Shailesh Advani

Classifying Colorectal Cancer by Tumor Location Rather than Sidedness Highlights a Continuum in Mutation Profiles and Consensus Molecular Subtypes

Purpose: Colorectal cancers are classified as right/left-sided based on whether they occur before/after the splenic flexure, with established differences in molecular subtypes and outcomes. However, it is unclear if this division is optimal and whether precise tumor location provides further information. Experimental Design: In 1,876 patients with colorectal cancer, we compared mutation prevalence and overall survival (OS) according to side and location. Consensus molecular subtype (CMS) was compared in a separate cohort of 608 patients. Results: Mutation prevalence differed by side and location for TP53, KRAS, BRAFV600, PIK3CA, SMAD4, CTNNB1, GNAS, and PTEN. Within left- and right-sided tumors, there remained substantial variations in mutation rates. For example, within right-sided tumors, RAS mutations decreased from 70% for cecal, to 43% for hepatic flexure location (P = 0.0001), while BRAFV600 mutations increased from 10% to 22% between the same locations (P < 0.0001). Within left-sided tumors, the sigmoid and rectal region had more TP53 mutations (P = 0.027), less PIK3CA (P = 0.0009), BRAF (P = 0.0033), or CTNNB1 mutations (P < 0.0001), and less MSI (P < 0.0001) than other left-sided locations. Despite this, a left/right division preceding the transverse colon maximized prognostic differences by side and transverse colon tumors had K-modes mutation clustering that appeared more left than right sided. CMS profiles showed a decline in CMS1 and CMS3 and rise in CMS2 prevalence moving distally. Conclusions: Current right/left classifications may not fully recapitulate regional variations in tumor biology. Specifically, the sigmoid-rectal region appears unique and the transverse colon is distinct from other right-sided locations. Clin Cancer Res; 24(5); 1062–72. ©2017 AACR. See related commentary by Dienstmann, p. 989

Association of SMAD4 mutation with patient demographics, tumor characteristics, and clinical outcomes in colorectal cancer.

SMAD4 is an essential mediator in the transforming growth factor-β pathway. Sporadic mutations of SMAD4 are present in 2.1–20.0% of colorectal cancers (CRCs) but data are limited. In this study, we aimed to evaluate clinicopathologic characteristics, prognosis, and clinical outcome associated with this mutation in CRC cases. Data for patients with metastatic or unresectable CRC who underwent genotyping for SMAD4 mutation and received treatment at The University of Texas MD Anderson Cancer Center from 2000 to 2014 were reviewed. Their tumors were sequenced using a hotspot panel predicted to cover 80% of the reported SMAD4 mutations, and further targeted resequencing that included full-length SMAD4 was performed on mutated tumors using a HiSeq sequencing system. Using The Cancer Genome Atlas data on CRC, the characteristics of SMAD4 and transforming growth factor-β pathway mutations were evaluated according to different consensus molecular subtypes of CRC. Among 734 patients with CRC, 90 (12%) had SMAD4 mutations according to hotspot testing. SMAD4 mutation was associated with colon cancer more so than with rectal cancer (odds ratio 2.85; p<0.001), female sex (odds ratio 1.71; p = 0.02), and shorter overall survival than in wild-type SMAD4 cases (median, 29 months versus 56 months; hazard ratio 2.08; p<0.001 [log-rank test]). SMAD4 mutation was not associated with age, stage at presentation, colonic location, distant metastasis, or tumor grade. A subset of patients with metastatic CRC (n = 44) wild-type for KRAS, NRAS, and BRAF who received anti-epidermal growth factor receptor therapy with mutated SMAD4 (n = 13) had shorter progression-free survival duration than did patients wild-type for SMAD4 (n = 31) (median, 111 days versus 180 days; p = 0.003 [log-rank test]). Full-length sequencing confirmed that missense mutations at R361 and P356 in the MH2 domain were the most common SMAD4 alterations. In The Cancer Genome Atlas data, SMAD4 mutation frequently occurred with KRAS, NRAS, and BRAF mutations and was more common in patients with the consensus molecular subtype 3 of CRC than in those with the other 3 subtypes. This is one of the largest retrospective studies to date characterizing SMAD4 mutations in CRC patients and demonstrates the prognostic role and lack of response of CRC to anti-epidermal growth factor receptor therapy. Further studies are required to validate these findings and the role of SMAD4 mutation in CRC.

