Metastatic colorectal cancers (mCRCs) are clinically heterogeneous, but the genomic basis of this variability remains poorly understood. We performed prospective targeted sequencing of 1,134 CRCs. We identified splice alterations in intronic regions of APC and large in-frame deletions in CTNNB1, increasing oncogenic WNT pathway alterations to 96% of CRCs. Right-sided primary site in microsatellite stable mCRC was associated with shorter survival, older age at diagnosis, increased mutations, and enrichment of oncogenic alterations in KRAS, BRAF, PIK3CA, AKT1, RNF43, and SMAD4 compared with left-sided primaries. Left-sided tumors frequently had no identifiable genetic alteration in mitogenic signaling, but exhibited higher mitogenic ligand expression. Our results suggest different pathways to tumorigenesis in right- and left-sided microsatellite stable CRC that may underlie clinical differences.

Background: Racial inequities for patients with heart failure (HF) have been widely documented. HF patients who receive cardiology care during a hospital admission have better outcomes. It is unknown whether there are differences in admission to a cardiology or general medicine service by race. This study examined the relationship between race and admission service, and its effect on 30-day readmission and mortality Methods: We performed a retrospective cohort study from September 2008 to November 2017 at a single large urban academic referral center of all patients self-referred to the emergency department and admitted to either the cardiology or general medicine service with a principal diagnosis of HF, who self-identified as white, black, or Latinx. We used multivariable generalized estimating equation models to assess the relationship between race and admission to the cardiology service. We used Cox regression to assess the association between race, admission service, and 30-day readmission and mortality. Results: Among 1967 unique patients (66.7% white, 23.6% black, and 9.7% Latinx), black and Latinx patients had lower rates of admission to the cardiology service than white patients (adjusted rate ratio, 0.91; 95% CI, 0.84–0.98, for black; adjusted rate ratio, 0.83; 95% CI, 0.72–0.97 for Latinx). Female sex and age >75 years were also independently associated with lower rates of admission to the cardiology service. Admission to the cardiology service was independently associated with decreased readmission within 30 days, independent of race. Conclusions: Black and Latinx patients were less likely to be admitted to cardiology for HF care. This inequity may, in part, drive racial inequities in HF outcomes.

Purpose Pancreatic ductal adenocarcinoma (PDAC) is associated with the breast ovarian cancer syndrome (BRCA1/BRCA2) mutations. It is unknown if this association is causal. Experimental Design This is a single-site study of patients who underwent surgical pancreatic tumor resection and self-identified as Ashkenazi Jewish. DNA from normal pancreatic tissue was genotyped for the three Ashkenazi Jewish BRCA1/2 founder mutations BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT, and loss of heterozygosity (LOH) was determined by sequencing DNA from microdissected tumor. When additional tumor tissue was available, p53 immunohistochemistry (IHC) was conducted. Results Thirty-seven patients underwent surgery for PDAC, seven for intraductal papillary mucinous neoplasm (IPMN), and 19 for other diseases. A high prevalence of BRCA1/2 mutations was found in the surgical cohort (12/63; 19.0%; P < 0.001), PDAC cohort (8/37; 21.6%; P < 0.001), and IPMN cohort (2/7; 28.6%; P =.01) compared with published control mutation frequency. A high prevalence of BRCA1 185delAG (8.1%; P < 0.001) and BRCA2 6174delT (10.8%; P < 0.001) in Ashkenazi Jewish patients with PDAC was shown. BRCA1/2 LOH was found in 2 of 4 BRCA1-associated PDACs and 3 of 4 BRCA2-associated PDACs. Positive p53 IHC was found in 5 of 8 BRCA1/2 PDACs. Conclusions We show a high prevalence of BRCA1/2 mutations with LOH in an Ashkenazi Jewish cohort of surgically resected PDAC and neoplastic lesions, suggesting that these germline mutations are causal in selected individuals.

inhibition of BTK downregulates expression of myriad downstream signaling molecules, most prominently PLCγ2, some mutations in which seem to mediate ibrutinib resistance. Interestingly, a clinically similar eruption-a lymphohistiocytic infiltrate with eosinophils responsive to corticosteroids-has been described in patients with mutations in the PLCγ2 gene. 6 In conclusion, treatment of lymphoid leukemias with the BTK inhibitor ibrutinib can lead to development of a panniculitis, which may be induced by drug-induced immune modulation. Previously uncharacterized, this painful rash typically occurs early during drug exposure and responds well to systemic corticosteroid use; however, low-dose maintenance therapy may be necessary to prevent recurrence.

Pancreatic cancer (PC) is typically a fatal disease due to its rapid growth and the lack of early diagnostic techniques. Because approximately 10% of PCs are attributable to a hereditary susceptibility, identifying and studying patients with a family history of PC or known genetic predisposition to PC can improve the prevention, diagnosis, and treatment of PC. A skilled team of study investigators, physicians, genetic counselors, and data managers must work with patients and families to confidentially store and organize data from PC patients and high-risk patients. This data, collected in conjunction with patients' tissue and blood specimens, will contribute to the understanding of the biology, etiology, and epidemiology of PC, and can ultimately improve screening and management for patients with an underlying hereditary predisposition to PC.

