Guest Editor

Brandon Hayes-Lattin, MD, FACP

Adolescent and Young Adult Oncology explores the unique physical, psychosocial, social, emotional, sexual, and financial challenges adolescents and young adults with cancer face. The column is guest edited by Brandon Hayes-Lattin, MD, FACP, Associate Professor of Medicine and Medical Director of the Adolescent and Young Adult Oncology Program at the Knight Cancer Institute at Oregon Health and Science University in Portland, Oregon.

According to the American Cancer Society, over 252,700 new cases of invasive breast cancer will be diagnosed in 2017, and about 40,610 women will die of their disease. Between 7% and 10% of those new cases will be diagnosed in women younger than age 40, accounting for more than 40% of all cancer in women in this age group.¹

The disease in adolescent and young adult (AYA) women is often more aggressive and deadlier than it is in older women—possibly due to a distinct tumor biology or an overrepresentation of aggressive molecular and cellular processes, delayed diagnosis, and/or a high tumor burden—and can be especially devastating emotionally, sometimes robbing them of their fertility and impacting their relationships with partners as well as interrupting their education or careers.

Moreover, after adjusting for all known prognostic factors, just being young appears to be the crucial determinant in higher risk for breast cancer recurrence and survival, even when the cancer is found at an early stage. An analysis of the clinicopathologic and prognostic features of breast cancer in younger women compared with older women by Carey K. Anders, MD, and her colleagues showed that women younger than age 40 were 39% more likely to die of their cancer than those 40 years and older, even when the cancer was found at stage I or II.

Advances in next-­generation sequencing are allowing us to test for additional breast cancer predisposition genes and will provide greater insight about how best to treat younger patients in the future.

— Carey K. Anders, MD

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In addition, Dr. Anders’ research found that the triple-negative phenotype—estrogen receptor–, progesterone receptor–, and HER2-positive breast cancer—the most lethal type of breast cancer—is most commonly found in young women, especially African American women.²

The ASCO Post talked with Dr. Anders, Associate Professor of Medicine at the University of North Carolina at Chapel Hill School of Medicine, about the unique characteristics of breast cancer in AYAs, how to improve survival outcomes for these patients, and promising new treatments on the horizon.

Common and Aggressive Cancers

Although a rare occurrence, breast cancer is the most common cancer for women between the ages of 15 to 39, and they die more frequently of the disease than any other cancer. Why is breast cancer this common in younger women, and why is it so deadly in this age group?

Our and other research findings have shown that the types of breast cancer affecting young women can be different from the types diagnosed in older patients. For instance, it’s much more common for a younger woman to be diagnosed with triple-negative breast cancer than estrogen receptor–positive breast cancer.

The reasons for that are probably multifactorial. For example, the breast milieu of a younger woman who is in her childbearing and breastfeeding years is different from the composition of the breast of an older woman who has been menopausal for a long time. Thus, there are different schools of thought surrounding the cell of origin that is giving rise to the breast cancer, which may, in fact, be impacting the type of breast cancer a younger patient develops.

And aren’t those cancers typically more aggressive?

Yes. Younger women are more commonly diagnosed with triple-negative breast cancer, which has a more aggressive phenotype compared with estrogen receptor–positive breast cancer, so one factor is the biology of the disease.

Triple-negative breast cancer is also much more likely to recur within 2 to 3 years of diagnosis as opposed to what we see with estrogen receptor–positive breast cancer, which has a much lower rate of recurrence in those early years but could recur as late as 10 to 15 years after diagnosis; however, the initial recurrence peak is much lower.

The other reason triple-negative breast cancer is more deadly in younger women is due to the available treatments for the disease. As its name implies, triple-negative breast cancer lacks expression of the estrogen/progesterone receptors and HER2, so traditional targeted therapies, such as estrogen receptor– and/or HER2-directed treatments, intended to get at the Achilles heel of the tumor, are not useful.

Is another reason breast cancer is much deadlier in this younger age group because it is being diagnosed at a later stage?

Yes, absolutely. Our most conservative guidelines indicate that we should start screening mammograms at the age of 40, so women in their 20s and 30s would not even have mammogram screening on their radar yet and are more likely to present with a self-palpated mass or at clinical breast exam with a palpable lump at a later stage.

Biology of Breast Cancer in Younger Women

What does the research show about the biology of breast cancer in younger women compared with older women?

There are five main molecular subtypes of breast cancer: luminal A, a low-grade cancer that tends to grow more slowly; luminal B, typically estrogen receptor–positive but of a higher grade; basal-like, which is typically triple-negative and more common in women with BRCA1 gene mutations; HER2-enriched, which is typically HER2-positive; and normal-like breast cancer.

The proportion of younger women diagnosed with triple-negative breast cancer and HER2-positive breast cancer as compared with older women is much higher, and we are seeing a subtype shift across the ages. The more difficult thing to understand is whether a triple-negative breast cancer diagnosed in a younger patient is different from a triple-negative breast cancer diagnosed in an older patient. And we do not know the complete answer to that yet.

