Understanding Etiology of TNBC is Critical for Discovering Effective Preventive Approaches

A higher incidence rate of estrogen receptor (ER)–negative breast cancers, and specifically of triple-negative breast cancers (TNBC) among younger African American women vs White women is a source of racial disparities in breast cancer mortality, according to Mark E. Sherman, MD.

Data from a recent study suggest that dysregulated immune responses play a critical role in the pathogenesis of TNBC, based on the molecular biology of the cancers and the mechanisms proposed to mediate disease risk factors. Proposed risk factors for disease include childbearing without breastfeeding, high parity, and obesity—which are all more prevalent among African American vs their White counterparts.

“Pretty compelling data [indicate that] parity protects patients from breast cancer in the long term…There's pretty good evidence [to suggest that in] the years after a childbirth, the risks of breast cancer are transiently increased; that's [true] for both ER-positive and -negative breast cancers,” Sherman said. “However, [we] also [have] evidence [to suggest] that breast feeding is protective [in terms of] breast cancer. Historically, what we have seen in African American women is [high] parity and not breastfeeding. That combination creates the risk for some of these postpartum breast cancers.”

In an interview with OncLive^®, Sherman, a professor of Epidemiology and Pathology at the Mayo Clinic College of Medicine, further discusses research efforts evaluating immune responses and risk of TNBC and implications for higher rates of disease among African American women.

OncLive^®: What are some of the racial disparities observed with regard to breast cancer incidence?

Sherman: The most notable racial disparity is the fact that African American women get more early-onset breast cancers that are ER-negative—particularly TNBC. The importance of this is that, besides the fact that these tumors are intrinsically clinically aggressive, targeted therapies that work against hormones or against HER2 growth factor, don't apply here because the targets aren't expressed on the tumors. That's the problem, because when you look at outcomes for breast cancer, African Americans have worse outcomes for basically all types of the disease. The problem here that we are trying to draw attention to is the increased occurrence of a particularly aggressive type of cancer.

Have similar data been reported with regard to other subtypes of this disease?

The interesting thing here is that TNBC is more common among African American women than White women. When you consider incidence patterns of this disease, we rarely see an increase in ER-positive breast cancers in both racial groups—particularly among younger women. There's an interesting suggestion that late age at first [child]birth, which is a risk factor of breast cancer, [could be] applied to early-onset ER-positive breast cancers. Since delaying childbirth is a pretty universal phenomenon, that might be one of the reasons why [the number of] ER-positive cancers is increasing.

What other risk factors might account for these differences in incidence rates?

The other area, which is perhaps not as perfectly established, is that obesity after menopause [might] increase the risk of ER-positive breast cancer, whereas obesity prior to menopause may lower the risk of those tumors. There is some evidence to suggest that obesity may increase risk, specifically [in terms] TNBC. African American women have a bigger problem with obesity than White women, and there is weight gain after childbirth. After gaining [this] weight, African American women are less likely to restore their lower baseline, pre-pregnancy weight. There are a few lifestyle factors that seem to apply. There's also some evidence [to suggest that] stresses [experienced] early in life can reprogram your immune system and, perhaps, make it more vulnerable to certain kinds of cancers. There's some evidence that African Americans have genetically different immune responses than White women.

Part of the reason that we believe having a child might increase breast cancer risk transiently comes from some very elegant studies [that were done] in mice. [In those models, it was] shown that after [a mother] stops breast feeding, that breast needs to return to its baseline state. When you think about it, the breast becomes very hyperplastic during pregnancy. That could be an evolutionary adaptation to help with milk production. However, when [mothers] stop weening, that tissue has to go back down to normal. That [process] involves a huge amount of cell death and inflammation—something akin to wound healing.

Years ago, there was a famous paper in the New England Journal of Medicine that referred to cancer as ‘a wound that wouldn't heal.’ This is just a hypothesis that isn't proven, but what we think could be happening is that women could have a late age at first childbirth and have a lot of these mutations in their cells because the breast has been stimulated through multiple uninterrupted menstrual cycles. The breast tissue expands because it's given growth signals during pregnancy and then it's given this wound-healing response afterward that is immune suppressive and conducive to cancer development. It could be that this interaction of factors is bringing these cells [closer to] cancer. We're interested in understanding [this better] because we want to [stop this from happening].

One way that we may be able to block this is with anti-inflammatory agents. Every woman is going to remodel her breasts; that's normal. That may not be the problem in and of itself, but dysregulated involution of the breast could be a problem. To clear out all the dead cells, you need inflammation, you need to repair the wound, and then you need to bring this process to a close. That's the subtlety that makes biology very complicated. It's a necessary physiological function that maintains homeostasis, but it's a subtle thing.

What if it doesn't turn off properly, continues, and becomes a chronic mastitis or mastopathy? The breast keeps [experiencing] inflammation, [and] then it can be a driver of cancer. We're interested in understanding that process and if the inflammation really is immune mediated. [If it is,] we have ways to deal with that. [When this occurs in] young women…[the answer] may be a short course with an anti-inflammatory drug that's well tolerated.

