Key Recent Articles from CBCS Phase 3
Identifying More Subtypes of Breast Cancer
TP53 is one of the most important tumor suppressor genes. (A tumor suppressor is a gene whose normal functioning is an important part of the body’s defense against tumors). TP53 is commonly mutated in all cancer types. In breast cancer research, mutations in the estrogen receptor (ER) gene form a major subtype of the disease. CBCS researchers led by Amber Hurson wanted to look into the complex interplay of risk factors (also called “risk factor heterogeneity”) and how those risk factors might correlate with mutations in the TP53 and estrogen receptor genes. What Hurson et al. found was that mutations in the TP53 and ER genes were associated with different risk factors. A higher body mass index (BMI) and a medical history with changes in the body’s hormones (for example, a history of using oral contraceptives, menopausal status, and age at menopause) were associated with TP53 mutations. Smoking and reproductive history (in particular, never having children or “nulliparity”) were associated with mutations in the ER gene. This study is an important step forward to identifying the biological subtypes of breast cancer, a process that so far as helped oncologists determine the best treatment options for their patients.
For more information, see the article by Hurson et al., “TP53 pathway function, estrogen receptor status, and breast cancer risk factors in the Carolina Breast Cancer Study” in Cancer Epidemiology, Biomarkers & Prevention (2022), vol. 31, issue 1 (PMID: 34737209, PMCID: PMC8755611).
Testing a Model to Predict Black Women’s Risk of Breast Cancer
Risk prediction models are a potentially powerful tool in the clinic. They can help healthcare providers, for example, identify who is most at risk of breast cancer before the age at which women are recommended to start having annual mammograms. This identification of who is most at risk can become the basis for increased surveillance, which can lead to earlier detection, better outcomes, and more lives saved. A team led by Julie Palmer at Boston University combined CBCS3’s data collected from the almost 1500 Black women who enrolled with about 2000 more cases from two similar studies to develop an absolute risk model for Black women, especially young Black women whose risk is greater and outcomes are poorer. Using the information of these cases and an equal number of similarly-aged controls, Palmer et al. tested their model on the landmark Black Women’s Health Study. This study, began in 1995, has enrolled and tracked over 50,000 Black women’s health and behaviors. Palmer et al.’s new model performed on par with models developed using primarily White women, showing that it is now possible to use risk models in the Black community to identify those at greatest risk of developing breast cancer.
For more information, see the article by Palmer et al., “A validated risk prediction model for breast cancer in US Black women” in the Journal of Clinical Oncology (2021), vol. 39, issue 34 (PMID: 34623926, PMCID: PMC8608262).
Examining How Women’s Reproductive History Affects Breast Cancer Subtype
Half of those enrolled in CBCS3 were under the age of 50, which is to say closer to the ages at which they had (or could have had) children. CBCS researchers led by Sanah Vohra separated these women into three groups: recent postpartum (10 years or less since last birth), remotely postpartum (more than 10 years since last birth), and those who never gave birth (“nulliparous”). Comparing the recent postpartum women with those who never had children, Vohra et al. found that women whose diagnosis of breast cancer was “recent” to their last pregnancy had greater odds of three subtypes of breast cancer: (1) estrogen receptor-negative, (2) triple-negative, and (3) cancer that had spread to the lymph nodes. And compared with the remotely postpartum, recently postpartum women had greater odds of having a larger tumor at the time of diagnosis, a mutation involving the TP53 tumor suppressor gene, and basal-like breast cancer. The most exciting findings came with looking at the number and types of immune system-related cells within the tumor. The tumors of recently postpartum women had more of these. This opens up new avenues for research into the effects of childbirth on breast cancer risk, the biology of the cancer when it develops, and the effects on the immune system’s response to the cancer.
For more information, see the article by Vohra et al., “Molecular and clinical characterization of postpartum-associated breast cancer in the Carolina Breast Cancer Study Phase I-III, 1993-2013” in Cancer Epidemiology, Biomarkers & Prevention (2022), vol. 31, issue 3 (PMID: 34810211, PMCID: PMC8901538).
Comparing the Tumor Microenvironments of Basal-like and Luminal Breast Cancers
Just because the body’s usual checks and balances that inhibit tumor growth did not work, it does not mean that body stopped trying to get rid of the tumor on its own. There are white blood cells of the immune system, called tumor infiltrating lymphocytes (TILs) that will invade the tumor. Research into these is still getting going, but early findings suggest the presence and number of these is an important biomarker in predicting how treatment efficacy and outcome. What researchers are learning is that how many TILs a tumor has differs by the cancer subtype. In this study, first Andrea Walens and her team showed that you can use a tool called a tumor microarray to gain important information about the immune environment in the tumor tissue that other methods are not able to collect. (A tumor microarray allows researchers to look at hundreds of different genes and their activity at the same time. As certain genes are strongly associated with even just one type of cell, it is a powerful way of finding out what types of cell are in a tumor sample.) Walens et al. gave further support to the growing body of studies that show that basal-like breast cancers, which include some of the toughest-to-treat breast cancers, have more of regulatory T cells (Treg) than luminal subtypes. These cells are important checks on the immune system that, for example, prevent autoimmune disorders. More of these cells means less of an immune response fighting the tumor overall. Overall, learning more about how the body responds to different breast cancer subtypes can hopefully one day help clinical oncologists design more effective plans of care.
