Charles F. Lynch

Cigarette Smoking and Colorectal Cancer Risk by Molecularly Defined Subtypes

BACKGROUNDnCigarette smoking is an established risk factor for colorectal cancer. Because colorectal carcinogenesis is a heterogeneous process, we investigated whether cigarette smoking is differentially associated with molecularly defined subtypes of colorectal cancer.nnnMETHODSnWe evaluated associations between smoking and incident colorectal cancer, overall and by microsatellite instability (MSI) phenotype (MSI-high vs MSI-low or microsatellite stable), CpG island methylator phenotype (CIMP positive or CIMP negative), and BRAF mutation status (BRAF mutation positive or BRAF mutation negative), among 37 399 participants in a population-based cohort study (the Iowa Womens Health Study). Cigarette smoking (and other exposures) was assessed by self-report at baseline in 1986, including smoking status (never and ever [former or current]), age at initiation, total duration, average number of cigarettes smoked per day, cumulative pack-years, and induction period. Vital status and state of residence were determined by mailed follow-up questionnaires in 1987, 1989, 1992, and 1997 and by linkage to Iowa death certificate records. Nonrespondents were checked via the National Death Index to identify descendants. Participants with newly diagnosed (ie, incident) colorectal cancer were identified through annual linkage with the Iowa Cancer Registry. Archived paraffin-embedded tumor tissue specimens were obtained for 555 patients with colorectal cancer who were diagnosed from January 1, 1986, through December 31, 2002, and MSI status, CIMP status, and BRAF status were determined. Multivariable Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs).nnnRESULTSnEver-smokers were at moderately increased risk for incident colorectal cancer (RR = 1.19, 95% CI = 1.05 to 1.35) compared with never-smokers. Higher risk estimates were observed for current smokers with MSI-high tumors (RR = 1.99, 95% CI = 1.26 to 3.14), CIMP-positive tumors (RR = 1.88, 95% CI = 1.22 to 2.90), and BRAF mutation-positive tumors (RR = 1.92, 95% CI = 1.22 to 3.02). Other smoking-related variables (ie, age at initiation, total duration, average number of cigarettes smoked per day, cumulative pack-years, and induction period) were also associated with MSI-high, CIMP-positive, and BRAF mutation-positive tumor subtypes. Conversely, cigarette smoking status (ever vs never) was not associated with the MSI-low or microsatellite stable (RR = 1.00, 95% CI = 0.79 to 1.25), CIMP-negative (RR = 1.02, 95% CI = 0.81 to 1.30), or BRAF mutation-negative subtypes (RR = 1.00, 95% CI = 0.65 to 1.27).nnnCONCLUSIONSnIn this prospective study of older women, cigarette smoking was associated with the MSI-high, CIMP-positive, and BRAF mutation-positive colorectal cancer subtypes, which indicates that epigenetic modification may be functionally involved in smoking-related colorectal carcinogenesis.

Breast Cancer Family History and Contralateral Breast Cancer Risk in Young Women: An Update From the Women’s Environmental Cancer and Radiation Epidemiology Study

Purpose The Womens Environmental Cancer and Radiation Epidemiology (WECARE) study demonstrated the importance of breast cancer family history on contralateral breast cancer (CBC) risk, even for noncarriers of deleterious BRCA1/2 mutations. With the completion of WECARE II, updated risk estimates are reported. Additional analyses that exclude women negative for deleterious mutations in ATM, CHEK2*1100delC, and PALB2 were performed. Patients and Methods The WECARE Study is a population-based case-control study that compared 1,521 CBC cases with 2,212 individually matched unilateral breast cancer (UBC) controls. Participants were younger than age 55 years when diagnosed with a first invasive breast cancer between 1985 and 2008. Women were interviewed about breast cancer risk factors, including family history. A subset of women was screened for deleterious mutations in BRCA1/2, ATM, CHEK2*1100delC, and PALB2. Rate ratios (RRs) were estimated using multivariable conditional logistic regression. Cumulative absolute risks (ARs) were estimated by combining RRs from the WECARE Study and population-based SEER*Stat cancer incidence data. Results Women with any first-degree relative with breast cancer had a 10-year AR of 8.1% for CBC (95% CI, 6.7% to 9.8%). Risks also were increased if the relative was diagnosed at an age younger than 40 years (10-year AR, 13.5%; 95% CI, 8.8% to 20.8%) or with CBC (10-year AR, 14.1%; 95% CI, 9.5% to 20.7%). These risks are comparable with those seen in BRCA1/2 deleterious mutation carriers (10-year AR, 18.4%; 95% CI, 16.0% to 21.3%). In the subset of women who tested negative for deleterious mutations in BRCA1/2, ATM, CHEK2*1100delC, and PALB2, estimates were unchanged. Adjustment for known breast cancer single-nucleotide polymorphisms did not affect estimates. Conclusion Breast cancer family history confers a high CBC risk, even after excluding women with deleterious mutations. Clinicians are urged to use detailed family histories to guide treatment and future screening decisions for young women with breast cancer.