What is known so far about differences regarding race and immune responses?

There may be subtle hints that immune responses might differ between African American women and White women. I wouldn't say it's proven, but historically we know that African American women have certain differences in disease prevalence that might speak to inflammation and wound healing. The example that many people may be familiar with is keloids or skin scarring; these are very dense, hypertrophic scars that seem to be more common in African American women. Why is that? It has something to do with a wound-healing response that's not controlled. The same analogous notion may be thought of in the breast.

Historically, a theory that has been raised, and I don't know how solid this is, is that people whose ancestry is from Africa developed immune systems from evolutionary pressures to fight off infection. We think about immunity a lot in [the] cancer [space right] now, but prior to any medical intervention, one has to think that people weren't living long enough to get cancer thousands of years ago. The real threat was infectious [diseases]. Therefore, there's this notion that people with African ancestry might have an immune response that is very well adapted to fighting off pathogens and parasites that are endemic in Africa [through] the Th2 immune response. That's an immune healing response, but it's not the kind of Th1 response that we see as being very potent in killing cancer cells.

What research efforts do you have planned to further understand immune responses and breast cancer risk?

First, we'd really like to understand what distinguishes a woman who just gave birth within the past 5 years, for example, from a woman who has never given birth. We’re talking about abnormal physiology. One of the things we've done is [we have looked at] a tissue bank that had a collection of breast samples collected from over 5,000 women; that [provided] blood and epidemiological data. These are tissues that are obtained for research only; they are not biopsies [that were performed] because a patient had an X-ray. They're just normal tissues, but they have all this epidemiological inclination. We compared 725 samples, some of whom were nulliparous, and the rest were parous and had kids at different time, including within 5 years of the last childbirth. We’re trying to use those tissues to understand immune responses in the women who were pregnant versus the women who were not. That will help us to define the immune response associated with this postpartum reconstitution.

The next thing we're trying to do is study breast cancers that have developed within 5 to 10 years of a pregnancy. Those may be examples where the immune response that was a part of breast remodeling after weening could show us some hints about how that response was not controlled and is present in those early-onset cancers in surrounding tissues.

Finally, we just published a paper showing how non-steroidal anti-inflammatory drugs might lower breast cancer risk in [patients] with benign disease—in other words, early breast cancer precursors. The other thing we're interested in is developing a trial to treat these women with anti-inflammatory agents, but specifically focusing on young women who have had a recent birth. In trying to see whether we can define this immune signature that separates the breast cancers from normal involution and breast remodeling, we [may determine] whether that signature can be reduced by giving those agents in those women. It's very aspirational, but that is what we have been working on.

What is your take-home message regarding this research?

There are a couple of things I feel passionately about. The big picture is that we spend a large amount of time and energy on treating cancer and not enough on understanding its etiology and causes. Without understanding the causes, it's very difficult to predict risk and prevent [these diseases]. I started my [career conducting] human papillomavirus research [HPV] in [relation to] cervical cancer. I spent 20 years working [closely] with the National Institutes of Health; that led to tremendous fruition around HPV testing and vaccinations. [Breast cancer] is much more complicated, without a strong, single exogenistic cause such as a viral infection. Still, understanding the causes and risks [of this disease] are essential for prevention.

The risk prevention and assessment we do is not focused enough. It looks too much at breast cancer overall and because of that, it focuses on when most breast cancers occur, which is among older women. More of those cancers are less aggressive than the types found among younger [patients]. We need a more mechanistic-driven approach to prevention. The beauty of this paradigm is we can [potentially] learn the mechanism and know when the mechanism is operating. We know the mechanism is inflammation and we know the mechanism is acting now. If we know that, we can give an intervention that is very short term and targeted to the mechanism. Because these are young women, they could tolerate a treatment that involves ibuprofen or another anti-inflammatory drug for a few weeks.

We see this hint fairly consistently that breast feeding would reduce risk [of breast cancer], particularly with regard to aggressive breast cancers among African Americans, but we don't really understand why and how breast feeding does that and we don't do enough to support breast feeding in this country. Therefore, African American women are less likely to initiate and less likely to persist for 6 months exclusively. If we can [tap into] the protective factor of breast feeding to understand the biology on a public health level—to facilitate and support breast feeding as an intervention—we would accomplish a lot. Not only does breast feeding protect [patients] against some breast cancers, but it also protects [them] against ovarian cancer, endometrial cancer, and lowers risks of infection in the infant. [Breastfeeding also] has other psychosocial strengths.

References

1. Ogony JW, Radisky DC, Ruddy KJ, et al. Immune responses and risk of triple negative breast cancer: implications for higher rates among African American women. Cancer Prev Res (Phila). 2020;13(11):901-910. doi:10.1158/1940-6207.CAPR-19-0562