivariate binomial regression models were used for statistical analyses. Results: Genomic profiling was performed on 339 tumors from 301 AA/B patients (44.6% metastatic), and 2,607 tumors from 2,248 NHW patients (48.5% metastatic). Age of AA/B and NHW patients at diagnosis was similar (51.5 vs. 52.8 years, p = 0.065). However, AA/B patients were more likely to be pre- or peri-menopausal at diagnosis (51.6 vs. 44%, p = 0.013), have triple-negative disease (26.5 vs. 13%, p < 0.001), and have higher stage at diagnosis (p = 0.024). Of note, invasive lobular carcinomas were significantly less frequent in AA/B patients compared to NHW (5.9 vs. 14.5%; p < 0.001), a trend that persisted when controlling for receptor subtype. In the unadjusted analysis, AA/B women were more likely to have TP53 mutations (53.4 vs. 36.5%; q < 0.01) and NF1 loss of function mutations (9.9% vs. 3.7%; q < 0.01), and less likely to have CDH1 mutations (6.3% vs. 15.4%; q < 0.01) and PIK3CA mutations (25.7 vs. 35.6%, q = 0.017). However, in a multivariate analysis adjusted for receptor subtype, histology, and sample type (primary vs. metastatic), NF1 was the only gene found to be more commonly mutated in AA/B women (odds ratio: 2.84; 95% CI: 1.73 - 4.08, q < 0.01). Focusing specifically on ER+/HER2- disease, AA/B women were more likely to have mutations in TP53 (31.6% vs. 24.6%), NF1 (7.7% vs. 3.1%) and FGFR1 amplification (21.4% vs. 13.1%), and less likely to have mutations in CDH1 (9.2% vs. 18.8%) or PIK3CA (29.6% vs. 39.6%), however these results did not retain statistical significance when adjusted for multiple comparisons. In triple-negative breast cancer patients, TP53 was mutated at equal rates in AA/B and NHW patients (88.9% vs. 85.9%; p = 0.59), and there was a numerically higher frequency of NF1 mutations in AA/B patients (11.1% vs. 5%). There was no significant difference in tumor mutational burden between AA/B and NHW women (4.24 vs. 4.87; p = 0.19), and no difference in the frequency of microsatellite instability (defined as MSISensor score > 10, 0.9% vs. 0.5%; p = 0.44). Conclusions: In this large clinico-genomic analysis, as previously reported, AA/B patients were more likely to have the clinical hallmarks of aggressive disease, as defined by triple-negative subtype, higher stage, and premenopausal status at diagnosis. Our analysis demonstrated trends towards enrichment for some of the genomic alterations previously identified to be associated with poor outcome in the AA/B population, however, after controlling for the aforementioned clinical factors, breast cancer in AA/B did not differ significantly from breast cancer in NHW in terms of their driver genomic alterations, MSI or tumor mutation burden. Further studies are required to fully characterize the genomics of breast cancer in AA/B women, which may play a role in larger efforts to equalize the disparities observed in this population. Citation Format: Cristian Serna-Tamayo, Joshua Z Drago, Carlos Dos Anjos, Joshua Herbert, Fresia Pareja, Shanu Modi, Komal Jhaveri, Chau Dang, David B Solit, Larry Norton, Mauricio Scaltriti, Jorge S Reis-Filho, Sarat Chandarlapaty, Mark E. Robson, Pedram Razavi. The genomic landscape of breast cancer in African American women [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-10-01.
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