For more information, see the article by Walens et al., “Protein-based immune profiles of basal-like vs. luminal breast cancers” in Laboratory Investigation (2022), vol. 101, issue 6 (PMID: 33623115, PMCID: PMC8140991).[return to top]
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Phase 1 & 2 Summary Presentation
The Carolina Breast Cancer Study: Past, Present, and Future was a presentation given at the start of Phase 3 of the study (October 31, 2008). It summarizes the lessons from Phases 1 and 2 and set forth Phase 3’s goals.[return to top]
Key Findings from CBCS 1 and 2
Subtypes of breast cancer vary across age and race, which may be a part of an explanation for differences in survival.
Previously, researchers established that African American women with breast cancer had higher mortality rates than White women, and that this disparity grew when comparing just women under the age of 50. In addition to socioeconomic factors that can lead to delayed screening and different treatments, CBCS researchers wanted to know if there were any biological differences in the types of breast cancer African American and White women contract and to look further comparing women of both races over age 50 and under age 50.
Previous studies also showed that there are two main subtypes of breast cancer, depending upon whether the cells have (ER+) or don’t have (ER-) estrogen receptors. Each subtype gets broken down further, typically based upon what other genes are being expressed in the cells. For example, different gene expression profiles allow physicians and researchers to classify ER+ breast cancer cells as either luminal A or luminal B and ER- breast cancer cells either as basal-like or human epidermal growth factor receptor-2 positive (HER2+). This is important because some cancer treatments work better or worse depending upon the specific subtype of breast cancer being treated.
This study found that African American women, prior to menopause, have both high rates of basal-like ER- breast cancer compared to both postmenopausal African American women and White women of any age. Premenopausal African American women also have lower rates of luminal A ER+ breast cancer compared both to older women of the same race and White women of any age. Finally, researchers found that having one of the ER- subtypes correlated with the shortest survival time. This suggests that the higher incidence of these ER- breast cancer subtypes is a contributing factor to why younger African American women overall have worse outcomes.
For more information, see the article by Carey et al., “Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study” in The Journal of the American Medical Association (2006), vol. 295, issue 11 (PMID: 16757721).
Comparing long-term survival of African American and White women from breast cancer based upon subtype.
CBCS researchers looked at the hazard ratios to compare the the long-term survival of women after breast cancer diagnosis based upon race (African American vs. white) and intrinsic breast cancer subtype (ER-: basal-like & HER2+; ER+: luminal A & B) and controlling for other factors, such as age, date of diagnosis, and what stage breast cancer a woman had at diagnosis. Previous studies had established that African American women with breast cancer have higher mortality rates than their White counterparts, that breast cancer subtypes differ by race, and that the subtypes with poorer outcomes were more prevalent among African American women. This study re-confirmed that ER- breast cancer overall correlates with higher mortality compared to ER+ breast cancer, with HER2+/ER- having the highest risk of death (HR=2.3, 95% CI: 1.5, 3.6), followed by basal-like (HR=1.7, 95% CI: 1.2, 2.4). (Editor’s Note: This study occurred prior to the development of treatments specific for the HER2+ breast cancer, which has changed this.)
Furthermore, this study, however, found when looking at just long-term survival among each intrinsic subtype by race, African American and White women fared no differently from each other for the luminal B, basal-like, and HER2+/ER- subtypes. Only with luminal A breast cancer was there a statistically significant difference (HR=1.9, 95% CI: 1.3, 2.9), with African American women having a higher mortality rate than White women. This finding dispelled the notion that basal-like breast cancer in African American women was particularly aggressive.
However, when looking at the effect of breast cancer subtype on mortality among African American and White women separately, a different pattern emerged. Using the mortality rate of women with the luminal A subtype as a baseline, CBCS researchers found that mortality for patients with basal-like breast cancer was higher among White women (HR=2.0, 95% CI: 1.2, 3.4) than African American women (HR=1.5, 95% CI: 1.0, 2.4). Mortality was even higher for postmenopausal White women (HR=3.9, 95% CI: 1.5, 10.0) for this subtype.
Overall, this study showed the need for more research into why African American women have worse outcomes for the luminal A subtype, which for a long time has been the most successfully treatable type of breast cancer.
For more information, see the article by O’Brien et al., “Intrinsic breast tumor subtypes, race, and long-term survival in the Carolina Breast Cancer Study” in Clinical Cancer Research (2010), vol. 16, issue 24 (PMID: 21169259 PMCID: PMC3029098).[return to top]