Alberts, Steven R.

Abstract Purpose: Colorectal cancers with deficient DNA mismatch repair (dMMR) are presumed to uniformly have dense lymphocytic infiltration that underlies their favorable prognosis and is critical to their responsiveness to immunotherapy, as compared with MMR-proficient (pMMR) tumors. We examined T-cell densities and their potential heterogeneity in a large cohort of dMMR tumors. Experimental Design: CD3+ and CD8+ T-cell densities were quantified at the invasive margin (IM) and tumor core (CT) in 561 stage III colon cancers (dMMR, n = 278; pMMR, n = 283) from a phase III adjuvant trial (N0147). Their association with overall survival (OS) was determined using multivariable Cox analysis. Results: Although CD3+ and CD8+ T-cell densities in the tumor microenvironment were higher in dMMR versus pMMR tumors overall, intertumoral heterogeneity in densities between tumors was significantly higher by 30% to 88% among dMMR versus pMMR cancers (P < 0.0001 for all four T-cell subtypes [CD3+IM, CD3+CT, CD8+IM, CD8+CT]). A substantial proportion of dMMR tumors (26% to 35% depending on the T-cell subtype) exhibited T-cell densities as low as that in the bottom half of pMMR tumors. All four T-cell subtypes were prognostic in dMMR with CD3+IM being the most strongly prognostic. Low (vs. high) CD3+IM was independently associated with poorer OS among dMMR (HR, 4.76; 95% confidence interval, 1.43–15.87; P = 0.0019) and pMMR tumors (P = 0.0103). Conclusions: Tumor-infiltrating T-cell densities exhibited greater intertumoral heterogeneity among dMMR than pMMR colon cancers, with CD3+IM providing robust stratification of both dMMR and pMMR tumors for prognosis. Potentially, lower T-cell densities among dMMR tumors may contribute to immunotherapy resistance.

e15757 Background: SPN is a rare neoplasia of the pancreas, defined by the World Health Organization (WHO) as an epithelial low-grade malignant neoplasm, with a high-grade malignant transformation potential. Literature in this subject is scarce and limited only to small retrospective series. Methods: This is a retrospective study aiming to characterize patients with the diagnosis of SPN at Mayo Clinic between 1992 and 2016. Demographics, clinical and pathological features, recurrence rate and overall survival were recorded. Malignant SPN was defined as per the WHO 2010 classification (Perineural invasion, angioinvasion or deep tissue invasion) and compared to Benign SPN. Results: 44 patients with SPN were identified. 39 patients (88.6%) were female. Median age at diagnosis was 27.5 (Range: 13-64). The most frequent presentation was abdominal pain (52.6%), whereas 36.8% were diagnosed based on incidental imaging findings. Majority (60.4%) of the tumors were located at the pancreatic tail, and 48.5% were solid-cystic lesions. Vascular and lymph node involvement were infrequent. 15 cases (30.23%) were classified as malignant. Tumor size was associated with malignant behavior (Table). Three patients had a metastatic presentation. All but 1 patient were treated with surgery. R1 resection was more frequent in malignant SPN, and 2 patients experienced disease recurrence. Two Stage IV patients were treated with surgery and experienced long term survival, one of them without evidence of disease. There was only 1 death recorded. Conclusions: SNP presents predominantly on young women. The prognosis is excellent even in presence of malignant features, and a complete surgery remains as the main treatment. [Table: see text]

e15616 Background: Cholangiocarcinoma (CCA) is a progressively fatal disease with an annual incidence of 1-2 cases per 100,000 people in the USA. Complete surgical resection is the only curative option for CCA. However, the majority of patients (pts) have advanced disease at diagnosis, and those undergoing resection often develop local or distant recurrence. Gemcitabine and Cisplatin remains the only standard chemotherapeutic regimen for advanced CCA. Alternative and improved therapies are critically needed. Gemcitabine/nab-Paclitaxel (GA) is a regimen that has become standard therapy in advanced pancreatic cancer (PDAC). Given the morphologic and histologic similarities between PDAC and CCA, this regimen has been used in advanced CCA, but no data exists regarding its efficacy in this disease. The goal of our study is to evaluate the Mayo Clinic experience with GA for the treatment of metastatic CCA. Methods: We retrospectively analyzed records from adult pts at Mayo Clinic with metastatic cholangiocarcinoma who received at least 2 cycles of GA. Our aims were to assess the progression-free survival (PFS), overall survival (OS) and disease response. Results: We analyzed 9 pts, 3 male and 6 female. The median age at diagnosis was 50 years (range 41-64). Six pts had metastatic disease at diagnosis while 3 underwent surgery with subsequent distant disease recurrence. Pts received a median of 2 lines (range 0-5) of systemic therapy prior to receiving GA, and a median of 2 cycles (range 2-15) of GA. At the time of our analysis, 4 of the 9 pts (44%) had died. The median OS from initiation of GA was 7.3 months (95% CI 1.7- 12.9) and median PFS from initiation of GA was 4.7 months (95% CI 0.48-8.9). The best overall responses using RECIST criteria were: partial response in 1 (11%), stable disease in 5 (55%) and disease progression in 3 (33%) pts. One pt remained on therapy 14.9 months after initiating GA. Conclusions: In our study, the combination of gemcitabine and nab-paclitaxel has demonstrated similar OS and PFS as other systemic therapies. To the best of our knowledge, this is the first report of this regimen in CCA. Ongoing, prospective trials are currently evaluating this regimen in advanced CCA.

