Impact of Fertility Concerns on Tamoxifen Initiation and Persistence

Abstract

Background

Adjuvant tamoxifen reduces breast cancer recurrence risk and mortality; however, initiation and treatment persistence are poor for younger patients. We hypothesized that a unique set of factors, including fertility concerns, would contribute to the poor tamoxifen use among premenopausal patients.

Methods

From 2007 to 2012, 515 premenopausal patients younger than age 45 years, with stage 0 to III hormone receptor–positive breast cancer, for whom tamoxifen was recommended, were identified. Clinical and pathologic tumor characteristics, treatment regimens, and fertility concerns were recorded. Clinical factors associated with tamoxifen noninitiation and discontinuation were identified using univariate and multivariable analysis. After the recommendation for tamoxifen, patient reasons for tamoxifen noninitiation or discontinuation were also documented. All statistical tests were two-sided.

Results

Based on multivariable analysis, fertility concerns were statistically associated with both noninitiation (odds ratio = 5.04, 95% confidence interval (CI) = 2.29 to 11.07) and early discontinuation (hazard ratio = 1.78, 95% CI = 1.09 to 3.38) of tamoxifen. Other independent predictors of noninitiation included a diagnosis of ductal carcinoma in situ, declining radiation, and not receiving chemotherapy (stage I-III). Additionally, smoking and not receiving radiation therapy were statistically significant predictors of early withdrawal from therapy. Primary patient reasons for noninitiation and early discontinuation included concerns about side effects and fertility.

Conclusion

This study provided insight into factors associated with tamoxifen use for reproductive-aged breast cancer survivors, with a new focus on fertility. Fertility concerns negatively impacted tamoxifen initiation and continuation among premenopausal patients. Interventions to optimize treatment initiation and persistence for young cancer patients should include access to fertility preservation options.

Approximately 25 000 women under age 45 years are diagnosed with invasive or in situ breast cancer annually (1). As advances in cancer care have improved life expectancy, young survivors can prioritize both cancer treatment and survivorship goals. Fertility is a vital survivorship issue, with many cancer treatments involving chemotherapy, radiation, and hormonal modulation, all of which may impair ovarian function (2–5). For women of childbearing age, fertility concerns can have an important role in treatment decision-making (6,7). A survey of young breast cancer patients showed that more than half had concerns about treatment-related infertility, and 29% stated that fertility concerns influenced treatment decisions (8).

Hormonal modulation with tamoxifen is recommended for patients with hormone receptor–positive disease, representing approximately 70% of breast cancers. Five years of tamoxifen treatment reduces recurrence risk by 47% and mortality by 26%; recent data suggest continuing tamoxifen for up to ten years may also be beneficial (9,10). Despite these benefits, tamoxifen adherence is poor, particularly among young women (11–13). Many reproductive-aged patients who would benefit from tamoxifen have plans for future pregnancy (6); however, tamoxifen is teratogenic and pregnancy is contraindicated during treatment (14,15). As fertility declines with age, length of therapy may deter premenopausal patients (16). Although tamoxifen may not directly damage the ovaries, several studies report a higher rate of treatment-related amenorrhea, particularly after age 40 years (17–21). Additionally, recent data suggest that examestane, used in conjunction with ovarian suppression, may result in improved disease-free survival when compared with tamoxifen for premenopausal estrogen receptor–positive patients (22). This approach would also pose substantial challenges to young patients regarding childbearing and anti-estrogenic side effects.

Despite poor tamoxifen utilization among younger patients (12,23), no study has evaluated predictors of noninitiation or early discontinuation unique to this population or examined fertility concerns as a possible causative factor. Given the importance of fertility to young patients and its effect on treatment decisions (8), we hypothesized that fertility concerns negatively impacted tamoxifen initiation and continuation. Examination of the impact of fertility concerns on tamoxifen use is highly timely, serving as primary data supporting the rationale for the actively accruing International Breast Cancer Study Group POSITIVE trial for hormone receptor–positive, premenopausal breast cancer patients planning a pregnancy. Outcomes of the POSITIVE study, regarding the safety of taking a hiatus from tamoxifen as well as pregnancy outcomes, will provide critical information for young breast cancer suvivors with fertility concerns (24). The goal of the current study was to investigate the potential association between fertility concerns and noninitiation or early discontinuation of tamoxifen in a cohort of premenopausal breast cancer patients, while taking into account additional factors that might also have a role in treatment implementation.

