Young women with breast cancer who receive neoadjuvant chemotherapy (NAC) are more likely to decline referral to reproductive endocrinology and infertility (REI) specialists than women who receive adjuvant chemotherapy, according to our retrospective study published recently in the Annals of Surgical Oncology. (1)
This finding suggests that despite NAC’s advantages, its recommendation may be associated with a “scare factor” and an urgency to initiate chemotherapy. The resulting anxiety, together with difficulty reconciling elevating estradiol levels for ovarian stimulation while a tumor lies in place, likely contributes to some patients who are receiving NAC to forgo REI consultation on fertility preservation options. (2)
Breast cancer treatment may be associated with infertility. (3) Cytotoxic chemotherapies lead to fibrosis, apoptosis of primordial follicles, and vascular damage, accelerating natural declines in ovarian reserve and compromising ovarian function. (4) Adjuvant therapies typically impose a delay on childbearing of two years after the completion of treatment. (5), (6), (7) Chemotherapy-induced infertility is associated with negative quality of life, increased anxiety, and psychological burden. (8), (9)
Recognizing these issues, the American Society of Clinical Oncology recommends early referral to REIs to discuss fertility preservation options at the time of a new cancer diagnosis. (10) Despite this guidance, studies have shown that women do not receive adequate counseling about the impact of their cancer treatment on future fertility and options for fertility preservation. (11), (12), (13), (14), (15)
The timing of fertility preservation is more challenging in the NAC setting, but not impossible. We found that delayed initiation of chemotherapy more than six weeks after initial diagnosis in the NAC setting and more than 12 weeks in the adjuvant chemotherapy setting were uncommon. Overall, our study underscores the need for further counseling and education among young women with breast cancer undergoing NAC. (1)
Researchers continue to investigate refining ovarian stimulation cycles to minimize estradiol levels while maximizing oocyte yields and limiting treatment delays. Some recent studies have reported favorable oncologic and pregnancy outcomes following fertility preservation in women with breast cancer, but additional research in the NAC setting is needed. (16)
Intersecting Trends: Delayed Childbearing and Increased Use of NAC
Although breast cancer is rare in women under 40 years of age, (17), (18) an increasing number of women are delaying having children for personal and professional reasons. As a result, more women are being diagnosed with breast cancer before completing their childbearing years. (19), (20)
NAC has some compelling advantages compared to adjuvant chemotherapy, including the potential to deescalate surgery and provide prognostic and predictive information. As a result, there is a growing trend toward the use of NAC in women with invasive breast cancer, (21), (22), (23) with recommendations increasing for women with early-stage disease who have high-risk molecular tumor subtypes. (24), (25)
Additionally, young women with breast cancer are more likely than their older counterparts to have locally advanced disease and harbor high-risk molecular subtypes, such as triple-negative and human epidermal growth factor receptor 2 (HER2)-positive breast cancer. (22)
Together, these intersecting trends mean that more young women with breast cancer who still wish to have children are likely to receive a NAC recommendation.
We conducted a retrospective review of our prospectively maintained breast cancer database at Memorial Sloan Kettering Cancer Center (MSK), and identified premenopausal women diagnosed with stage 0–III breast cancer between 2009 and 2015 who had completed a consultation with a fertility nurse specialist in the MSK Cancer and Fertility Program. Our objective was to evaluate the factors associated with referral to REI specialists and the effect of NAC on the decision to pursue an REI consultation.
