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

Abstract

In the United States, one in 196 women is diagnosed with breast cancer under the age of 40 years. Adolescents and young adults (AYAs), of age 15-39 years at diagnosis, experience a number of unique challenges when confronting breast cancer. The incidence of invasive breast cancer has increased among AYA women in the United States since 2004, and most of this change is due to an increase in young women diagnosed with distant disease. AYAs are more likely than older women to present with aggressive subtypes and advanced disease, and they often require systemic staging at diagnosis. Clinical trials should be considered whenever possible, particularly in AYAs with locally advanced or metastatic disease at diagnosis and those with disease progression or recurrence. A significant proportion of AYAs carry germline cancer predisposition mutations, which necessitates prompt genetic testing for all AYAs at diagnosis and may influence choice of local therapy. Suppression of ovarian function, as an adjunct to chemotherapy, may improve breast cancer survival in AYAs. To provide optimal care for AYAs with breast cancer, clinicians should engage multidisciplinary teams that offer fertility preservation, genetic counseling, physical and occupational therapy, nutrition, and psychosocial support, along with medical expertise in tailoring cancer-directed therapy and symptom management toward young women.

Introduction and Epidemiology

Breast cancer is the most common cancer type among adolescents and young adults (AYAs) of age 15-39 years at diagnosis, accounting for 30% of cancers among AYA women. According to SEER, 5.6% of all invasive breast cancers occur in AYAs.1 The incidence of invasive and all breast cancer in AYA women in the United States increased after 2004, and more for invasive cancer (average annual percent change [AAPC] = 0.54, P = .004) than all cancer (AAPC = 0.38, P = .02) (Fig 1A). Most of the increase in invasive cancer was because of late-stage cancer (distant disease) (AAPC = 3.54, P < .0001) (Fig 1B). Incidence also increased, at a lower rate, among women of age ≥ 40 years (AAPC = 0.21, P = .01). The incidence trend predicts that more than 12,000 AYA women will be diagnosed with invasive breast cancer in the United States during 2020. AYAs are more likely than older women with breast cancer to present with unfavorable biology and advanced disease, translating into poorer survival. Even among patients with early-stage breast cancer, AYA women are 39% more likely to die compared with older women.2 In addition, AYAs are more likely to experience side effects from therapy and psychosocial issues after diagnosis.3
Fig 1. Annual incidence of breast cancer in women, age 15-39, 2004-2017, SEER18, with Joinpoint Regressions and associated average AAPC and P-value. (A) All and invasive breast cancer. (B) Invasive breast cancer by stage per combined summary available since 2004. Data source: SEER. AAPC, average annual percent change.
Cancer care for AYAs should be carefully coordinated and multidisciplinary, incorporating strategies that maximize both survival and psychosocial outcomes.1

Risk Factors

AYA breast cancer is frequently familial, and approximately half of AYA women with breast cancer under the age of 30 harbor a germline mutation in BRCA1, BRCA2, or TP53.4 Hormonal factors that increase breast cancer risk among AYAs include early menarche, oral contraceptives, anovulatory infertility, and late parity after age 30.5,6 As in older women, breastfeeding decreases breast cancer risk,7 whereas a history of mantle radiation increases the risk.8
Some modifiable risk factors differ between AYAs and older women.1,9 Although obesity increases breast cancer risk among postmenopausal women, several large epidemiologic studies report that breast cancer is more frequent in young women with low or normal compared with higher body mass index. Other studies suggest that body habitus and a higher waist-to-hip ratio are more predictive of AYA breast cancer risk than body mass index.10-13 Associations between alcohol intake and breast cancer risk are also less clear among AYAs than in postmenopausal women.14-16 Exercise and a plant-based diet are potentially protective against breast cancer among AYAs, as they are in older populations, although these studies are small.17-20

Evaluation and Workup

AYA women with breast cancer are typically premenopausal. However, if a patient is amenorrheic for any reason, including previous uterine ablation or hysterectomy, then follicle-stimulating hormone and estradiol levels should be obtained to confirm menopausal status.
Breast magnetic resonance imaging is a valuable adjunct to mammography in the workup of a breast abnormality in AYAs since they are more likely than older women to have dense breast tissue.21,22 AYAs are more likely than older women to present with distant disease at diagnosis,23 so clinicians may have a lower threshold for ordering systemic staging in AYAs with newly diagnosed breast cancer.24
The National Comprehensive Cancer Network guidelines suggest a consideration of referral to a tertiary care center for women under age 40 years with breast cancer (Fig 2). Referrals must be obtained promptly since treatment delays have a deleterious impact on survival among AYAs with breast cancer.25
Fig 2. Reasons to prioritize referral of AYAs with breast cancer to a tertiary cancer center. AYA, adolescent and young adult.
AYA care is particularly complex and involves coordination among a number of subspecialists. We recommend following the algorithm outlined in Figure 3. In addition to a surgeon, medical oncologist, and radiation oncologist, AYAs may also benefit from consultation with a geneticist, reproductive endocrinologist, gynecologist, psychologist, and either an occupational or a physical therapist. Care at a multidisciplinary clinic is strongly encouraged to facilitate timely, coordinated decision making for AYAs with breast cancer.
Fig 3. Special considerations for the clinical management of AYAs with breast cancer. AYA, adolescent and young adult; IUD, intrauterine device; OT, occupational therapy; PT, physical therapy.