Methods

Patient Selection

With institutional review board (IRB) approval, women treated at Northwestern Memorial Hospital’s Lynn Sage Comprehensive Breast Center (Chicago, IL) were identified in the electronic medical record (EMR) as younger than age 45 years, diagnosed with stage 0-III, estrogen receptor–positive and/or progesterone receptor–positive breast cancer between January 1, 2007 and May 31, 2012. The study was restricted to premenopausal patients for whom adjuvant tamoxifen was recommended. Patients were also excluded if information about tamoxifen use was unavailable or for recurrence prior to initiating tamoxifen (Supplementary Figure 1, consort diagram, available online). We identified 703 women ages 25 to 45 years; after exclusions, the study consisted of 515 patients.

Chart Review

Patient charts were reviewed for demographic, disease, and treatment characteristics and fertility concerns; findings based on tamoxifen use are listed in Table 1. Data collected was documented in the EMR in a standardized prospective fashion through Breast Center intake procedures. New cancer patients completed a questionnaire addressing demographics, social and medical history, and disease-specific history. Surgical management and disease characteristics were confirmed from operative notes and pathology reports. To address questions about fertility concerns, in 2007, after initiation of an oncofertility program at the study institution, a prompt was placed in the EMR requiring oncologists to ask premenopausal patients about interest in fertility preservation prior to closing the initial encounter. Information regarding fertility concerns was obtained from responses to this prompt and documented in provider’s notes. Also, the EMR interfaced with patient pharmacies to obtain prescription data (dates of tamoxifen refills and number of pills received with each refill). Oncology notes were reviewed for information about tamoxifen use and patient reasons for noninitiation or discontinuation. Potential predictors of tamoxifen utilization were stable factors identified at time of diagnosis, prior to patient decision-making about tamoxifen.

Table 1.

Baseline characteristics of premenopausal patients age <45 y diagnosed with stage 0-III estrogen and/or progesterone receptor–positive breast cancer, advised to take tamoxifen (n = 515)