Screening adherence and cancer risk perceptions in colorectal cancer survivors with Lynch-like syndrome

Cancer screening recommendations for patients with Lynch‐like syndrome (LLS) are not well defined. We evaluated adherence to Lynch syndrome (LS) screening recommendations, cancer risk perceptions, and communication within the families among colorectal cancer (CRC) survivors with LLS. Thirty‐four participants with LLS completed a questionnaire about risk perception, adherence to LS screening recommendations, and communication with relatives. Clinical data were obtained from medical records. Most participants (76%) believed they should undergo colonoscopy every 1–2 years. Only 41% correctly interpreted their genetic tests as uninformative negative or as variant of unknown significance for LS. Less than half had had an upper gastrointestinal endoscopy for screening purpose. Among female participants, 86% had been screened for endometrial cancer (EC) and 71% for ovarian cancer. Most participants had informed relatives about the CRC diagnosis and advised them to undergo CRC screening, but only 50% advised female relatives to be screened for EC and only one‐third advised relatives to have genetic counseling. Most CRC survivors with LLS follow the same cancer screening recommended for LS patients but do not understand the meaning of LLS. Greater care must be devoted to communicating the implications of nondiagnostic germline mutation testing among patients with LLS.

Use of non-steroidal anti-inflammatory drugs in US adults: changes over time and by demographic

Objective Aspirin and non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) are preventive against cardiovascular disease (CVD) and several cancer types, but long-term use has been associated with significant health risks, resulting in conflicting recommendations on NSAID use for prevention of CVD and cancer. Previous research indicates that aspirin use increases with age and CVD risk factors and that a large percentage of the US population regularly use analgesics, including NSAIDs, but there has not been a recent, in-depth assessment of NSAID use prevalence, changes in use over time or predictors of NSAID use in the USA. Methods We used the cross-sectional, National Health And Nutrition Examination Survey (NHANES) from 1988 to 1994 and three continuous cycles (1999–2004) to assess regular NSAID use prevalence, changes over time and predictors of regular NSAID use. Results Overall, regular NSAID use increased over time and varied by demographic features. Participants over 60 years of age, women, participants with high body mass index, increased waist circumference or heart disease were significantly more likely to be regular NSAID users. By contrast, non-Hispanic African American and Mexican American participants were significantly less likely to regularly use NSAIDs. Conclusions This study uses a nationally representative data set (NHANES) to provide an exploration of regular NSAID use patterns over time, highlighting several demographic, lifestyle and clinical conditions associated with regular NSAID use. Understanding who is likely to regularly use NSAIDs enables more targeted messaging both for increasing the preventive benefits and for limiting the toxicities associated with regular use of NSAIDs.

Local Control Modality and Outcome for Ewing Sarcoma of the Femur: A Report From the Children’s Oncology Group

BackgroundThe choice of a local control (LC) modality for Ewing sarcoma (EWS) of the femur is controversial. This study aimed to determine the effect of LC modality on tumor LC and patient outcomes.MethodsThe study reviewed the treatment and outcomes for 115 patients who had EWS of the femur treated with similar chemotherapy in three cooperative group trials. Patient outcomes were analyzed according to the LC modality using the log-rank test and the cumulative incidence of local or distant failure using competing risks regression.ResultsThe median age of the patients was 13 years. The most common tumor location was the proximal femur followed by the mid femur. For 55 patients with available data, the tumor was larger than 8 cm in 29 patients and 8 cm or smaller in 26 patients. For 84 patients (73 %), surgery only was performed, whereas 17 patients (15 %) had surgery plus radiation, and 14 patients (12 %) had radiation only. The 5-year event-free survival (EFS) rate was 65 % (95 % confidence interval [CI], 55–73 %), and the 5-year overall survival (OS) rate was 70 % (95 % CI, 61–78 %). Patient outcomes did not differ significantly according to tumor location within the femur (proximal, mid or distal) or tumor size (<8 vs ≥8 cm). The findings showed no statistically significant differences in EFS, OS, cumulative incidence of local failure, or cumulative incidence of distant failure according to LC modality (surgery, surgery plus radiation, or radiation).ConclusionsThe LC modality did not significantly affect disease outcome for EWS of the femur. Further study of treatment complications and functional outcome may help to define the optimal LC modality.