Research at my institution suggests that if you look at these cancers on the gene-expression level, a basal-like or triple-negative breast cancer in a young woman looks similar to the same subtype of breast cancer found in an older woman, even when all the other components of the cancer, including the grade of the tumor, estrogen-receptor and progesterone-receptor status, and age of the patient, are accounted for. So, it has been difficult to tease out true “age-related” genes that are making a younger woman’s breast cancer more aggressive than an older woman’s beyond that of subtype.

Treatment Strategies

How does the treatment of breast cancer in younger women differ from that in older women?

As previously mentioned, the research we have done shows that the biology of triple-negative breast cancer is similar in both younger and older patients, so many times the question of treatment rests with trying to balance the health of the patient with the aggressiveness of the approach to therapy. We tend to be much more aggressive in our therapeutic recommendations for younger patients than for older patients, because younger patients usually better tolerate anthracycline- and taxane-based cytotoxic drugs than older patients.

Also, it is important when treating younger women to consider their BRCA mutation status, because there is solid evidence showing that tumors arising in BRCA mutation carriers respond much more vigorously to DNA-damaging platinum-based chemotherapy compared with non–BRCA-mutated tumors.

Reducing Breast Cancer Incidence

How do we reduce the incidence of breast cancer in AYAs and improve their survival rates? By incorporating earlier mammography screenings?

One of the most important aspects of evaluating the risk of breast cancer in this age group is family history. Although our current guidelines call for starting mammographic screening at age 40, the other consideration is if a woman has a first-degree relative, especially her mother, diagnosed with premenopausal breast cancer. This patient should start screening 10 years prior to that relative’s diagnosis. So, if a woman’s mother was diagnosed at age 42, for example, she should start mammography screening at age 32.

Also, research is showing that breastfeeding is protective against breast cancer, so promoting breastfeeding and supporting our patients in this process may be protective against a breast cancer diagnosis in younger women.

Quality-of-Life Impact on AYAs

Please talk about how breast cancer affects the lives of AYAs differently than those of older women.

The list is very long and includes a unique variety of psychosocial and emotional challenges, such as the impact of therapy on sexuality and body image and on childrearing and other family responsibilities; the possibility of premature menopause; and disruptions in career to take time off for treatment and recovery. There is also the challenge of having to face the possibility of mortality at a much earlier age.

Organizations such as the Young Survival Coalition (youngsurvival.org) and Living Beyond Breast Cancer (lbbc.org) can help younger survivors find resources and support each other. Many of my patients have become actively involved in these organizations and have greatly benefited from having this type of community support (See sidebar on “Resources for AYAs With Breast Cancer.”)

Immunotherapy as Potential Treatment

What progress is being made in new therapies that may be more effective than current ones against breast cancer in AYAs?

We have learned a lot over the past 5 years about the impact of BRCA-mutation status on the response to individual therapeutics. From my perspective, the field of genetics is exploding, and we are learning a great deal more about the genetic predisposition to cancer. I am hoping this will lead to more tailored approaches for treating breast cancer beyond that of just BRCA-mutation status.

Testing for germline mutations in BRCA1/2 is standard for select patients with breast cancer to help determine treatment. Advances in next-generation sequencing are allowing us to test for additional breast cancer predisposition genes and will provide greater insight about how best to treat younger patients in the future.

Currently, surgery, radiotherapy, and adjuvant therapies, including cytotoxic chemotherapy, ovarian ablation, and antiestrogen therapy, or any combination of these modalities, are appropriate for premenopausal patients. The newer area we are investigating now is how to utilize immunotherapy to improve outcomes for patients with breast cancer and in what setting it would be most effective to boost a patient’s immunity to cancer and kill any resistant residual cells that can lead to recurrence in the postneoadjuvant setting. Immunotherapy is also being developed in the advanced setting.

Although breast cancer tumors are thought to be less immunogenic than other cancers such as melanoma, recent data from clinical studies have shown that breast cancers, especially HER2-positive and triple-negative tumors, are more immunogenic than previously believed, increasing our enthusiasm for the potential of immunotherapy in the treatment of breast cancer. There are multiple clinical trials now underway evaluating novel immunotherapies in the management of breast cancer, and we should have some definitive answers soon.

Disclosure: Dr. Anders has received research funding from Novartis, Sanofi, toBBB, GERON, Angiochem, Merrimack, PUMA, Lilly, Merck, Oncothyreon, Cascadian, Nektar, and Tesaro; has an uncompensated advisory role with Novartis, Sanofi, toBBB, GERON, Angiochem, Merrimack, Lilly, Genentech, Nektar, Kadmon; and has received royalties from UpToDate and Jones & Bartlett. ■

References

1. American Cancer Society: How Common Is Breast Cancer? Available at https://www.cancer.org/cancer/breast-cancer/about/how-common-is-breast-cancer.html. Accessed March 14, 2017.

2. Anders CK, Johnson R, Litton J, et al: Breast cancer before age 40 years. Semin Oncol 36:237-249, 2009.