Characteristic	Continued tamoxifen therapy (n = 366) No. (%)	Early discontinuation of tamoxifen (n = 80) No. (%)	Delayed initiation or no initiation (n = 69) No. (%)	Total number (n = 515)	Total percentage
Age at diagnosis, y
<37	89 (24.6)	21 (26.3)	17 (24.6)	127	24.7
>37	277 (76.0)	59 (73.8)	52 (75.4)	388	75.3
Median age	41	41
Race/ethnicity
White	262 (71.6)	55 (68.8)	46 (66.7)	363	70.5
Black	42 (11.5)	12 (15.0)	9 (13.0)	63	12.2
Hispanic	32 (8.7)	2 (2.5)	5 (7.2)	39	7.6
Asian	23 (6.3)	7 (8.8)	8 (11.6)	38	7.4
Other	7 (1.9)	2 (2.5)	1 (1.4)	10	1.9
Missing	0 (0.0)	2 (2.5)	0 (0.0)	2	0.4
Marital status
Unmarried	120 (32.8)	37 (46.3)	25 (41.7)	182	35.3
Married, partnered, domestic partner	246 (67.2)	43 (53.8)	44 (63.8)	333	64.7
Missing	0 (0.0)	0 (0.0)	0 (0.0)	0	0.0
Smoking status
Current smoker	21 (5.7)	9 (11.3)	8 (11.6)	38	7.4
Never smoker	265 (72.4)	47 (58.8)	53 (76.8)	365	70.9
Former smoker	79 (21.6)	22 (27.5)	7 (10.1)	108	21.0
Missing	1 (0.3)	2 (2.5)	1 (1.4)	4	0.8
Alcohol use
None or < 1 drink per week	180 (49.2)	31 (38.8)	31 (44.9)	242	47.0
1–4 drinks per wk	126 (34.4)	34 (42.5)	28 (55.1)	188	36.5
5–9 drinks per wk	44 (12.0)	9 (11.3)	6 (8.7)	59	11.5
10–19 drinks per wk	13 (3.6)	0 (0.0)	3 (4.3)	16	3.1
>19 drinks per wk	0 (0.0)	4 (5.0)	0 (0.0)	4	0.8
Missing	3 (0.8)	2 (2.5)	1 (1.4)	6	1.2
Parity
Nulliparous	128 (35.0)	34 (42.5)	34 (49.3)	196	38.1
Parity > 1	234 (63.9)	44 (55.0)	34 (49.3)	312	60.6
Missing	4 (1.1)	2 (2.5)	1 (1.4)	7	1.4
Insurance status
Private insurance	313 (85.5)	68 (85.0)	64 (92.8)	445	86.4
Public insurance/uninsured	53 (14.5)	12 (15.0)	5 (7.2)	70	13.6
Fertility concerns
Desired future fertility at diagnosis	61 (16.7)	27 (33.8)	24 (34.8)	112	21.7
Did not express fertility concerns at diagnosis	305 (83.3)	53 (66.3)	45 (65.2)	403	78.3
Anxiety/depression
Anxiety/depression	83 (22.7)	24 (30.0)	10 (14.5)	117	22.7
No anxiety/depression	282 (77.0)	56 (70.0)	59 (85.5)	397	77.1
Missing	1 (0.3)	0 (0.0)	0 (0.0)	1	0.2
Obesity		-
Body mass index < 30kg/m2	298 (81.4)	65 (81.3)	60 (87.0)	423	82.1
Body mass index > 30kg/m2	68 (18.6)	13 (16.3)	9 (13.0)	90	17.5
Missing	0 (0.0)	1 (1.3)	0 (0.0)	1	0.2
Surgery		-
Mastectomy	198 (54.1)	45 (56.3)	29 (42.0)	272	52.8
Lumpectomy	165 (45.1)	35 (43.8)	40 (66.7)	240	46.6
Axillary dissection only	1 (0.3)	0 (0.0)	0 (0.0)	1	0.2
No surgery	2 (0.5)	0 (0.0)	0 (0.0)	2	0.4
Chemotherapy (stage I-III)
No	83 (25.8)	24 (52.5)	14 (50.0)	121	29.0
Yes	239 (74.2)	42 (30.0)	14 (50.0)	295	71.0
Radiation
Declined radiation therapy	18 (4.9)	3 (3.8)	15 (25.0)	36	7.0
Yes	269 (73.5)	49 (61.3)	37 (61.7)	355	68.9
Radiation therapy not indicated*	79 (21.6)	28 (35.0)	17 (28.3)	124	24.1
Stage
0	44 (12.0)	14 (17.5)	41 (59.4)	99	19.2
I	116 (31.7)	27 (33.8)	13 (18.8)	156	30.3
II	140 (38.3)	33 (41.3)	10 (14.5)	183	35.5
III	66 (18.0)	6 (7.5)	5 (7.2)	77	15.0

* Patients who underwent mastectomy: tumor < 5cm, < 4 positive axillary lymph nodes, and no skin or chest wall involvement.

Duration of tamoxifen use was documented including patients who declined to initiate and delayed initiation by more than four months (noninitiation), or discontinued for more than four months prior to five years (nonpersistence). Reasons for noninitiation and nonpersistence were documented in the EMR after the patient’s treatment decision and were not included in analyses evaluating predictors of noninitiation and early discontinuation.

Defined Reasons for Noninitiation or Early Discontinuation

Documented primary patient reasons for noninitiation or early discontinuation, identified after a patient’s diagnosis, included: concerns about side effects, side effects (early discontinuation patients), and pursuit of fertility. Study terms were defined: patients who had concerns about side effects were wary of potential effects but did not experience these effects. Those with side effects experienced an effect. Pursuit of fertility encompassed attempted conception, pregnancy, and concerns that tamoxifen use would result in infertility. Patient declined indicated a patient-driven refusal to initiate or early discontinuation documented without additional information.