Regional lymph node involvement and outcomes in appendiceal neuroendocrine tumors: a SEER database analysis

Background Appendiceal neuroendocrine neoplasms are most often diagnosed incidentally during appendectomy. The need for subsequent right hemicolectomy (RHC) is determined based on the risk of regional lymph node (LN) involvement. Tumor size has historically been used as an indicator of this risk, but controversy remains regarding its cut off. Furthermore, the impact of RHC on survival is unclear. Methods We used the SEER database to identify patients diagnosed with appendiceal neuroendocrine tumors. Results Of 1731 patients, 38.0% had well-differentiated neuroendocrine tumors (WDNETs), 60.8% had mixed histology tumors (MHTs), and 1.2% had poorly differentiated neuroendocrine carcinomas (PDNECs). In patients with WDNETs and MHTs who had adequate lymphadenectomy, higher rates of LN involvement were noted for tumors size 11–20 mm than ≤10 mm (56.8% vs. 11.6%, p <0.001; 32.9% vs. 10.4%, p=0.004, respectively). The type of surgery did not affect OS in cases with MHTs with LN involvement (HR 1.00; 95% CI, 0.53–1.89; p =0.99). Patients with regionally advanced WDNET showed excellent survival and only 3 patients (out of 118) died from cancer within 10 years. Conclusions 10 mm appears to be a more appropriate cutoff than 20 mm for predicting LN metastasis in appendiceal NETs. Cases with WDNETs and nodal involvement demonstrate overall excellent prognosis irrespective of type of surgery (i.e. RHC may not improve outcome). In MHTs with LN metastases, survival is markedly worse in spite of RHC. The role of adjuvant therapy should be evaluated in this subset.

Analysis of HSP27 and the Autophagy Marker LC3B+ Puncta Following Preoperative Chemotherapy Identifies High-Risk Osteosarcoma Patients

Chemotherapy-induced autophagy is a proposed mechanism of chemoresistance and potential therapeutic target in osteosarcoma. We evaluated heat shock protein 27 (HSP27) and autophagy-related proteins as predictors of pathologic treatment response and prognostic markers among osteosarcoma patients who received standard chemotherapy. We analyzed 394 tumor specimens (pre-treatment, post-treatment, and metastases) from 260 osteosarcoma patients by immunohistochemistry for cytoplasmic light chain 3B (LC3B)-positive puncta, sequestosome 1 (SQSTM1), high mobility group box 1 (HMGB1), and HSP27 expression. The staining percentage and intensity for each marker were scored and the extent to which marker expression was correlated with pathologic response, relapse-free survival (RFS), and overall survival (OS) was assessed. LCB3+ puncta in post-treatment primary tumors (50%) and metastases (67%) was significantly higher than in pre-treatment biopsy specimens (30%; P = 0.023 and <0.001). Among 215 patients with localized osteosarcoma, both pre-treatment [multivariate hazard ratio (HR), 26.7; 95% confidence interval (CI), 1.47–484; P = 0.026] and post-treatment HSP27 expression (multivariate HR, 1.85; 95% CI, 1.03–3.33; P = 0.039) were associated with worse OS. Lack of LC3B+ puncta at resection was an independent poor prognostic marker in both univariate (HR, 1.78; 95% CI, 1.05–3.03; P = 0.034) and multivariate models (HR, 1.75; 95% CI, 1.01–3.04; P = 0.045). Patients with LC3B+/HSP27− tumors at resection had the best 10-year OS (75%) whereas patients with LC3B−/HSP27+ tumors had the worst 10-year survival (25%). Neither HSP27 expression nor the presence of LCB3+ puncta was correlated with pathologic treatment response. Our findings establish HSP27 expression and LC3B+ puncta as independent prognostic markers in osteosarcoma patients receiving standard chemotherapy and support further investigation into strategies targeting HSP27 or modulating autophagy in osteosarcoma treatment. Mol Cancer Ther; 17(6); 1315–23. ©2018 AACR.

