CpG island methylator phenotype is associated with response to adjuvant irinotecan-based therapy for stage III colon cancer.

BACKGROUND & AIMS: The CpG island methylator phenotype (CIMP), defined by a high frequency of aberrantly methylated genes, is a characteristic of a subclass of colon tumors with distinct clinical and molecular features. Cohort studies have produced conflicting results on responses of CIMP-positive tumors to chemotherapy. We assessed the association between tumor CIMP status and survival of patients receiving adjuvant fluorouracil and leucovorin alone or with irinotecan (IFL). METHODS: We analyzed data from patients with stage III colon adenocarcinoma randomly assigned to groups given fluorouracil and leucovorin or IFL after surgery, from April 1999 through April 2001. The primary end point of the trial was overall survival and the secondary end point was disease-free survival. DNA isolated from available tumor samples (n = 615) was used to determine CIMP status based on methylation patterns at the CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1 loci. The effects of CIMP on survival were modeled using Kaplan-Meier and Cox proportional hazards; interactions with treatment and BRAF, KRAS, and mismatch repair (MMR) status were also investigated. RESULTS: Of the tumor samples characterized for CIMP status, 145 were CIMP positive (23%). Patients with CIMP-positive tumors had shorter overall survival times than patients with CIMP-negative tumors (hazard ratio = 1.36; 95% confidence interval: 1.01-1.84). Treatment with IFL showed a trend toward increased overall survival for patients with CIMP-positive tumors, compared with treatment with fluorouracil and leucovorin (hazard ratio = 0.62; 95% CI: 0.37-1.05; P = .07), but not for patients with CIMP-negative tumors (hazard ratio = 1.38; 95% CI: 1.00-1.89; P = .049). In a 3-way interaction analysis, patients with CIMP-positive, MMR-intact tumors benefited most from the addition of irinotecan to fluorouracil and leucovorin therapy (for the interaction, P = .01). CIMP was more strongly associated with response to IFL than MMR status. Results for disease-free survival times were comparable among all analyses. CONCLUSIONS: Patients with stage III, CIMP-positive, MMR-intact colon tumors have longer survival times when irinotecan is added to combination therapy with fluorouracil and leucovorin.

Molecular markers predictive of chemotherapy response in colorectal cancer.

Recognition of the molecular heterogeneity of colorectal cancer (CRC) has led to the classification of CRC based on a variety of clinical and molecular characteristics. Although the clinical significance of the majority of these molecular alterations is still being ascertained, it is widely anticipated that these characteristics will improve the accuracy of our ability to determine the prognosis and therapeutic response of CRC patients. A few of these markers, such as microsatellite instability and the CpG island methylator phenotype (CIMP), show promise as predictive markers for cytotoxic chemotherapy. KRAS is a validated biomarker for epidermal growth factor receptor (EGFR)-targeted therapy, while NRAS and PI3KCA are evolving markers for targeted therapies. Multiple new actionable drug targets and potential response biomarkers are being identified on a regular basis, but most are not ready for clinical use at this time. This review focuses on key molecular features of CRCs and the application of these molecular alterations as predictive biomarkers for CRC.

High risk of colorectal and endometrial cancer in Ashkenazi families with the MSH2 A636P founder mutation.

BACKGROUND & AIMS: The MSH2 A636P mutation is a founder mutation in Ashkenazi Jews that causes Lynch syndrome, with a prevalence of 0.4%-0.7%. Estimates of age-specific cumulative risk and lifetime risk for colorectal cancer (CRC) and endometrial cancer (EC) specific to carriers of this mutation are not available. METHODS: We studied 27 families with MSH2 A636P gene mutations identified in Israel; 13 were identified via a population-based, case-control study and 14 were identified from a clinical genetics service. Age-specific cumulative risks (penetrance) and hazard ratio (HR) estimates of CRC and EC risks were calculated and compared with the general Ashkenazi population using modified segregation analysis. An ascertainment-corrected likelihood that combined population-based and clinic-based sampling provided a powerful analysis for estimating penetrance. We analyzed 74 cases of CRC (40 in the clinic series and 34 in the population-based series), diagnosed at median ages of 50 years (men) and 49 years (women) in the combined sample. RESULTS: The cumulative risk of CRC at age 70 was 61.62% for men (95% confidence interval [CI], 37.49%-76.45%) and 61.08% for women (95% CI, 39.39%-75.14%), with overall HRs of 31.8 (19.9-51.0) and 41.8 (27.4-64.0), respectively. There were 28 cases of EC, diagnosed at a median age of 53.0 years. The cumulative risk of EC was 55.64% (95% CI, 33.07%-70.58%) with an overall HR of 66.7 (41.7-106.7). CONCLUSIONS: Lifetime risks of CRC and EC in MSH2 A636P carriers are high even after adjusting for ascertainment. These estimates are valuable for patients and providers; specialized cancer screening is necessary for carriers of this mutation.