Telephone Interviews

With IRB approval and patient consent, patients who did not initiate or discontinued tamoxifen were contacted by phone for a semistructured interview to further evaluate reasons for tamoxifen noninitiation and nonpersistence. Patients were asked if tamoxifen had been offered as part of their treatment plan, duration of tamoxifen use, if any, and reasons for noninitiation or nonpersistence. Fifty-six percent (39 of 69) of noninitiators and 61% (49 of 80) of early discontinuers agreed to participate.

Statistical Analyses

For factors associated with noninitiation, univariate analyses were performed using the chi-square test, with multivariable analysis performed using logistic regression. All 14 factors in Table 1 were considered in univariate analyses. Among patients initiating tamoxifen, time to early discontinuation was computed from date of tamoxifen initiation and was censored in adherent patients at time of death, menopause, metastasis, cancer recurrence, or last known date taking tamoxifen. Patients without a documented interest in future fertility were scored as not having fertility concerns. Univariate and multivariable analyses of time to early discontinuation were performed using log-rank test and Cox proportional hazards model, respectively. The proportional hazards assumption was tested based on the Schoenfeld residuals. No deviation from proportionality was found (P = .468). Factors significant by univariate analysis at P values of .05 were included in multivariable analysis to determine factors that retained an association with study endpoints after accounting for effects of remaining factors. A Kaplan-Meier curve was generated to illustrate the proportion of patients on tamoxifen as a function of time after initiation of therapy. Analyses were conducted using Stata (StataCorp. 2013; Stata Statistical Software: Release 13). All statistical tests were two-sided.

Results

Study Population

Of 515 premenopausal patients diagnosed from 2007 to 2012, 366 (71.1%) persisted with treatment, 69 (13.4%) declined initiation, and 80 (15.5%) discontinued tamoxifen prior to five years (Table 1). Of those patients who initiated, Figure 1 shows the fraction of patients who remained on tamoxifen as a function of time. At diagnosis, 112 patients in the study (22%) expressed a desire for future fertility.

Figure 1.

Proportion of patients continuing tamoxifen by year among premenopausal patients younger than age 45 years diagnosed with stage 0-III estrogen receptor– and/or progesterone receptor–positive breast cancer that initiated tamoxifen without delay (n = 446).

Clinical Factors Associated With Noninitiation

The 14 factors in Table 1 were considered in univariate analyses for potential association with noninitiation (Table 2). Significant univariate factors retaining significance in multivariable analysis included a diagnosis of ductal carcinoma in situ (DCIS) (P < .001), declining radiation therapy (P < .001), not receiving chemotherapy (for patients with invasive disease) (P = .012), and expressing a desire for future fertility at diagnosis (P = .009; odds ratio [OR] = 5.04, 95% confidence interval [CI] = 2.29 to 11.07) (Tables 2 and 3). Being a current smoker (P = .041), being nulliparous (P = .038), or having a lumpectomy (P = .049) were also associated with noninitiation in univariate but not multivariable analysis (Table 2).

Table 2.

Univariate analysis of factors examined for noninitiation or delayed initiation of tamoxifen among patients age < 45 y diagnosed with stage 0-III estrogen and/or progesterone receptor–positive breast cancer*

Characteristic	% of patients who delayed initiation or did not initiate tamoxifen	Chi-square P
Age at diagnosis, y		.996
<37	13.4
>37	13.4
Race/ethnicity		.272
White	21.0
Black	14.3
Hispanic	4.0
Asian	20.8
Other	12.7
Marital status		.868
Unmarried	13.2
Married, partnered,  domestic partner	13.7
Smoking status		.041
Current or former smoker	21.0
Never smoker	14.5
Alcohol use		.835
None	14.3
<5 drinks per wk	13.5
>5 drinks per wk	13.4
Parity		.038
Nulliparous	17.3
Parity > 1	10.9
Insurance status		.098
Private insurance	7.1
Public insurance/uninsured	14.4
Fertility concerns		.009
Desired future fertility at  diagnosis	21.4
Did not express fertility  concerns at diagnosis	11.2
Anxiety/depression		.078
Anxiety/depression	8.6
No anxiety/depression	14.9
Obesity		.294
Body mass index < 30kg/m2	14.1
Body mass index > 30kg/m2	10.0
Surgery		.049
Mastectomy	10.7
Lumpectomy	16.6
Chemotherapy (stage I-III)		.012
No	11.6
Yes	4.8
Radiation		<.001
Declined radiation therapy	41.7
Yes	10.4
Radiation therapy not  indicated†	13.7
Stage		<.001
0	14.4
I	8.3
II	5.5
III	6.5

* Noninitiators/delayed initiators: n = 69; initiators: n = 446. Univariate analysis was performed via the two-sided Chi-square test.

