Reproductive risk factors and oestrogen/progesterone receptor-negative breast cancer in the Breast Cancer Family Registry.
Work ME, John EM, Andrulis IL, Knight JA, Liao Y, Mulligan AM, Southey MC, Giles GG, Dite GS, Apicella C, Hibshoosh H, Hopper JL, Terry MB.
British Journal of Cancer, 2014 Mar 4;110(5):1367-77.
There is increasing evidence that not all breast cancers are the same. The majority of breast cancers are estrogen receptor (ER) and progesterone receptor (PR) positive and some of the known risk and protective factors for breast cancer only apply to this common subtype. However, there is an urgent need to find factors that protect against ER/PR negative breast cancer, a subtype that occurs more often in African American and Latina women than in non-Latina white women, responds more poorly to treatment, and has worse survival than other subtypes. Because of its large size with over 11,000 participating families, the Family Registry is a unique resource to study factors that are associated with less common breast cancer subtypes. Here is a synopsis of our recently published research article on ER/PR negative breast cancer:
It has been long known that high parity (number of live births) is associated with a lower risk of ER/PR positive breast cancer, the most common breast cancer subtype. Recent studies, however, have shown that high parity is associated with a higher risk of ER/PR negative cancer. New evidence points to breastfeeding as a factor that may reduce this increased risk. In this Family Registry study, reproductive risk factors in more than 4,000 women with breast cancer were compared to reproductive factors in about 3,000 women without breast cancer. Women with 3 or more live births who never breastfed were approximately 50% more likely to be diagnosed with ER/PR negative breast cancer. No increased risk was found in women with 3 or more live births who reported a history of breastfeeding. Oral contraceptive (OC) use was also associated with a 30% higher risk of ER/PR negative breast cancer, but only for women who started OC use before 1975 when OC formulations were different. This report’s findings help to identify modifiable factors for ER/PR negative breast cancer, a subtype for which few risk factors are known. Breastfeeding in particular may decrease the risk of ER/PR negative tumors in women with high parity. This finding is particularly important for African American women who are more likely to be diagnosed with ER/PR negative breast cancer than other racial/ethnic groups.
Genome-wide association study of breast cancer in Latinas identifies novel protective variants on 6q25.
Fejerman, L, Ahmadiyeh N, Hu D, et al.
Nature Communications, 2014 Oct 20 [e-published ahead of print]
Rates of breast cancer diagnosis and survival are not equal across all racial/ethnic groups. Differences in genetic factors may explain some of the differences by race/ethnicity. In order to explore genetic risk factors, very large studies are needed, especially since some genetic changes are so rare. The Family Registry has participated in a number of scientific collaborations that combine data from multiple studies. The Northern California Family Registry is part of one such large, international study that recently discovered a genetic change that protects Latina women from developing breast cancer. The results of this important study are summarized here:
Latina women have a lower incidence of breast cancer compared to non-Latina whites. Furthermore, breast cancer risk is lower among Latinas with more Indigenous American ancestry than among those with less Indigenous American ancestry. A study of Latina women enrolled in the Northern California Family Registry and other California studies discovered that a single difference in just one of the three billion letters of biochemical DNA in the human genome was associated with a lower risk of breast cancer. Those who inherited a copy of this genetic change were 40% less likely to be diagnosed with breast cancer. The protection was even stronger for ER negative disease. This genetic change is found in 5% to15% of Latin American populations, depending on the proportion of Indigenous American ancestry. In other racial/ethnic groups, it is rare or absent. These findings were also confirmed in DNA samples from women in Mexico and Columbia. This study highlights the importance of understanding the genetics of breast cancer in all racial/ethnic groups, as genetic factors may differ between populations.
Breast cancer risk assessment across the risk continuum: genetic and nongenetic risk factors contributing to differential model performance.
Quante AS, Whittemore AS, Shriver T, Strauch K, Terry MB.
Breast Cancer Res. 2012 Nov 5;14(6):R144.
To evaluate a patient’s risk for breast cancer, a doctor chooses a prediction model based on the patient’s health information, including family history and genetic factors. The Breast Cancer Risk Assessment Tool (BRCAT, or the Gail model), which does not incorporate extended family history of breast cancer or BRCA1/2 mutation status, is typically used for patients at average risk, while the more advanced International Breast Cancer Intervention Study (IBIS, or the Tyrer Cuzick) model is used for patients with above-average risk.
This study followed 1,857 women over an average period of 8.1 years and compared predictions from the BRCAT and the IBIS models to their observed breast cancer outcomes. The women in the study, all non-cancer participants in the Breast Cancer Family Registry, ranged from low breast cancer risk to very high risk.
