Clinical and Psychosocial Challenges of Breast Cancer in Adolescent and Young Adult Women Under the Age of 40 Years

Despite significant advances in clinical research, breast cancer remains one of the most common cancers in women worldwide including adolescent and young adults (AYAs) with increasing incidence and mortality rates. Younger age at diagnosis is an independent prognostic factor of poor survival with higher rates of aggressive breast cancer subtypes (triple-negative [TN] or human epidermal growth factor receptor 2 [HER2]–positive) and advanced stage at diagnosis.¹ In this issue, Cathcart-Rake et al² review the unique challenges of breast cancer treatment and survivorship of AYAs. Given the complex treatment and supportive needs of AYAs, the authors highlight the need for upfront coordinated multidisciplinary team approach for optimal care.

The increasing incidence of breast cancer in AYA women is highly concerning. Understanding the risk factors, tumor biology, and management strategies of AYAs with breast cancer is crucial for improving patient outcomes. Local and systemic treatments for AYAs are quite similar to treatments offered to older women with breast cancer; however, a few key differences are worth mentioning. In regard to surgical management, the rates of bilateral mastectomies are much higher in AYAs compared with older women because of higher lifetime risk of local recurrence, ipsilateral or contralateral new primaries, desire for better cosmetic outcomes, and, most importantly, higher frequency of deleterious germline genetic mutations (BRCA1/2, CHEK2, PALB2, TP53, ATM, etc). AYA women with breast cancer diagnosis should be promptly referred for genetic testing and counseling for informed surgical planning. Standard indications for locoregional radiation like breast conservation, tumor size, and nodal status apply to AYAs as well; however, additional factors to consider in younger women include risk of radiation-induced malignancies in the presence of germline cancer predisposition mutations, fertility plans, and desire to breast feed.

Systemic treatment decisions for AYAs are guided by their disease stage and subtype with low threshold for systemic staging and chemotherapeutic agents. For locally advanced nonmetastatic TN and HER2-positive breast cancers, neoadjuvant chemotherapy is warranted to assess pathologic response rates and make adjuvant treatment decisions accordingly. Carboplatin in addition to standard anthracycline- and taxane-based chemotherapy in TN disease is associated with significantly improved pathologic complete responses (pCRs).^3,4 Of note, these trials were not powered to demonstrate long-term survival benefit. KEYNOTE-522 trial showed further improvement in pCR rates of up to 65% with the addition of pembrolizumab to anthracycline-, taxane-, and platinum-containing regimens, regardless of programmed death ligand-1 (PD-L1) status.⁵ Although addition of pembrolizumab is associated with increased pCR rates, it is currently not recommended because of added toxicity, lack of survival data, cost, and insurance concerns. Treatment for HER2-positive breast cancer is not significantly affected by patient’s age, and it is reasonable to treat AYAs with stage I HER2-positive breast cancers with adjuvant paclitaxel and trastuzumab given the excellent long-term outcomes in the APT trial.⁶ However, for AYAs with larger tumors or node-positive, HER2-positive cancers, neoadjuvant chemotherapy with dual HER2-directed treatment is recommended. For patients with residual disease post-neoadjuvant chemotherapy, adjuvant trastuzumab emtansine (T-DM1) provides significant recurrence risk reduction.

AYA women with locally advanced, node-positive, estrogen receptor–positive, HER2-negative cancers are routinely treated with neoadjuvant chemotherapy to downstage breast and nodal disease although the pCR rates in this subtype are low. Most patients with early-stage, node-negative disease undergo surgery first for pathologic staging to guide the adjuvant treatment decisions. Genomic assays like Oncotype Dx and MammaPrint, among others, provide accurate prediction of recurrence, risk stratification, and potential benefit of adjuvant chemotherapy. In contrast to older women, where the use of adjuvant chemotherapy has significantly decreased by incorporating these genomic assays with lack of chemotherapy benefit seen in low- and intermediate-risk disease, clinical trials of genomic assays have consistently shown chemotherapy benefit in younger women.^7,8 It is unclear if the improvement in long-term outcomes is from chemotherapy or aggressive endocrine treatment with ovarian suppression (OS) in these younger women. Adjuvant endocrine therapy reduces the risk of distant recurrence by approximately 50% and remains the cornerstone of systemic treatment for estrogen receptor–positive, HER2-negative breast cancer. Tamoxifen for five years is a reasonable choice for AYAs with early-stage, low-risk disease; however, most AYAs are recommended OS with either tamoxifen or an aromatase inhibitor (AI) because of high-risk clinicopathological features, disease burden, and chemotherapy use. Long-term follow-up of SOFT and TEXT trials⁹ showed significantly improved disease-free survival with tamoxifen and OS compared with tamoxifen alone and even better recurrence risk reduction with AIs and OS, particularly in women < 35 years, premenopausal women, and those treated with chemotherapy. Benefits of OS and AIs must be weighed against the acute and late toxic effects such as depression, weight gain, sexual side effects, cardiovascular disease, hyperlipidemia, diabetes, and osteoporosis. This dual approach is warranted for recurrence risk reduction in high-risk AYAs; however, prompt treatment strategies, appropriate referrals, and counseling are needed to manage these challenging side effects and ensure compliance. Clinical trials should always be considered for AYAs at any stage of breast cancer, particularly those with advanced and metastatic disease.

Fertility preservation and pregnancy management are additional unique challenges to consider in AYAs with breast cancer. Risk of premature ovarian failure with chemotherapy is significant, and hence, early referral to reproductive endocrinologist is crucial for oncofertility counseling and planning. Oocyte and embryo cryopreservation is an effective strategy; however, invasive techniques, cost, and delay in breast cancer treatment are some of the concerns. Gonadotropin-releasing hormone agonists given during chemotherapy significantly reduce the rates of premature ovarian failure, and although fertility preservation is not guaranteed, it is reasonable to add gonadotropin-releasing hormone agonists to chemotherapy treatment for AYAs with desire for future childbearing. The duration of adjuvant endocrine treatment of 5-10 years is also a challenge in pregnancy planning. However, it is encouraging to know that a recent meta-analysis showed no detrimental prognostic effects of pregnancy after breast cancer diagnosis irrespective of patient’s stage, nodal status, chemotherapy exposure, BRCA status, or pregnancy interval.¹⁰ The higher risk of pregnancy and fetal complications particularly in women with prior chemotherapy call for close monitoring of these high-risk pregnancies.

AYAs with breast cancer require a proactive multidisciplinary approach to manage all aspects of treatment and survivorship care including cancer management, toxicities, mental health, sexual health, fertility preservation, and clinical trial opportunities. Additional research and clinical trials are needed to optimize care for the unique age-specific challenges and to improve patient outcomes.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Clinical and Psychosocial Challenges of Breast Cancer in Adolescent and Young Adult Women Under the Age of 40 Years

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