† Patients who underwent mastectomy: tumor < 5cm, < 4 positive axillary lymph nodes, and no skin or chest wall involvement.

Table 3.

Multivariable logistic regression of delayed or noninitiation of tamoxifen*

Patient characteristic	OR (95% CI)
Stage 0 cancer	28.07 (10.99 to 71.64)
Declined radiation therapy	7.97 (3.15 to 20.15)
Desired future fertility at diagnosis	5.04 (2.29 to 11.07)
No chemotherapy (stage I-III)	5.02 (1.92 to 13.10)

* Multivariable logistic regression model of tamoxifen noninitiation and delayed initiation among premenopausal patients younger than age 45 years diagnosed with stage 0-III estrogen and/or progesterone positive–breast cancer (n = 515). CI = confidence interval; OR = odds ratio.

Patient Reasons for Noninitiation

Of 69 patients who did not initiate treatment, 24 (34%) stated that they did so because they planned to become pregnant (Table 4). Concerns about potential side effects impacted 25 (36%) patients. The most common concerns about potential side effects were development of uterine cancer (6, 24%), thromboembolism (5, 20%), and hot flashes (3, 12%). Nine patients (13%) perceived little benefit.

Table 4.

Patient reasons for tamoxifen noninitiation, delayed initiation, and early discontinuation among premenopausal patients younger than age 45 y diagnosed with stage 0-III estrogen and/or progesterone receptor–positive breast cancer

Reason	No. (%)
Patient reasons for noninitiation or delayed initiation of tamoxifen (n = 69)
Concerns about side effects	25 (36.2)
Pursuit of fertility	24 (34.8)
Perceived little benefit	9 (13.0)
Patient declined	9 (13.0)
Desired alternative medicine and diet change	1 (1.5)
Length of therapy	1 (1.5)
Patient reasons for early discontinuation of tamoxifen (n = 80)
Side effects	51 (63.7)
Pursuit of fertility	20 (25.0)
Concerns about side effects	4 (5.0)
Patient declined	3 (3.7)
Lack of refills	1 (1.3)
Perceived little benefit	1 (1.3)

Clinical Factors Associated With Early Discontinuation

The 14 factors in Table 1 were also considered in univariate analyses for potential association with discontinuation (Table 5). Being unmarried was a predictor by univariate analysis (P = .037). Significant predictors by univariate and multivariable analysis included expressing a desire for future fertility (P = .001, hazard ratio [HR] = 1.78, 95% CI = 1.09 to 3.38) and being a current or former smoker (P = .012). Patients who underwent mastectomy, for whom adjuvant radiation was not specifically indicated (tumor < 5cm, < 4 positive axillary lymph nodes, no skin or chest wall involvement), withdrew from treatment at a higher rate than those for whom radiation was recommended (P = .007); this factor also retained significance in multivariable analysis (Table 6).

Table 5.

Univariate analysis of factors examined for early discontinuation of tamoxifen among patients younger than age 45 y diagnosed with stage 0-III estrogen and/or progesterone receptor–positive breast cancer that initiated tamoxifen without a delay (n = 446)*

Characteristic	Log-rank P
Age at diagnosis, y	.63
<37
>37
Race/ethnicity	.437
White
Black
Hispanic
Asian
Other
Marital status	.037
Unmarried
Married, partnered, domestic partner
Smoking status	.012
Current or former smoker
Never smoker
Alcohol use	.865
None
<5 drinks per wk
>5 drinks per wk
Parity	.277
Nulliparous
Parity > 1
Insurance status	.708
Private insurance
Public insurance/uninsured
Fertility concerns	.001
Desired future fertility at diagnosis
Did not express fertility concerns diagnosis
Anxiety/depression	.119
Anxiety/depression
No anxiety/depression
Obesity	.868
Body mass index < 30kg/m2
Body mass index > 30kg/m2
Surgery	.351
Mastectomy
Lumpectomy
Chemotherapy (stage I-III)	.185
No
Yes
Radiation	.007
Declined radiation therapy
Yes
Radiation therapy not indicated†
Stage	.167
0
I
II
III

* All statistical tests were two-sided.