Treatment and Management

Local Therapy for Early-Stage Disease

Survival is similar among AYAs who pursue breast conservation therapy compared with mastectomy (assuming all other disease characteristics are equal); however, AYAs are more likely than older women to choose bilateral mastectomies.26 This finding may be explained by several issues of particular importance to AYAs with breast cancer.
First, 16.9% of AYAs with breast cancer harbor a deleterious genetic mutation that might impact surgical decision making, compared with 10.7% of women with breast cancer at any age.27 As genetic testing typically takes 2-3 weeks to result, it is imperative to offer germline genetic testing to all AYAs as soon as possible after diagnosis. Guidelines recommend consideration of risk-reducing bilateral mastectomy among women harboring BRCA1/2, PALB2, TP53, and other germline mutations that predispose to breast cancer.24 AYAs with germline TP53 mutations may opt for mastectomy due to their high risk for secondary radiation-induced malignancies.28 Lifetime risk of ipsilateral or contralateral new primary breast cancer is significant among AYAs with breast cancer, and patients with contralateral breast cancers have inferior survival compared with patients with primary breast cancers.29,30
Second, when compared with women older than 60 years, AYAs have a nine-fold higher risk for local recurrence after breast conservation therapy.31 This finding is likely due, at least in part, to differences in disease biology.
Third, concerns about sexuality, fertility, and body image impact decision making about local therapy options in young women. This underscores the importance of multidisciplinary psychosocial support for AYAs with breast cancer.32 On the one hand, desire for breast symmetry may drive some AYAs to opt for bilateral mastectomy with reconstruction over lumpectomy or unilateral mastectomy.33 On the other hand, women who hope to bear children in the future may choose unilateral (rather than bilateral) mastectomy in hopes of supporting future breastfeeding; lumpectomy and radiation may decrease lactation in the treated breast.34

Systemic Therapy for Early-Stage Disease

In comparison with older women, AYAs have a higher risk for distant recurrence after treatment for early-stage breast cancer.2,23,35,36 Breast cancers of AYAs more often have high-risk features, including estrogen receptor–negative (ER−)/progesterone receptor (PR)–negative or HER2-enriched subtypes, grade 3 histology, and vascular or lymphatic invasion.37 However, even when matched by histologic subtype and hormone receptor expression subgroup, survival is worse among AYAs compared with older women.37
Despite the inferior outcomes among AYAs with breast cancer, there are little data to inform treatment decisions.38 Although meta-analyses of clinical trials suggest that women under age 50 years and women of age ≥ 50 years derive similar benefit from adjuvant chemotherapy, it is less common for trials to report data on AYAs diagnosed under age 40 years.39,40 When caring for AYAs with breast cancer, clinicians should consider the possibility of referral for a clinical trial at each juncture of the treatment plan.

Triple-negative breast cancer.

Neoadjuvant chemotherapy is preferred for AYAs with early-stage triple-negative breast cancer. Pathologic response data are prognostic and allow for triaging of systemic therapy in the adjuvant setting.41 Because AYAs with triple-negative histology experience poorer survival,37 the threshold for the addition of agents such as carboplatin with or without immunotherapy to the traditional chemotherapy backbone of paclitaxel, before or after doxorubicin and cyclophosphamide, is lower for AYAs compared with older women who have a similar stage and subtype.42-45 Neither carboplatin nor pembrolizumab improves complete response rate, but they do increase the toxicity of therapy and have not been proven to improve overall survival.

HER2-positive breast cancer.