We performed an integrated clinical and bioinformatic analysis of colorectal cancers (CRCs) genotyped at our institution from 4/2014-7/2016 to comprehensively characterize genomic alterations in metastatic CRC (mCRC). We analyzed 1008 samples (474 primaries, 534 metastases) from 985 mCRC patients and 128 early stage CRCs sequenced with MSK-IMPACT, a hybridization capture next generation sequencing assay. Metastatic CRCs were divided into 3 groups by mutation burden and MSIsensor algorithm score: microsatellite stable (MSS) (n=939; 95%), microsatellite-high (MSI-H) (n=41; 4%), and ultra-mutated (n=5; 1%). Early stage CRC were enriched for MSI-H due to clinical selection and were 53% MSS, 44% MSI-H, and 4% ultra-mutated. Ultra-mutated tumors exhibited &gt;100 mutations and harbored hotspot mutations in POLE in 8 cases and a potential novel POLE alteration in 1 case. We evaluated the frequency of oncogenic alterations in MSI-H and MSS mCRCs. The frequency of the resistance biomarkers KRAS and NRAS did not vary between MSI-H and MSS mCRCs (46% v 41%, p=0.6). Potentially actionable alterations were enriched in MSI-H tumors (78% v 33%, p&lt;0.001). Metastases did not have more actionable alterations than primary tumors. We classified clinically relevant targets using the OncoKB classification as level 2B (FDA-approved target in another disease type), 3A (target with compelling early clinical evidence in CRC), and 3B (target with compelling early clinical evidence in another disease type). Twelve percent (109/939) of MSS mCRCs had a level 2B target: BRAF V600E (5%), ERBB2 amplification (AMP) (4%), MET AMP (1%), BRCA1/BRCA2 alteration (1%), TSC1/TSC2 mutation (1%), EGFR mutation (&lt;1%), RET fusion (&lt;1%); there was significant enrichment of BRAF V600E (24%) and BRCA1/BRCA2 alterations (29%) in MSI-H versus MSS mCRC (p&lt;0.001). NTRK fusions, the main 3A alteration identified, occurred in 7% of MSI-H and &lt;1% MSS CRC (p&lt;0.01). Level 3B alterations at ≥ 1% in MSS CRC included PIK3CA (15%), NRAS (3%), AKT1 (1%), MAP2K1 (1%), and ERBB2 (1%) mutations and FGFR1 AMP (2%). PIK3CA and PTCH1 mutations were both enriched in MSI-H versus MSS mCRC (32% v 15%, p&lt;0.01; 27%,v &lt;1%, p&lt;0.001, respectively). Analysis of mutation frequencies in 3 MSS CRC disease states - early stage resected primary (The Cancer Genome Atlas, TCGA), primary site of mCRC, and metastatic site - found significant depletion of FBXW7 mutations in metastases. We also found significant and progressive enrichment of TP53 alterations (58% TCGA, 73% primaries of mCRC, 79% metastases) and BRAF mutations (4% TCGA, 9% primaries of mCRC, 10% metastases) in advanced disease, suggesting a role of these genes in aggressive disease. One third of the BRAF mutations in our cohorts were not V600 but known to be oncogenic. In this large dataset, we identified markers of advanced CRC and found that while MSI-H and MSS CRC have a similar frequency of resistance biomarkers, MSI-H CRC more commonly harbor actionable alterations. Citation Format: Marla Lipsyc, Walid Chatila, Jaclyn F. Hechtman, Francisco Sanchez-Vega, Sumit Middha, Andrea Cercek, Zsofia Stadler, Ritika Kundra, Aijazuddin Syed, David M. Hyman, Ahmet Zehir, Armin Shahrokni, Anna Varghese, Diane Reidy, Neil H. Segal, Efsevia Vakiani, David B. Solit, Marc Ladanyi, Michael F. Berger, Nancy Kemeny, Leonard Saltz, Nikolaus Schultz, Rona Yaeger. Integrative genomics analysis of metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4380. doi:10.1158/1538-7445.AM2017-4380

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3581 Background: Half of patients diagnosed with colorectal cancer (CRC) develop metastases and most are CRC liver metastasis (CRLM). A mere 20% of these patients undergo complete resection of their liver disease and 5-year overall survival (OS) is only 50%. We hypothesized that we could identify a specific molecular profile associated with extraordinary survivorship in CRLM patients that would more precisely inform underlying tumor biology beyond standard clinical and pathologic features. Methods: Tumor samples were identified from patients who underwent curative resection. Patients with disease-specific survival (DSS) ≥10 years following resection were compared to those with ≤2-year survival (10yr vs. 2yr). Evaluable DNA was obtained from 36 cases (2yr, n = 17; 10yr, n = 19) then sequenced and analyzed with MSK-IMPACT (MSK-I), a hybridization capture, next generation sequencing platform. Differentially altered genes in 10yr vs. 2yr cohorts were identified (Fisher’s exact). Findings in the extraordinary survivors group were validated using MSK-I in an independent cohort of 965 metastatic CRCs (metCRCs). Kaplan-Meier estimates and log-rank test were used. Results: In the 2yr group, we noted higher clinical risk scores and more complex chemotherapy regimens vs. the 10yr group. Molecularly, mutually exclusive KRAS and TP53 mutations were noted in the 10yr group, whereas significant co-occurrence of KRAS and TP53 mutations was seen in the 2yr group. Further, we noted significant enrichment of VEGF copy number gains in the 2yr group vs. the 10yr group. APC mutation was equally common. In the validation cohort, KRASmut/TP53wt and TP53mut/KRASwt patients (median OS of 10 and 15 years respectively) had significantly better OS than the co-occurring KRASmut / TP53mutpatients (median OS of 4.9 years; (P = 0.0001)). Conclusions: Single mutation of either KRAS or TP53 is associated with better outcomes than co-occurring KRAS/TP53 mutations in metCRC. These data demonstrate use of an extraordinary survivor cohort to identify a molecular profile associated with significant survival differences in an independent cohort of metCRC patients.