† Patients who underwent mastectomy: tumor < 5cm, < 4 positive axillary lymph nodes, and no skin or chest wall involvement.

Table 6.

Multivariable model of early discontinuation of tamoxifen*

Patient characteristic	HR (95% CI)
Desired future fertility at diagnosis	1.78 (1.09 to 3.38)
Radiation therapy not indicated†	2.10 (1.30 to 3.38)
Current or former smoker	1.73 (1.09 to 2.75)

* Multivariable Cox model of tamoxifen early discontinuation among premenopausal patients younger than age 45 y diagnosed with stage 0-III estrogen and/or progesterone receptor–positive breast cancer (n = 515), nonsignificant factors not shown. CI = confidence interval; HR = hazard ratio.

† Patients who underwent mastectomy: tumor < 5cm, < 4 positive axillary lymph nodes, and no skin or chest wall involvement.

Patient Reasons for Early Discontinuation

Fertility concerns were second to side effects as the most common stated reason for discontinuation (Table 4). Of 80 patients who discontinued, 20 (25%) did so to attempt pregnancy or became pregnant on tamoxifen. Of 51 (63%) patients impacted by side effects, most frequently noted events were mood disturbances (17, 34%), hot flashes (17, 34%), irregular menses (9, 18%), and weight gain (6, 12%).

Interview Findings for Patients Who Did Not Initiate or Discontinued Tamoxifen

During interviews with 88 patients who did not initiate or discontinued tamoxifen, 31 (35.2%) stated that fertility concerns primarily influenced their decision, 47 (53.4%) were primarily concerned about side effects, and 10 (11.4%) perceived little benefit. While 31% of patients who attempted pregnancy reported initiating or resuming tamoxifen, 28% were unaware of the potential benefit of tamoxifen after a delay or hiatus. Nine percent felt inadequately informed about fertility preservation, and 3% faced financial constraints pursuing fertility preservation. Median time between noninitiation or discontinuation and corresponding patient interviews was 36.5 months. Responses generated regarding tamoxifen use during telephone interviews showed concordance (96%) with matched patient data obtained from the EMR. Baseline demographic data included in the study (Table 1) were analyzed for association with interview participation, and no statistical differences were found when comparing interview responders to nonresponders.

Discussion

This work supports the hypothesis that fertility concerns may influence treatment decisions regarding tamoxifen use for premenopausal breast cancer patients. We found that fertility concerns at diagnosis negatively impacted tamoxifen initiation and continuation. While other predictors of noninitiation were distinct from those of discontinuation, both patient groups reported that issues with side effects impacted tamoxifen utilization.

In addition to fertility concerns, predictors of noninitiation included a diagnosis of DCIS and declining radiation therapy. Patients with invasive disease who did not receive chemotherapy also did not initiate tamoxifen. The finding that patients with DCIS initiated tamoxifen at a lower rate than those with invasive cancer is consistent with previous reports (25,26). In our cohort, 93% of patients with invasive disease initiated tamoxifen, compared with 58% of patients with DCIS. These findings support prior work showing that patients with an estimated lower risk for cancer recurrence were less likely to comply with tamoxifen (27,28). Additionally, we found that declining radiation therapy predicted noninitiation, and this has also been associated with poor tamoxifen utilization (12). Patients who decline adjuvant treatments may be motivated by a perceived low risk for recurrence or belief that adjuvant treatments carry an unfavorable risk-benefit ratio. To this end, we found that noninitiators declined because of reported concerns about potential side effects while others perceived little benefit. Patients at high risk for noninitiation, including those with early-stage disease and those who decline other adjuvant treatments, may benefit from education about personal recurrence risk and benefits of tamoxifen. Young patients who decline to initiate should also receive focused counseling about side effects. Importantly, 24% of patients cited concerns about tamoxifen and risk of endometrial cancer as a reason for noninitiation. Physician insight into patient concerns and the ability to respond with appropriate data-driven information is critical for patients to make informed decisions about treatment options (29,30). As premenopausal women treated with tamoxifen have not been found to be at increased risk for endometrial cancer, identification of this patient concern points toward another factor for which directed patient education could improve adjuvant utilization of tamoxifen in the premenopausal setting (31).