Health-Related Quality of Life and Survival Outcomes of Pediatric Patients With Nonmetastatic Osteosarcoma Treated in Countries With Different Resources

Purpose Health-related quality of life (HRQOL) improves throughout treatment of patients with nonmetastatic osteosarcoma. We compared HRQOL for patients in the United States and Chile treated on an international trial (OS99) with polychemotherapy and surgery, and we assessed the relationships among HRQOL measures, event-free survival (EFS), and overall survival (OS). Materials and Methods Patients with newly diagnosed, localized osteosarcoma and their parents completed three HRQOL instruments (PedsQL v.4, PedsQL Cancer v.3, and Symptom Distress Scale [SDS]). Data were collected at four time points throughout therapy. Repeated measures models were used to investigate the effect of treatment site on instrument scores. The log-rank test examined the impact of treatment site on survival outcomes, and Cox proportional hazards regression models evaluated baseline HRQOL measures as predictors of EFS and OS. Results Of 71 eligible patients, 66 (93%) participated in the HRQOL studies in the United States (n = 44) and Chile (n = 22). The median age was 13.4 years (range, 5 to 23 years). Clinical characteristics were similar between treatment sites. US patients reported better scores for physical (P = .030), emotional (P = .027), and school functioning (P < .001). Chilean patients reported poorer scores for worry (P < .001) and nausea (P = .007). Patient and parent nausea scores were similar between patients treated in the United States and Chile by the end of therapy. Differences in symptom distress were not observed between the countries. Neither HRQOL measures nor treatment site were associated with EFS or OS. Conclusion Although significant differences in HRQOL were observed between countries, outcomes were similar, and HRQOL measures were not associated with prognosis.

Abstract C27: Lifestyle and cancer screening behaviors among Asian Indians compared to BRFSS rates in Texas

Background: Asian Indians are a rapidly growing population in the US. Little is known about their dietary and lifestyle behaviors and their impact on chronic disease and cancer. The association of poor diet, tobacco use, alcohol consumption, excessive weight, and lack of physical activity are well documented as risk factors for development of various cancers. In addition, cancer screening is an equally important aspect of cancer prevention. The Centers for Disease Control annually conducts the Behavioral Risk Factor Surveillance System (BRFSS) survey to monitor these factors among the US population. We compared these factors among Asian Indians in Houston with Whites, African Americans and Hispanics who were surveyed in the Texas BRFSS. Methods: The Indian American Cancer Network (IACAN) in partnership with the University of Texas M.D. Anderson Cancer Center conducted the South Asian Health Needs Assessment study (SAHNA) to understand the health status of Asian Indians in the Greater Houston area from August 2013 to September 2014. A total of 1525 Asian Indians completed a health survey. Responses on the lifestyle and cancer risk factors questions were compared for the SAHNA participants with those of Whites, Hispanics and Blacks in the Texas 2013 BRFSS. Results: Using BMI>=25 to define overweight/obesity 63% of Whites, 73% of Hispanics and 73% of Blacks were overweight/obese as compared to 49% of Asian Indians. Smoking status was defined as being someone who has smoked >=100 cigarettes in their lifetime. About 45% of whites, 31% of Hispanics and 33% of Blacks met this criterion, while 7% of Asian Indians were in this category. Alcohol intake was defined as consumption of any alcohol drink in the past month. About 56% of whites, 43% of Hispanics and 44% of Blacks reported this level of consumption, as compared to 40% of Asian Indians. Recommended physical activity was defined as >150 minutes of moderate exercise per week. 54% of whites, 64% Hispanics and 61% of African Americans and 46% of Asian Indians were found to have inadequate physical activity ( Similarly we compared cancer screening behaviors between these groups. For women>=40 years of age, 70% of Whites, 63% Hispanics, 76% AA and 86% Asian Indians reported ever having a mammogram. For women>=18 years of age, 76% Whites, 72% Hispanics, 85% African Americans and 88% of Asian Indians had a pap test in the past 3 years. For males>=40 years, 50% of Whites, 25% of Hispanics, 48% of Blacks and 63% of Asian Indians reported ever having a PSA or DRE test for prostate cancer screening. Among all participants>=50 years of age, 13% of whites, 10% of Hispanics, 20% of Blacks and 23% of Asian Indians underwent a fecal occult blood test (FOBT), whereas 70% of Whites, 45% of Hispanics, 67% of African Americans and 45% of Asian Indians underwent colonoscopy for colorectal cancer screening. Conclusion: This study helps us to assess health behaviors of Asian Indians in Houston, relative to other racial and ethnic groups in Texas. Although Asian Indians compared favorably for most lifestyle factors and cancer screening rates, there is still need for improvement in controlling weight, increasing physical activity and adhering to recommended cancer screening practices. Citation Format: Shailesh Advani, Pragati Advani, Beverly Gor, Vaithianathan K. Dorai, Kanchan Kabad, Mala Pande. Lifestyle and cancer screening behaviors among Asian Indians compared to BRFSS rates in Texas. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr C27.

