Background. The treatment of pancreatic cancer and other periampullary neoplasms is complex and challenging. Major high-volume cancer centers can provide excellent multidisciplinary care of these patients but almost two-thirds of pancreatic cancer patients are treated at low volume centers. There is very little published data from low volume community cancer programs in regards to the treatment of periampullary cancer. In this study, a review of comprehensive periampullary cancer care at two low volume hospitals with comparison to national standards is presented. Methods. This is a retrospective review of 70 consecutive patients with periampullary neoplasms who underwent surgery over a 5-year period (2006–2010) at two community hospitals. Results. There were 51 successful resections of 70 explorations (73%) including 34 Whipple procedures. Mortality rate was 2.9%. Comparison of these patients to national standards was made in terms of operative mortality, resectability rate, administration of adjuvant therapy, clinical trial participation and overall survival. The results in these patients were comparable to national standards. Conclusions. With adequate commitment of resources and experienced surgical and oncologic practitioners, community cancer centers can meet national tertiary care standards in terms of pancreatic and periampullary cancer care.
Background: Non-colorectal MSI-H tumors are increasingly identified by CGP. Rare types such as MSI-H BC remain poorly defined with an evidence gap on how to optimally sequence or combine with standard of care treatment. MSI can be measured by either IHC, PCR, or CGP and can be caused by both sporadic and germline variants within different tumor types. Prior studies in BC have shown evidence of dMMR by IHC cases MSS based on PCR. This could be due to intra-tumor heterogeneity, specific microsatellite loci evaluated, or penetrance of germline, somatic, or epigenetic alterations. Published data suggests carriers of germline pathogenic MMR variants have a BC risk equivalent to the normal population and currently germline testing is recommended only for BRCA. Currently in advanced BC, standard tumor biomarker testing includes IHC, PCR, and FISH; however, with increasing use of CGP we demonstrate additional actionable biomarkers as well as potential germline variants in MSI-H BC. Methods: DNA was extracted and hybrid capture CGP was performed on 29,160 BC cases. TMB was determined on 0.8-1.2 Mb of DNA and MSI status on 95-114 loci. Genomic LOH was also evaluated. Comparative analysis was done with 101 MSI-H BC, 841 MSS BC and 4,988 non-breast MSI-H cancers. Histological subtype was obtained from the pathology along with orthogonal testing for ER/PR/HER2 status. Somatic-germline-zygosity (SGZ) status was predicted using a published research use algorithm. Select case reports with clinical outcomes will be presented. Results: We identified 101 (0.35% of total) MSI-H BC cases: 29 ER+/HER2-, 5 HER2+, 29 TNBC, and 28 unknown. Amongst BC cases with known subtype, TNBC was enriched for MSI-H vs MSS (53.4 vs 35.8%, p=0.005). The median TMB in MSI-H BC (26.1 mut/Mb, IQR 17.4;42.8) was significantly lower than that of MSI-H colon (46.1mut/MB) and higher than that of MSI-H uterine tumors (22.6mut/Mb) in our comparison group (p<0.001 for both, Kruskal-Wallis test). Pathogenic variants in an MMR gene were found in 61.4% of MSI-H BC with MLH1 loss being the most common (13.6%) and much higher vs. the non-breast MSI-H cohort (2.4%, p<0.0001). Germline mutations in MMR genes in BC are rare yet 5/52 MMR short variants identified in 101 MSI-H BCs were predicted to be germline, 34 somatic, and 13 could not be determined. We identified 21 MSI-H BC patients with a total of 25 pathogenic BRCA1/2 alterations of which 4 were likely germline, 10 were homozygous, and were enriched in TNBC. These were mainly frameshift mutations, including BRCA2 T3033fs* in 5/18 (28%) cases; however, 7/25 were deletions, rearrangements, or nonsense mutations. Median gLOH was significantly higher in BRCA altered (19.7%) compared to BRCA wild-type MSI-H BC cases (9.6%) (p=0.007, Wilcox test). Additional potentially targetable biomarkers included 26 CDx eligible PIK3CA mutations, 11 ERBB2 activating point mutations in the TKD or ECD domain, 1 FGFR2 rearrangement, and 6 AKT1 E17K mutations. Four cases also had concurrent (CD274) PD-L1 amplifications. Conclusion: MSI-H BC is rare but CGP can identify additional therapeutic options for rational combination with targeted therapies such as PI3K, PARP, and HER2 inhibitors. BRCA alterations may be of germline or somatic origin and they may be targetable, as demonstrated by gLOH, rather than passenger mutations. Further characterization of these tumors and comparison to both MSS BC and non-breast MSI-H tumor types, combined with treatment outcomes, can provide insights on rationale combinations and/or sequencing of therapeutic agents. Citation Format: Kimberly McGregor, Natalie Danzinger, Jeffrey S. Ross, Kyle Gowen, Alexa B. Schrock, Garrett M. Frampton, Dean C. Pavlick, Jan W. Davis, Carl R. Gray, Jeffrey M. Venstrom. Therapeutic considerations in microsatellite instability high (MSI- H) breast cancers (BC) identified by comprehensive genomic profiling (CGP) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-04.
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