Multivariable analysis for predictors of early discontinuation included smoking history. Smoking has been associated with poor tamoxifen adherence in both the chemopreventive (NSABP P-1 Breast Cancer Prevention Trial) and adjuvant settings. Smokers are more likely to report medication side effects (23,32,33). Counseling regarding risk of thrombotic events among patients who smoke while taking tamoxifen may also negatively impact treatment implementation (34). Smokers should be counseled towards cessation to improve overall wellness and, potentially, tamoxifen adherence (23,32,33). Furthermore, although stage was not an independent predictor of early discontinuation, patients who underwent mastectomy and for whom postmastectomy radiation was not indicated discontinued tamoxifen at a higher rate than those patients for whom radiation was recommended. Young patients should be counseled regarding the important role of tamoxifen in a multidisciplinary treatment plan designed to maximize prevention and disease-free survival. In addition to multivariable predictors of discontinuation, more than half the patients who discontinued reported stopping because of side effects, including mood disturbances and hot flashes. Thus, tamoxifen use among discontinuers could be optimized through interventions to minimize side effects. Low-dose venlafaxine reduced hot flashes in patients on tamoxifen and may also reduce depression associated with tamoxifen use (35–37).

In addition to addressing smoking and side effects, our data suggest that tamoxifen use may be improved by prioritizing fertility preservation as part of the multidisciplinary care plan. A desire for future fertility was a significant factor in our multivariable models and was the only predictor of both noninitiation and early cessation. Among patients who delayed or declined initiation, 34% cited pursuit of fertility as the reason for noninitiation. Furthermore, 25% of patients who discontinued stated they prioritized fertility. These findings provide an avenue for intervention that may improve tamoxifen adherence and, thus, potentially survival in this patient subgroup. Several options are available for young patients who wish to preserve reproductive potential before undergoing fertility-threatening treatments (38). Embryo cryopreservation is the most established method, and oocyte cryopreservation is also a viable option (39,40). Ovarian tissue cryopreservation remains an experimental procedure, and technologies to expand this technique are evolving (39,40). Gonadotropin releasing hormone analogs (GNRHa) are also being investigated to help preserve ovarian function during exposure to chemotherapy. Recent results from the Prevention of Early Menopause Study intergroup trial appear promising (41). In this trial for hormone receptor–negative premenopausal breast cancer patients, when compared with patients treated with chemotherapy alone, those treated with goserelin and chemotherapy showed protection from ovarian failure and an increased rate of pregnancy (42–46). Although these results were encouraging, prior studies with GNRHa failed to show benefit; accordingly American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) guidelines currently state this treatment to be “unproven or inconclusive,” until additional data is obtained (47,48).

For patients who plan to become pregnant before completing tamoxifen therapy, sequencing pregnancy and tamoxifen treatment may be considered (Figure 2) (38,49). Evidence from the TAM-02 trial and Wisconsin Tamoxifen Study suggests that tamoxifen can be delayed with retained treatment benefits. In TAM-02, patients who delayed initiation by two years and then completed a five-year course showed 35% reduction in recurrence risk relative to control patients. The Wisconsin Tamoxifen Study showed benefit for patients who delayed tamoxifen up to eight years when compared with control patients (50–52). Additionally, several retrospective studies of breast cancer survivors have not found an association between pregnancy and increased risk for disease recurrence or poorer survival (53–62); yet the retrospective nature of these studies remains a limiting factor (63). Regarding safety of infertility treatments, in vitro studies examining impact of ovarian hyperstimulation drugs on normal and malignant mammary cell growth found no increase in proliferation or malignant transformation, outside of direct effects of escalating estrogen exposures (64,65). Furthermore, a meta-analysis of eight cohort studies comprising more than 1.5 million women found no increased risk of breast cancer among patients who underwent ovarian hyperstimulation for in vitro fertilization (66). Together, these data support the possibility of a delay or break in tamoxifen therapy to allow for pregnancy, with the goal of completing the recommended treatment course. As stated, this approach is being examined prospectively and is the focus of the POSITIVE trial, currently accruing premenopausal, hormone receptor–postive patients to investigate safety of a hiatus from endocrine therapy to allow for pregnancy (24). Until data from this trial have matured, appropriateness of a delay or break in tamoxifen treatment should be evaluated on a patient-specific basis with consideration given to physician recommendations and patient survivorship goals.