AYAs with small, < 2 cm, HER2-positive breast cancers may be well-treated with 12 weeks of adjuvant paclitaxel combined with a year of trastuzumab (TH).46 In the adjuvant paclitaxel-trastuzumab trial, 33% of the 406 patients were under age 50 years, and recurrences occurred in only four patients within 7 years. Furthermore, only 28% of premenopausal women (median age of 44) receiving TH developed long-term amenorrhea, suggesting that TH has less gonadotoxicity than regimens containing alkylators.47
T-DM1 (ado-TH emtansine) is another adjuvant therapy option for women with small, HER2-positive breast cancers, on the basis of the ATEMPT clinical trial, although only 3-year follow-up data are available.48 Amenorrhea rates appear to be at least as low with T-DM1 as TH,47,49 and T-DM1 causes less hair loss and neuropathy than TH.
In AYAs with larger or node-positive HER2-positive cancers, neoadjuvant chemotherapy including dual HER2-directed therapy (TH and pertuzumab) is preferred. On the basis of KATHERINE trial data, AYAs with residual disease after neoadjuvant chemotherapy had superior 3-year disease-free survival when treated with adjuvant T-DM1 compared with adjuvant TH (86.5% v 74.9%).50

Estrogen Receptor–Positive, HER2-Negative Breast Cancer

Neoadjuvant chemotherapy is indicated for AYAs with estrogen receptor–positive (ER+) HER2− cancers when a tumor is unresectable at diagnosis, when tumor characteristics are highly suggestive of chemotherapy sensitivity (eg, estrogen receptor expression < 50% and/or high-grade), or when downstaging of the breast tumor or axillary nodal disease is desired prior to surgery. Otherwise, adjuvant treatment allows for the incorporation of information gleaned at surgery into decision making regarding the need for chemotherapy in addition to or prior to endocrine therapy.
Although chemotherapy clearly benefits AYAs with high recurrence scores on genomic testing (eg, Oncotype DX or MammaPrint), it is more difficult to gauge the potential benefit of chemotherapy for women with low-to-intermediate recurrence scores. For women under age 50 with high clinical risk and low-to-intermediate genomic risk, chemotherapy increases long-term survival by up to 10%.51,52
Some or all the survival advantages that younger women with ER+ HER2− tumors derive from chemotherapy may be because of the suppression of ovarian function, which occurs as a side effect of chemotherapy. The STEPP analysis, a combined analysis of SOFT and TEXT trials, showed that when suppression of ovarian function was added to an aromatase inhibitor, absolute disease-free survival interval increased by 4%-5% over tamoxifen alone for patients with intermediate clinical risk for recurrence and 10%-15% for patients at high clinical risk for recurrence.53 This benefit is sizable, and compared with data from TAILORx—which showed that women under age 50 with high clinical risk for recurrence and an intermediate Oncotype DX score of 21-25 have an invasive disease–free survival benefit of 8.7% with chemotherapy—suggesting that this population may benefit from ovarian suppression as a part of endocrine therapy, in lieu of chemotherapy.51 Further data are needed, however.
Adjuvant endocrine therapy is the standard of care for hormone receptor–positive breast cancer, and it reduces risk for recurrence by 50%.54 AYA women with early-stage, hormonally sensitive breast cancer have fewer recurrences if their endocrine therapy includes suppression of ovarian function. A subgroup analysis of the SOFT trial reported that, among women < 35 years of age, 8-year disease-free survival was 64.3% with tamoxifen alone; 73% with tamoxifen plus ovarian function suppression; and 77.4% with exemestane in addition to ovarian function suppression.55 Because suppression of ovarian function in combination with tamoxifen has more toxicity than tamoxifen alone, including more vaginal dryness, sexual dysfunction, and vasomotor symptoms,56 some AYAs with node-negative T1 tumors may opt not to suppress their ovarian function.
The duration of endocrine therapy is an additional consideration for AYAs. The extension of tamoxifen monotherapy from 5 to 10 years decreases breast cancer mortality by 2.8%,57 but 10 years of ovarian function suppression–based treatment has not yet been tested in premenopausal survivors.
If ovarian function suppression is well-tolerated and future fertility is not a concern, some women might prefer a salpingo-oophorectomy over monthly injections to suppress ovarian function. Women with germline cancer predisposition mutations, including women with BRCA1, BRCA2, BRIP1, RAD51C/D, or the Lynch syndrome genes, have varying degrees of increased risk for ovarian cancer and may benefit from prophylactic bilateral salpingo-oophorectomy.24
Bisphosphonates confer a very mild adjuvant benefit among premenopausal women with a history of ER+ breast cancer receiving ovarian function suppression.58,59

Systemic Therapy—Metastatic Disease

Clinical trial participation should be considered at each treatment juncture for AYAs with metastatic breast cancer. Treatment of metastatic disease does not significantly differ for AYAs in comparison with older women except that bilateral salpingo-oophorectomy soon after diagnosis is recommended for AYAs with hormone receptor–positive disease to ensure optimal suppression of estrogen. Survival is the same for women treated with ovarian suppression versus bilateral salpingo-oophorectomy in this setting.60