We identified 334 women as receiving a referral to an REI specialist by a fertility nurse specialist. The median age was 35 years (interquartile range (IQR) 32–39). A majority of women were single (n = 198, 59 percent), nulligravid (n = 185, 55 percent), and nulliparous (n = 239, 72 percent). (1)
Germline mutations were found in 14 percent of women (n = 46). A history of breast or ovarian cancer in a first-degree family member was uncommon (n = 38, 11 percent; and n = 5, 1.5 percent, respectively). Most women, 93 percent had invasive ductal carcinoma with a median tumor size of 2.0 cm (IQR 1.2–2.8 cm). Stage II disease was the most common stage at diagnosis (n = 158, 47 percent), followed by stage I (n = 121, 36 percent) and stage III (n = 45, 14 percent). (1)
Most women, 62 percent, had undergone mastectomy, and 66 percent of these patients elected to have contralateral prophylactic mastectomy for risk reduction. Almost all patients, 98 percent, underwent axillary staging, and a majority (65 percent) had sentinel lymph node biopsy alone. The eight women who did not undergo axillary staging had pure ductal carcinoma in situ. (1) Most women received systemic therapy: 58 percent had adjuvant chemotherapy and 19 percent had neoadjuvant chemotherapy. Endocrine therapy was prescribed to 73 percent of all patients and 91 percent of estrogen-receptor (ER) positive patients. (1)
Referral from the Breast Surgery Service and early-stage disease were associated with a higher acceptance of REI referral (p < 0.001 and p = 0.002, respectively). Interestingly, of the 195 women who received adjuvant chemotherapy, 151 (78 percent) pursued REI referral compared to 25 of 63 women (40 percent) who received NAC. Multivariate analysis found that only referring service and receipt of NAC were associated with the decision to pursue or forgo REI referral. (1)
Breast surgery was the most common referring service, accounting for 58 percent of referrals, and significantly higher than referrals from breast medicine and genetics services (p = 0.002). Previous studies at MSK have suggested that breast surgical oncologists are uniquely positioned to facilitate early referrals to REIs since they are often the first point of contact for newly diagnosed women. (11)
We performed a subset analysis to compare women who received NAC (n = 63) with those who received adjuvant chemotherapy (n = 195). Subgroups of patients who received NAC (n = 63) and adjuvant chemotherapy (n = 195) had similar demographics and tumor histology distribution, but tumor molecular profiles differed. Women who received NAC had more advanced disease, larger tumors, and a higher incidence of ER-negative and HER2-positive molecular subtypes than those who had received adjuvant chemotherapy (p = < 0.05 for all).
Women who had NAC also had a higher frequency of clinically node-positive disease (NAC n = 43, 68 percent) than women in the adjuvant chemotherapy subgroup (N = 93, 48 percent, p = 0.006) and more frequently underwent axillary lymph node dissection during surgery. Endocrine therapy use was similar between groups. (1)
Fertility Preservation and Delayed Treatment
Traditional protocols for fertility preservation require initiating ovarian stimulation during the follicular phase, which may require a delay of six weeks to complete a single cycle. (26) Newer random-start protocols now allow patients to complete a single cycle within two weeks. (19), (27) The preferred time to pursue cryopreservation cycles is between surgery and adjuvant chemotherapy initiation since waiting up to 12 weeks to start chemotherapy does not adversely affect survival. (28), (29)
The timing of fertility preservation is more complex in the NAC setting. However, recent studies have suggested that ovarian stimulation is not associated with meaningful delays in NAC initiation or negative oncologic outcomes. (30), (31)
In our study, delayed initiation of chemotherapy more than six weeks after initial diagnosis in the NAC setting and more than 12 weeks in the adjuvant chemotherapy setting were uncommon: Delays were noted for only four women in the NAC group and seven women in the adjuvant group. However, these numbers were too small to make statistical comparisons. (1)
Note that most women in our study were treated before 2015, before the results of the Prevention of Early Menopause Study (POEMS) were published. (32) Gonadotropin-releasing hormone agonists for fertility preservation have been routinely offered to patients starting in 2015.
The need for endocrine therapy was not associated with patient acceptance of referral to an REI in our study. However, it is important to note that other recent studies have shown that up to 40 percent of women receiving endocrine therapy for breast cancer are interested in pausing endocrine therapy to pursue pregnancy. (33) The ongoing Pregnancy Outcome and Safety of Interrupting Therapy for women with endocrine responsIVE breast cancer (POSITIVE) trial (NCT02308085) may answer questions about the oncologic safety of interrupting endocrine therapy. Prolonged endocrine therapy without interruption may change REI referral uptake and pursuit of fertility preservation options in the future.
The Cancer and Fertility Program at MSK
Timely referral to REI specialists is of paramount importance for young women with breast cancer: Early referral permits multiple cryopreservation cycles without delaying initiation of neoadjuvant or adjuvant chemotherapy. (28), (30)
Established in 2009, MSK’s Cancer and Fertility Program addresses the growing need for comprehensive patient education about the impact of cancer diagnosis and treatments on fertility and family planning for patients of all genders.
A fertility nurse specialist counsels patients on potential reproductive toxicities of proposed cancer treatments and opportunities for fertility preservation before beginning treatment, including referrals to REI specialists. All premenopausal women diagnosed with breast cancer are offered a consultation with a fertility nurse specialist before initiating therapy.
The study was accepted for presentation in poster format at the 21st Annual Meeting of the American Society of Breast Surgeons, held April 29 to May 3, 2020, Las Vegas, Nevada.
The manuscript preparation was funded in part by the NIH/NCI Cancer Center Support Grant No. P30 CA008748. Dr. Shari B. Goldfarb discloses research funding from Sprout Pharmaceuticals and Paxman Coolers Ltd, and consulting and advisory roles to Sermonix Pharmaceuticals, Bayer Healthcare, and Procter and Gamble. All other authors declare no conflicts of interest.