Figure 2.

Sequencing fertility preservation and tamoxifen therapy. A discussion about fertility as it pertains to cancer treatment is an integral part of breast cancer care. Patients receiving tamoxifen may attempt pregnancy naturally or via assisted reproductive technologies prior to initiating five to 10 years of therapy, during an interruption in a five- to 10-year course of therapy, or after the completion of five to 10 years of treatment (38,49). This figure was adapted from Figure 5.2 Llarena NC, Jeruss JS. Oncofertility communication and high-risk patients. In: Woodruff TK, Clayman ML, editor. Oncofertility communication. New York: Springer; 2013: 61–72. Reprinted with permission. ART = assisted reproductive technologies.

Despite the importance of fertility to young breast cancer patients, availability of fertility preservation options, and relative safety of pregnancy among breast cancer survivors, fertility preservation is often underutilized and underdiscussed in clinical settings (67–69). While the response rate for patient phone interviews was modest, of those patients who did respond, 35% discussed fertility as a factor in their decision about tamoxifen, 9% stated they felt inadequately informed about fertility preservation, and while 31% who attempted pregnancy reported resuming or initiating tamoxifen, 28% stated they were unaware of the potential benefit from using tamoxifen after a delay or hiatus. As stated, the response rates of 56% for noninitiators and 60% for discontinuers limited conclusions from this patient generated data and were not incorporated into statistical analysis of the dataset. Themes generated from patient phone calls helped to highlight importance of provider and patient education regarding fertility preservation options and potential for improved counseling regarding implementation of tamoxifen before and after pregnancy. To this end, critical components of an oncofertility program include urgent access to fertility care, a multilingual patient website (http://myoncofertility.org), fertility preservation hotline, and a prompt in the EMR confirming fertility preservation was discussed with new patients (70,71). As studies continue to show the beneficial impact of fertility preservation programs on treatment implementation and survivorship, it is expected that oncofertility guidelines delineated by ASCO, NCCN, and American Society for Reproductive Medicine will be more widely applied (72–74).

This study provides insight into factors associated with tamoxifen noninitiation and early discontinuation among reproductive-aged breast cancer survivors, with a new focus on fertility concerns. Young survivors are a unique patient population contending with survivorship issues that are distinct from the more routinely studied postmenopausal population. Given the largely retrospective nature of this study, future work will be directed toward validation of the multivariable models of noninitiation and discontinuation, in an effort to design targeted clinical tools to maximize outcomes for this cohort of young survivors.

Funding

This work was supported by the Center for Reproductive Health After Disease (P50HD076188) from the National Institutes of Health National Center for Translational Research in Reproduction and Infertility (JSJ) and by Northwestern University’s Medical Student Summer Research Program (NCL).

We acknowledge Drs Kevin Bethke, William Gradishar, Nora Hansen, Virgina Kaklamani, Seema Khan, and Jamie Von Roenn for their provision of patients for this study. We also thank Drs Teresa Woodruff, Marla Clayman, Gabriel Hortobagyi, Daniel Hayes, and Jennifer Griggs for their insightful discussions about this work, Justin Dreyfuss, John Cashy, Jessica Shepard, and Drs Omar Nuñez and Anna Kane for assistance with data management, and Dr Stacy Tobin for editorial assistance.

The authors declare no conflict of interest regarding this study, and the funding source had no role in the study design, the collection, analysis, or intrepretation of the data, writing of the manuscript, or decision to submit the manuscript for publication.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or author-affiliated institutions.