Special Issues for AYAs with Breast Cancer

Fertility Preservation

Breast cancer chemotherapy may cause premature ovarian failure, and AYAs rank infertility as a critically important issue in cancer survivorship.61,62 Referral to a reproductive endocrinologist is imperative for AYAs who desire to bear children following chemotherapy. Rates of premature ovarian failure are highest among older premenopausal patients receiving alkylating agents but depends on patient age, comorbidities, type of chemotherapy, and dose.63-65 Premature menopause occurs in 13% of AYAs treated with doxorubicin and cyclophosphamide; this risk increases to 57%-63% in women of age ≥ 40.66 Embryo and oocyte cryopreservation are effective strategies for preserving fertility, but both are invasive and costly.67,68
Gonadotropin-releasing hormone (GnRH) agonists, given before and during chemotherapy, offer the potential of preserving fertility, although data are mixed regarding efficacy.69-75 A recent systemic review and meta-analysis reported that, among premenopausal women treated with chemotherapy for breast cancer, the incidence of premature ovarian insufficiency was 30.9% for women who did not receive GnRH agonists, compared with only 14.1% for women treated with GnRH agonists.76 GnRH agonists appear to be particularly effective for AYAs: 8.3% of AYAs (v 24.7% of women ≥ 40) experienced premature ovarian insufficiency when treated with a GnRH agonist. Although more data on pregnancy rates after chemotherapy are needed, in this study, 10.3% of premenopausal women receiving GnRH agonists experienced a pregnancy after breast cancer treatment, compared with 5.5% of women who did not.
Years of planned endocrine therapy can disrupt pregnancy plans and limit the fertility window of AYAs with breast cancer. Women are unlikely to conceive while being treated with an aromatase inhibitor along with ovarian function suppression. Tamoxifen is a teratogen. Therefore, it is recommended that women who wish to conceive stop endocrine therapy for at least 3 months before attempting pregnancy. Poor adherence to endocrine therapy (< 80%) is associated with inferior survival outcomes, but the IBCSG48-14/BIG8-13 (POSITIVE) clinical trial is currently studying the safety of stopping endocrine therapy for a fixed period of time to allow for pregnancy.77
Use of TH and other HER2-directed therapies can also delay childbearing after breast cancer diagnosis. These agents are usually given for at least 12 months. Because they can cause oligohydramnios, the US Food and Drug Administration recommends delaying conception for at least 7 months after completion of therapy.

Pregnancy

A diagnosis of breast cancer during pregnancy or shortly after delivery of an infant is common; 20% of women of age 25-29 at the time of breast cancer diagnosis have completed a pregnancy within the past 12 months.78-81 Although women diagnosed during pregnancy are more likely to present with advanced-stage disease, after controlling for stage of disease and treatment, survival becomes similar to women who are not pregnant.82 Termination of pregnancy has not been shown to improve survival.83,84
Women who become pregnant within 6 months after a breast cancer diagnosis have a modestly higher 5-year survival than others; this observation may be due to the healthy mother effect (ie, women who become pregnant may have lower risk cancers and fewer comorbid conditions).85,86
Pregnancy rates after breast cancer diagnoses are significantly lower than in age-matched controls.87 In one study, < 10% of AYA breast cancer survivors had a live birth within 10 years of diagnosis, and AYAs with ER− disease had an increased risk for preterm delivery.88

Contraception

Contraception is recommended for premenopausal AYAs while receiving any teratogenic chemotherapy, including tamoxifen and TH. Traditional contraceptives containing systemic estrogen and progesterone are contraindicated in AYAs with hormone-sensitive cancers. Studies are mixed as to whether the progestin intrauterine device (IUD) (Mirena) increases the risk for breast cancer, which raises some concern for use—particularly in survivors of ER+ breast cancer.89-92 Survivors should ideally use nonhormonal contraception. Acceptable forms include the copper IUD, two simultaneous forms of barrier contraceptive, or—if future fertility is not desired—sterilization of the patient or patient's male partner. For women with ER− breast cancer, estrogen-containing contraceptives may be considered on a case-by-case basis.