Abstract 4763: Correlation of CpG island methylation with clinical and pathologic characteristics in metastatic colorectal cancer patients

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Background: Colorectal cancer morbidity and mortality rates vary by race and ethnicity. The combined contribution of genetics and environment to response to chemotherapy, progression-free and overall survival in colorectal cancer patients is unclear, but CpG island hypermethylation (CIMP), a discrete molecular subtype of colorectal cancer, is associated with inflammation and environmental exposures. Hence our main objective is to assess correlation between various modifiable risk factors and CIMP status among metastatic colorectal cancer patients. Methods: We characterized CIMP methylation (MINT1, MINT2, MINT31, p14, p16, and MLH1) in 229 metastatic colorectal cancer patients using PCR amplification of bisulfite treated DNA followed by pyrosequencing. The number of methylated probes were averaged to obtain the% methylation with CIMP-High (CIMP-H) being defined as ≥40% of probes methylated. Associations of demographic and clinical characteristics, including BMI, diabetes, obesity, physical activity, smoking and drinking status, as well as presence or absence of other molecular alterations (BRAF, KRAS, NRAS, PIK3CA and PTEN loss) with overall survival were assessed in multivariable-adjusted Cox proportional hazards models. Results: When treating methylation as a continuous variable, patients with BRAF mutation had higher methylation as compared to participants with BRAF wildtype (40.6% vs 20.5%, p = 0.001). White, non-Hispanic (WNH) patients had greater degree of tumor methylation (24.8%) as compared to other racial categories (p = 0.02). When classified as a categorical variable, moderate to vigorous physical activity was associated with higher rate of having any methylated probes, as compared to sedentary patients (p = 0.02). CIMP status was not associated with OS in these patients in multivariable-adjusted Cox models. However when stratified by CIMP status. When stratified by CIMP status; among patients with 0-40% methylation, KRAS mutation was associated with poor OS(HR = 3.19, p = 0.006) and diabetes was protective (HR = .14, p = 0.025). Among patients with high methylation(41-100%) methylation, obesity was associated with poor OS (HR = 5.20, p = 0.038) and former smoking was associated with poor OS(HR = 2.92, p = 0.05). When stratified by KRAS mutation status, among patients with KRAS wildtype, obesity was associated with poor OS(HR = 2.86, p = 0.019) and among patients with KRAS mutation, diabetes was protective (HR = 0.18, p = 0.033) Conclusion and Impact: CpG island methylator phenotype was associated with unique clinicopathologic characteristics. Methylation, as assessed by the 6-gene CIMP panel, was not associated with worse outcomes after correcting for the KRAS mutations, a well-established genetic marker of poor prognosis. Hypermethylation did appear to modulate outcomes in obese patients with hypermethylated tumors. Citation Format: Shailesh M. Advani, Michael Sangmin Lee, Michael James Overman, David Fogelman, Bryan K. Kee, Shanequa D. Manuel, Jennifer Davis, Van Karlyle Morris, Callisia Nathelee Clarke, Carrie R. Daniel, David G. Menter, Stanley R. Hamilton, Dipen Maheshbhai Maru, Scott Kopetz. Correlation of CpG island methylation with clinical and pathologic characteristics in metastatic colorectal cancer patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4763. doi:10.1158/1538-7445.AM2015-4763