A 66-year-old woman with newly diagnosed oligometastatic non-small cell lung cancer.

A 66-year-old woman presented with newly diagnosed stage IV non-small cell lung cancer (NSCLC) and a large adrenal metastasis. She initially had flu-like symptoms and dyspnea and was found to have a right upper lobe (RUL) lung nodule. Chest CT showed a 1.4-cm spiculated RUL lung nodule, peripheral right lung nodule, right perihilar mass, and 10.9-cm left adrenal mass. PET/CT showed enhancement of the RUL nodule, hilar mass, and left adrenal mass. She presented for evaluation of treatment options. This case was thought to represent an instance of oligometastatic stage IV NSCLC. Literature suggests that a select patient population with otherwise resectable disease may benefit from surgical resection of a lung primary and the isolated metastasis with improved survival. This seems to be most effective in patients who have undergone a complete staging evaluation with PET scan; CT of the chest, abdomen, and pelvis; and a brain MRI revealing T1-2, N0-1, M-oligo disease. This radical approach should be reserved for patients with potentially curative disease based on the staging evaluation and who are otherwise good surgical candidates.

Head circumference in the clinical detection of PTEN hamartoma tumor syndrome in a clinic population at high-risk of breast cancer.

PTEN Hamartoma Tumor Syndrome (PHTS) is often recognized by the presence of macrocephaly and associated mucocutaneous features, and is notable for a profound predisposition to breast and thyroid cancers. Head circumference (HC) is rarely measured when evaluating women at high risk for breast cancer, but may offer insight into characterizing cancer risk. Patients enrolled in the University of Michigan Cancer Genetics registry for breast cancer evaluation were analyzed for personal and family history of cancer and features of PHTS. This group of women was compared to all women who had undergone PTEN testing and whether or not they met clinical criteria for PHTS. Among the 164 women referred for breast cancer risk evaluation, a statistically significant difference in mean HC was found between women who did (57.3 cm) and did not (55.4 cm) meet clinical criteria for PHTS with both values below the established threshold for macrocephaly (58 cm). The sensitivity and specificity of macrocephaly for the presence of a PTEN mutation were 100 and 53%, respectively, among the 28 women tested. The positive predictive value was 14%. PTEN mutation positive and PTEN mutation negative women were not well differentiated by PHTS clinical criteria (P = 0.2348). The high sensitivity of HC suggests that this simple measure can improve the detection of unrecognized patients with PHTS. Measuring HC is a useful clinical feature, but is insufficient as a singular screening tool for PHTS. Even in a high risk population, the PPV of this test is low. Diagnosis of this important genetic syndrome still relies heavily on detailed history and full physical exam.

Molecular phenotypes of colorectal cancer and potential clinical applications.

Colorectal cancer (CRC) is a heterogeneous disease, arising from many possible etiological pathways. This heterogeneity can have important implications for CRC prognosis and clinical management. Epidemiological studies of CRC risk and prognosis-as well as clinical trials for the treatment of CRC-must therefore be sensitive to the molecular phenotype of colorectal tumors in patients under study. In this review, we describe four tumor markers that have been widely studied as reflections of CRC heterogeneity: (i) microsatellite instability (MSI) or DNA mismatch repair (MMR) deficiency, (ii) the CpG island methylator phenotype (CIMP), and somatic mutations in (iii) BRAF and (iv) KRAS. These tumor markers have been used to better characterize CRC epidemiology and, increasingly, may be used to guide clinical decision-making. Going beyond these traditional tumor markers, we also briefly review some more novel markers likely to be of clinical significance. Lastly, recognizing that none of these individual tumor markers are isolated attributes but, rather, a reflection of broader tumor phenotypes, we review some of the hypothesized etiological pathways of CRC development and their associated clinical differences.

Cancer-Directed Therapy and Hospice Care for Metastatic Cancer in American Indians and Alaska Natives.