3604 Background: Limited research has investigated the role of variation in the host genome as a determinant of colon carcinoma (CC) outcomes, including toxicity due to therapeutic agents. We examined the relationship between germline genetic factors and treatment-associated serious adverse events (SAEs) in a population of CC patients in which treatment was standardized and follow-up for outcomes was uniformly conducted. Methods: Using existing biospecimens from CC patients with resected stage III disease in a phase III randomized trial of FOLFOX adjuvant chemotherapy with and without cetuximab (NCCTG N0147), genome-wide genotyping arrays were conducted for 2200 patients for a total of ~20 million single nucleotide polymorphisms (SNPs). Using logistic regression models we assessed SNP-specific associations with SAEs, utilizing a discovery-based approach to search the genome in an unbiased manner. Detailed information on SAEs was collected using the Common Toxicity Criteria for Adverse Events (CTCAE, v3.0). Analyses evaluating associations with specific classes of common grade ≥3 SAEs were performed, including gastrointestinal toxicities, neutropenia, and paresthesias. A threshold of P < 5x10-8was used to denote genome-wide significance. Results: Among patients who received FOLFOX, several SNPs on chr 15 near the ANP32A gene and on chr 2 near the CD207 gene were statistically significantly associated with grade ≥3 neuropathy. The strongest SNP-specific associations in these regions were in the range of odds ratio (OR) = 1.3, P = 2.8×10−10 and OR = 1.5, P = 2.7×10−10, respectively. Conclusions: Findings from this genome-wide analysis demonstrate the potential importance of germline genetic variation in influencing CC patients’ experience of specific toxicities to FOLFOX regimens. These results highlight two genomic regions of potential interest for understanding the biological mechanism for such toxicities, although further evaluation and replication is needed. Support: U10CA180821, U10CA180882, U10CA180820, U10CA180863, U10CA180888, CCSRI 021039, R01CA176272, Eli Lilly & Co, Pfizer, Sanofi. Clinical trial information: NCT00079274 .

3579 Background: Tumor infiltrating lymphocytes (TIL) indicate a host immune response that may influence survival. Immunoscore was developed using CD3+ and CD8+density and location in primary CC pts with pooled stages, varying treatment and follow-up. We determined if individual immune markers and/or Immunoscore are prognostic in resected stage III CC pts (N=600). Methods: CD3+ and CD8+ T-cell or CD20+ B lymphocyte density in central tumor (CT) and invasive margin (IM) was evaluated by immunostaining and quantified by image analysis. Immunoscore was calculated on a scale of I0 to I4 with high densities of CD3+ and CD8+in both CT and IM scored as I4; low densities scored as I0. Associations with disease-free survival (DFS) were evaluated by multivariable Cox regression adjusting for covariates. Results: Data for CD3+, CD8+ and CD20+ were generated (N=595). Higher density of CD3+ CT, CD3+ IM and CD8+ IM were associated with longer DFS adjusting for covariates (Table). CD3+ IM had the strongest association with DFS, and was stronger in left-sided (HRadj.=0.81, 95% CI, 0.70-0.94, padj.= 0.0049) vs right-sided (HRadj.=0.93, 95% CI, 0.85-1.0 padj.=0.52) tumors (pinteraction=0.039). Higher density of CD3+ IM was associated with older age (p=0.034), T1/2 (p<.0001), N1 (p=0.017), right-sided (p=0.013), high TILs (p=0.0008), and deficient MMR (p=0.0003). Using a prior Immunoscore risk stratification, higher scores were associated with better DFS (HR.=0.62, CI, 0.44-0.87, p=0.006) (Table). Conclusions: Densities of CD3+ and CD8+, especially at IM, are individually prognostic in FOLFOX-treated pts. Association of CD3+IM with prognosis differed by primary CC site. Immunoscore was strongly prognostic, and this result provides validation in a clinical trial cohort. [Table: see text]

3516 Background: Epidemiological data suggest a protective effect of vitamin D on CC risk. However, association of serum vitamin D level with clinical outcome in pts with surgically resected CC remains unknown. We analyzed total circulating 25-hydroxyvitamin D [25(OH)D)] with clinical outcome in pts with resected stage III CC treated with FOLFOX +/- cetuximab in a phase III trial. Methods: Association of pre-treatment level of plasma 25(OH)D with disease-free survival (DFS) and time-to-recurrence (TTR) was analyzed with 25(OH)D as a continuous variable by a relative risk model with splines and as a binary variable (vitamin D deficient [<30 ng/mL]) using multivariable Cox regression. Results: Overall, 49% (291/600) of pts were vitamin D deficient. Prevalence of vitamin D deficiency was significantly higher in women vs men (52% vs. 48%, p=0.030) and in blacks vs whites (74% vs. 45%, p=0.0003). The continuous 25(OH)D level and pt sex were associated by the interaction test (pinteraction=0.044). There were no statistically significant associations with DFS/TTR for either continuous 25(OH)D level (DFS, p=0.22; TTR, p=0.26) nor for vitamin D deficiency (DFS, adjusted hazard ratio [HRadj]=1.01, 95% CI, 0.74-1.38; padj=0.94; TTR, HRadj=1.00; CI, 0.72-1.38; padj=0.99. A comparison of the highest vs lowest tertile showed a significant association between the highest 25(OH)D level and better outcomes in men (DFS, HRadj.=0.18, CI, 0.04-0.76, padj=0.020; TTR, HRadj.=0.12, CI, 0.02-0.64, padj=0.014), but not in women (DFS, pinteraction=0.039; TTR, pinteraction=0.033). Conclusions: Nearly one-half of pts in the clinical trial cohort were vitamin D deficient with lowest 25(OH)D levels found in women and blacks. While vitamin D deficiency was not associated with adverse outcome, high levels of vitamin D in men, but not women, were associated with longer survival. Support: U10CA180821, U10CA180882, U10CA180820, U10CA180863, U10CA180888, U10CA077202, CCSRI 021039. ClinicalTrials.gov Identifier: NCT00079274.