Association of Common Genetic Variants With Contralateral Breast Cancer Risk in the WECARE Study

Background: Women with unilateral breast cancer (UBC) are at risk of developing a subsequent contralateral breast cancer (CBC). Common variants are associated with breast cancer risk. Whether these influence CBC risk is unknown. Methods: Participants were breast cancer cases from the population-based Women’s Environmental Cancer and Radiation Epidemiology (WECARE) Study. Sixty-seven established breast cancer risk loci were genotyped directly or by imputation in 1459 case subjects with CBC and 2126 UBC control subjects. An unweighted polygenic risk score (PRS) was created by summing the number of risk alleles for each directly genotyped single nucleotide polymorphism (SNP), or for imputed loci, the imputed dosage. A weighted PRS was calculated similarly, but where each SNP’s contribution was weighted by the published per-allele log odds ratio. Unweighted and weighted polygenic risk scores and CBC risk were modeled using conditional logistic regression. Cumulative CBC risk was estimated and benchmarked using Surveillance, Epidemiology, and End Results population incidence rates. Results: Both unweighted and weighted PRS were statistically significantly associated with CBC risk. The adjusted risk ratio of CBC in women in the upper quartile of unweighted PRS compared with the lowest quartile was 1.63 (95% confidence interval [CI] = 1.33 to 2.00). The estimated 10-year cumulative risk for women in the upper quartile of the unweighted PRS was 7.4% (95% CIu2009=u20096.0% to 9.1%). For women in the upper quartile of the weighted PRS, the risk ratio for CBC was 1.75 (95% CIu2009=u20091.41 to 2.18) compared with women in the lowest quartile. There was no statistically significant heterogeneity by age, treatment (radiation therapy dose, tamoxifen, chemotherapy), estrogen receptor status of the first primary, histology of the first primary, length of at-risk period for CBC, or breast cancer family history. Conclusions: Common genomic variants associated with the development of first primary breast cancer are also associated with the development of CBC; the risk is strongest among those who carry more risk alleles.

Patient and tumor characteristics associated with contralateral breast cancer in a nested population-based case-control study.

1014 Background: The identification of patient and tumor characteristics associated with an increased risk of contralateral breast cancer (CBC) would be useful for counseling women with unilateral breast cancer (UBC) regarding risks and benefits of contralateral prophylactic mastectomy (CPM), a procedure increasingly chosen by young women.nnnMETHODSnThe WECARE (Womens Environmental Cancer and Radiation Epidemiology) study is a multicenter, population-based study of 708 cases with metachronous CBC and 1,399 matched controls with UBC nested within a cohort of 52,536 women under age 55 at diagnosis of an initial breast cancer between 1985-2000. Family history was collected by phone interviews; treatment and tumor characteristics were abstracted from medical records, and germline DNA was tested for deleterious mutations of BRCA1/2. Multivariable adjusted rate ratios (RR) and 95% confidence intervals (CI) were estimated using conditional logistic regression.nnnRESULTSnThe median age of cases and controls was 46. 111 cases and 74 controls carried BRCA1/2 mutations. Results are reported for non-carriers. Race, body mass index and menopausal status did not differ between cases and controls. Risk of CBC was elevated among women with a first primary with lobular histology (RR=1.5; 95% CI=1.1-2.2). Grade 2 (RR 0.6, 95% CI 0.5-0.9) and grade 3 tumors (RR 0.6, 95% CI 0.4-0.9) were associated with a lower risk of CBC compared to grade 1 tumors. ER status was not significantly associated with CBC, but only 35% of ER positive patients received tamoxifen. These results were not modified by age at diagnosis (<45, ≥45) or family history of breast cancer. The proportion of in situ CBC increased from 18.2% between 1985-1988 to 22.0% between 1997-2000 (p=0.04).nnnCONCLUSIONSnIn this large population based study, women with an initial diagnosis of lobular cancer or low grade histology were at increased risk of CBC in the absence of widespread use of endocrine therapy. Given the known benefit of endocrine therapy in reducing CBC, our findings suggest that consideration of standard tumor characteristics alone in women without BRCA1/2 mutations do not identify a subset of women likely to benefit from CPM.