The results of the study found that the 10-year breast cancer risks as predicted by the BRCAT model were consistently lower than the actual breast cancer levels found in the participants. On the other hand, the predictions from the IBIS model were generally close to the actual findings, even for the women who were considered at average risk (e.g., those with no family history and no BRCA1/2 genetic mutations). These findings suggest that extending the use of the IBIS model to women with average risk of breast cancer may yield more accurate risk predictions and may thereby lead to more informed health decisions by doctors and their patients.
Tumoral Lymphocytic Infiltration and Expression of the Chemokine CXCL10 in Breast Cancers from the Ontario Familial Breast Cancer Registry
Anna Marie Mulligan, Irene Raitman, Linda Feeley, Dushanthi Pinnaduwage, Linh T. Nguyen, Frances P. O’Malley, Pamela S. Ohashi and Irene L. Andrulis
Clin Cancer Res. 2013 Jan 15;19(2):336-46. doi: 10.1158/1078-0432.CCR-11-3314. Epub 2012 Dec 4. PMID:23213058
CXCL10 expression was detected in primary breast cancers and found to be associated with tumoral lymphocytic infiltrate and expression of its receptor, CXCR3. Analysis of the infiltrate revealed association of CXCL10 with peritumoral CD4+ and CD8+ lymphocytes, intratumoral CD8+ lymphocytes, as well as FOXP3+ Tregs and T-BET+ Th1 cells. The latter were associated with the BRCA1 subgroup and basal subtype. Overexpression of this chemokine axis in MCF7 cells increased in-vitro T-lymphocyte migration and invasion. These results suggest that CXCL10 may act in both a paracrine manner, affecting the tumor microenvironment, as well as an autocrine manner, acting on the tumor cells themselves. The host immune response is believed to be important in outcome in many cancers. The CXCL10/CXCR3 axis may play a role and serve as a potential drug target for BRCA1 and basal breast cancers which present with a prominent lymphocytic infiltrate and a poor prognosis.
Total energy intake and breast cancer risk in sisters: the Breast Cancer Family Registry.
Zhang FF, John EM, Knight JA, Kaur M, Daly M, Buys S, Andrulis IL, Stearman B, West D, Terry MB.
Breast Cancer Res Treat. 2013 Jan;137(2):541-51. Epub 2012 Dec 6.
Studies in animals have shown that consuming fewer calories reduces mammary tumor development, but among humans the connection between diet and breast cancer risk has not been so clearly established. Some research indicates that diet may work together with body size and physical activity to affect breast cancer risk.
This study examined breast cancer risk among 1,775 women diagnosed with breast cancer between 1995 and 2006 and among 2,596 of their unaffected sisters from the Breast Cancer Family Registry in relation to calorie consumption, physical activity, and body mass index (BMI). When comparing women with the highest levels of calorie consumption to those with the lowest levels, women with high calorie consumption were 60-70% more likely to develop breast cancer. This relationship persisted even after accounting for physical activity and BMI in the analyses. While further exploration is needed, these findings suggest that reducing calorie intake alone (without influencing physical activity or body size) may reduce breast cancer risk in some individuals.
Risk factors for uncommon histologic subtypes of breast cancer using centralized pathology review in the Breast Cancer Family Registry.
Work ME, Andrulis IL, John EM, Hopper JL, Liao Y, Zhang FF, Knight JA, West DW, Milne RL, Giles GG, Longacre TA, O’Malley F, Mulligan AM, Southey MC, Hibshoosh H, Terry MB.
Breast Cancer Res Treat. 2012 Aug;134(3):1209-20. Epub 2012 Apr 25.
Breast cancer is a diverse grouping of diseases with varying affects on breast tissue. To distinguish between types of breast cancer, disease pathologists generally use codes from the International Classification of Diseases-Oncology (ICD-O). Alternatively, some researchers, doctors, and institutions adopt more involved, centralized review processes to classify tumor types.
This study reviewed 3,260 breast cancer cases from the Breast Cancer Family Registry (BCFR) and compared ICD-O classifications with classifications obtained from the centralized BCFR pathology review. While the classification methods demonstrated excellent agreement for the commonly occurring ductal tumors, the agreement was lower for the less common tumor types. For instance, only 26% of the cases classified as medullary carcinomas in the BCFR review received an identical ICD-O classification. Further, statistical relationships between tumor status and tumor-specific risk factors (e.g., body mass index and oral contraceptive use) were more precise when using the BCRF classifications as compared to the ICD-O classifications.
The findings from this study highlight inconsistencies between current classification methods and demonstrate the particular value of centralized pathology review when classifying rare tumor types.