BACKGROUND: Little has been reported regarding patterns of oncologic care in American Indian/Alaska Natives (AI/AN). Observed worse survival has been attributed to later-stage presentation. We aimed to evaluate racial differences in cancer-directed therapy and hospice care utilization in AI/ANs and non-Hispanic whites (NHW) with metastatic cancer. METHODS: The linked Surveillance, Epidemiology, and End Results (SEER)-Medicare claims database was accessed for AI/AN and NHW metastatic-cancer cases diagnosed between 2001 and 2007. Utilization of cancer-directed therapy (surgery, radiation, and/or chemotherapy) and/or hospice services was compared between AI/ANs and NHWs. Minimally adjusted (age, sex, diagnosis year) and fully-adjusted (also Klabunde comorbidity score, sociodemographic factors) regression models were used to estimate odds (OR) and hazard ratios (HR) for receipt of care. RESULTS: AI/ANs were younger, more likely to reside in the West, be unmarried, have lower income, and live in a nonurban setting than NHWs. Fewer AI/ANs received any cancer-directed therapy (57% vs. 61% NHWs) within 3 months of diagnosis; sociodemographic factors accounted for much of this difference [fully-adjusted HR, 0.94; 95% confidence interval (CI), 0.83-1.08]. We noted differences in hospice utilization between AI/ANs (52%) and NHWs (61%). A significant difference in hospice utilization remained after adjustment for sociodemographics (OR, 0.78; 95% CI, 0.61-0.99). CONCLUSION: Observed absolute differences in care for AI/ANs and NHWs with metastatic cancer were largely accounted for by adjusting for socioeconomics, comorbidities, and demographic factors. A significant association between race and hospice utilization was noted. IMPACT: Efforts to improve metastatic-cancer care should focus on socioeconomic barriers and investigate the observed disparity in receipt of hospice services.

Dissemination of Quality-of-Care Research Findings to Breast Oncology Surgeons.

PURPOSE: In this era of rapidly evolving clinical knowledge, clinicians need to be aware of current research and how it might affect their practice. The Internet is a widely available, under-assessed tool for providing this information. In this two-phase pilot study, a novel Web site (www.cansortsurgeons.org) was developed to specifically disseminate relevant clinical information to community breast oncology surgeons. METHODS: The first phase targeted a sample of community surgeons identified from Surveillance, Epidemiology, and End Results catchment areas in Los Angeles, CA and Detroit, MI. The second phase broadened availability by linking the site through the American College of Surgeons (ACoS) Commission on Cancer (CoC) homepage. An eight-question, Web-based survey was used to obtain feedback regarding the Web site's utility and potential application to clinical practice. Journal continuing medical education credit was also offered through ACoS. RESULTS: For phase 1, of the 315 community surgeons invited to view the site, 114 (36%) participated in the study and 98 (86%) responded to the survey. Overall, there was a strongly supportive response, with 79 (81%) recommending the site to other clinicians. For phase 2, of the 516 site hits, 411 came from the ACoS site. Only 10 individuals completed the survey during this phase, but all positively endorsed the utility of the site. CONCLUSION: The implication for clinical practice is that the Internet is a useful tool for providing relevant clinical research to providers. In the future, this could be tailored to an individual's needs, aiding synthesis and, hopefully, improving the quality of clinical care.

Functional and genomic approaches reveal an ancient CHEK2 allele associated with breast cancer in the Ashkenazi Jewish population.

Functional and genomic approaches can be integrated to screen efficiently for pathogenic alleles in founder populations. We applied such approaches to analysis of the cancer-associated cell cycle regulator CHEK2 in the Ashkenazi Jewish population. We first identified two extended haplotypes at CHEK2 that co-segregated with breast cancer in high-risk families. We sequenced CHEK2 in a case representing each haplotype and discovered two novel amino acid substitutions, CHEK2.S428F in the kinase domain and CHEK2.P85L in the N-terminal region. To assay these alleles for loss of CHEK2 function, we tested their capacity to complement Rad53 deletion in Saccharomyces cerevisiae. CHEK2.S428F failed to complement Rad53 and thus largely abrogates normal CHEK2 function, whereas CHEK2.P85L complemented Rad53 as well as did wild-type CHEK2. Epidemiologic analyses were concordant with the functional tests. Frequencies of CHEK2.S428F heterozygotes were 2.88% (47/1632) among female breast cancer patients not selected for family history or age at diagnosis and 1.37% (23/1673) among controls (OR=2.13, 95% CI [1.26, 3.69], P=0.004), whereas frequencies of CHEK2.P85L were 0.92% among cases and 0.83% among controls. On the basis of the experience of mothers, sisters and daughters of probands, breast cancer risk due to CHEK2.S428F was estimated as 0.17 (+/-0.08) by age 60. We conclude that CHEK2.S428F increases breast cancer risk approximately 2-fold among Ashkenazi Jewish women, whereas CHEK2.P85L is a neutral allele. In general, these results suggest that selecting probands with extended haplotypes that co-segregate with disease can improve the efficiency of resequencing efforts and that quantitative complementation tests in yeast can be used to evaluate variants in genes with highly conserved function.