Survivorship Issues

In comparison with older women with breast cancer, AYAs more frequently report a compromised quality of life.93,94 AYAs receiving endocrine therapy or chemotherapy may experience pronounced symptoms related to estrogen depletion, including vaginal dryness, decreased sexual desire, and fatigue.94 AYA survivors may face decades of risk for cardiotoxicity related to anthracyclines and risk for fractures resulting from ovarian suppression or aromatase inhibitors. Suppression of ovarian function and oophorectomy may impart risk for cognitive impairment and dementia as these risks are noted among premenopausal women in the general population who undergo oophorectomy at a young age.95,96 In comparison with both age-matched peers and older breast cancer survivors, AYAs with breast cancer are also at higher risk for potentially serious psychosocial issues including depression, anxiety, sense of isolation, poor body image, disruptions in relationships, occupational difficulties, and financial toxicity.1,33,62,96-99
AYAs are less likely to be adherent to endocrine therapy than older women with breast cancer, adversely impacting survival.77 Nonadherence may at least be partly explained by the severity of side effects and the psychosocial stressors described above.
These significant survivorship issues underscore the importance of supporting AYAs throughout cancer-directed therapy and survivorship. This can be done by a multidisciplinary care team comprising physicians, nurses, psychologists, social workers, physical and occupational therapists, dieticians, and chaplains. Providers should also direct AYAs to nationwide support organizations for young women with breast cancer, including the Young Survival Coalition, the Living Beyond Breast Cancer Young Women's Initiative, and the Tigerlily Foundation. Other support organizations for AYAs with cancer include Stupid Cancer, Lacuna Loft, GRYT, and First Descents. These organizations, and many others like them, offer information, advocacy, individualized support, and peer connection.
In conclusion, the incidence of breast cancer is increasing among AYAs, who are more likely than older women to present with advanced disease at diagnosis.1,23 AYAs face unique, age-specific challenges as they confront breast cancer treatment and survivorship. As a result, they derive significant benefit from a coordinated, multidisciplinary treatment approach.
See accompanying commentaries on pages 314 and 317

Authors' Disclosures of Potential Conflicts of Interest

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

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/op/authors/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Kathryn J. Ruddy

Patents, Royalties, Other Intellectual Property: My husband is a co-inventor of technology licensed by Mayo Clinic to AliveCor (Mountain View, CA), which makes a smartphone-enabled remote ECG monitoring system.

Archie Bleyer

Honoraria: Jazz Pharmaceuticals, Shire
Speakers' Bureau: Shire, Jazz Pharmaceuticals
Patents, Royalties, Other Intellectual Property: F3 Platform Biologics
Expert Testimony: Neptune Generics

Rebecca H. Johnson

Consulting or Advisory Role: Servier
Speakers' Bureau: Servier, Jazz Pharmaceuticals
Travel, Accommodations, Expenses: Servier
No other potential conflicts of interest were reported.

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Information & Authors

Information

Published In

JCO Oncology Practice
Pages: 305 - 313
PubMed: 33449828

History

Published online: January 15, 2021
Published in print: June 01, 2021

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Authors

Affiliations

Elizabeth J. Cathcart-Rake, MD https://orcid.org/0000-0003-3532-4913
St Luke's Hospital, Kansas City, MO
Kathryn J. Ruddy, MD, MPH https://orcid.org/0000-0001-6298-332X
Mayo Clinic, Rochester, MN
St Charles Health System, Central Oregon Health and Science University, Portland, OR
Mary Bridge Hospital/MultiCare Health System, Tacoma, WA

Notes

Rebecca H. Johnson, MD, Mary Bridge Children’s Hospital/MultiCare Health System, Department of Pediatrics, PO Box 5299, 311 South L St., Tacoma, WA 98405; e-mail: [email protected].

Author Contributions

Conception and design: All authors
Collection and assembly of data: Elizabeth J. Cathcart-Rake, Archie Bleyer, Rebecca H. Johnson
Data analysis and interpretation: Elizabeth J. Cathcart-Rake, Kathryn J. Ruddy, Archie Bleyer, Rebecca H. Johnson
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors

Disclosures

Kathryn J. Ruddy
Patents, Royalties, Other Intellectual Property: My husband is a co-inventor of technology licensed by Mayo Clinic to AliveCor (Mountain View, CA), which makes a smartphone-enabled remote ECG monitoring system.
Archie Bleyer
Honoraria: Jazz Pharmaceuticals, Shire
Speakers' Bureau: Shire, Jazz Pharmaceuticals
Patents, Royalties, Other Intellectual Property: F3 Platform Biologics
Expert Testimony: Neptune Generics
Rebecca H. Johnson
Consulting or Advisory Role: Servier
Speakers' Bureau: Servier, Jazz Pharmaceuticals
Travel, Accommodations, Expenses: Servier
No other potential conflicts of interest were reported.

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Elizabeth J. Cathcart-Rake, Kathryn J. Ruddy, Archie Bleyer, Rebecca H. Johnson
JCO Oncology Practice 2021 17:6, 305-313

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