Abstract
Background
In premenopausal patients with human epidermal growth factor receptor 2 (HER2)–positive early breast cancer, the gonadotoxicity of trastuzumab and lapatinib remains largely uncertain, and the prognostic effect of treatment-related amenorrhea (TRA) is unknown.
Methods
In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (BIG 2-06) phase III trial, HER2-positive early breast cancer patients were randomized (1:1:1:1) to receive one year of trastuzumab, lapatinib, their sequence, or their combination. As per study protocol, menopausal status was collected in all patients at random assignment and at week 37 visit. We investigated TRA rates and whether TRA in patients with hormone receptor–positive and –negative tumors would impact disease-free survival (DFS) and overall survival (OS). Landmark and time-dependent modeling were used to account for guarantee-time bias. All statistical tests were two-sided.
Results
A total of 2862 premenopausal women were included, of whom 1679 (58.7%) had hormone receptor–positive disease. Median age was 43 (interquartile range = 38–47) years. Similar TRA rates were observed in the trastuzumab (72.6%), lapatinib (74.0%), trastuzumab→lapatinib (72.1%), and trastuzumab+lapatinib (74.8%) arms (P = .64). The association between TRA and survival outcomes differed according to hormone-receptor status (Pinteraction for DFS = .007; Pinteraction for OS = .003). For hormone receptor–positive patients, the TRA cohort had statistically significantly better DFS (adjusted hazard ratio [aHR] = 0.58, 95% confidence interval [CI] = 0.45 to 0.76) and OS (aHR = 0.63, 95% CI = 0.40 to 0.99) than the no TRA cohort. No difference was observed in hormone receptor–negative patients.
Conclusions
In this unplanned analysis, no association between TRA rate and type of anti-HER2 treatment was observed. TRA was associated with statistically significant survival benefits in premenopausal hormone receptor–positive/HER2-positive early breast cancer patients.
Breast cancer is the most common tumor type and the leading cause of cancer-related deaths in premenopausal women (1). As compared with older patients, young women have an increased risk of developing biologically aggressive forms of breast cancer, with 20% being human epidermal growth factor receptor 2 (HER2)–positive tumors (2). As per current guidelines, chemotherapy and one year of trastuzumab are standard of care for the majority of patients with HER2-positive early breast cancer (3,4).
In premenopausal women, the use of systemic anticancer therapies is associated with the added burden of gonadotoxicity, which can lead to the potential occurrence of treatment-related amenorrhea (TRA) (5,6). TRA appears to be associated with improved survival outcomes in breast cancer patients, specifically in women with hormone receptor–positive disease (7). Nevertheless, the loss of ovarian function can have negative short- and long-term quality of life implications and is associated with several side effects including infertility (8). Failure to address these concerns can influence patients’ choice of and adherence to the different anticancer treatment options (9–11).
The gonadotoxicity of anti-HER2-targeted agents remains largely uncertain, and no studies have investigated the prognostic impact of TRA in women with HER2-positive early breast cancer. The Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) trial is the largest study ever conducted in the adjuvant setting of HER2-positive disease (12). Updated results have confirmed the lack of statistically significant benefit in combining trastuzumab and lapatinib in this setting (13). The availability of menopausal status assessment at random assignment and during study follow-up for all patients included in the ALTTO trial represented a unique opportunity to conduct the present analysis aiming to describe TRA rates after chemotherapy combined with trastuzumab and/or lapatinib, and to evaluate the prognostic effect of its occurrence in premenopausal patients with HER2-positive early breast cancer.
Methods
Study Design and Patients
Details of the ALTTO study design have been previously reported (12). Briefly, ALTTO (Breast International Group [BIG] 2-06/EGF106708 and North Central Cancer Treatment Group [Alliance] N063D; ClinicalTrials.gov registration number: NCT00490139) was an international, intergroup, open-label, randomized phase III trial in patients with HER2-positive early breast cancer.
Eligible patients were women with histologically confirmed, completely excised, invasive nonmetastatic HER2-positive breast cancer, and either node-positive or node-negative disease with pathologic tumor size of 1 cm or larger. HER2 and hormone receptor status were centrally tested for all patients. HER2 positivity was defined based on the 2007 American Society of Clinical Oncology/College of American Pathologists guidelines (14). Hormone receptor–positive tumors were defined as 1% or more of tumor cells with expression of estrogen and/or progesterone receptors.
Study Procedures
Eligible patients were randomized with an interactive voice response system to one of the following anti-HER2 treatment arms, each of one-year duration: trastuzumab alone (trastuzumab arm), lapatinib alone (lapatinib arm), 12 weeks of trastuzumab followed, after a six-week washout period, by 34 weeks of lapatinib (trastuzumab→lapatinib arm), and trastuzumab plus lapatinib (trastuzumab+lapatinib arm). Random assignment lists were prepared with the use of stratified permuted blocks with a 1:1:1:1 allocation ratio. In 2011, the lapatinib arm was closed after the first interim analysis, and adjuvant commercial trastuzumab was offered; out of 2100 patients, 1087 (51.8%) received at least one dose of trastuzumab.
Three modalities of chemotherapy administration, as per physician’s choice, were allowed. Investigators could administer anti-HER2 treatment at the completion of all chemotherapy (design 1), at the completion of anthracycline-based chemotherapy and concomitantly with a taxane (paclitaxel or docetaxel; design 2), or together with an anthracycline-free regimen (six cycles of docetaxel and carboplatin [ie, TCH]; design 2B).
Women with hormone receptor–positive disease received adjuvant endocrine therapy, as per local guidelines, unless contraindicated. Radiation therapy was mandatory after breast-conserving surgery and was performed according to the guidelines of each participating institution after mastectomy. Both treatments were administered after completion of chemotherapy and concomitantly with anti-HER2 treatment.
Per the study protocol, menopausal status was systematically reported at random assignment and at the week 37 visit (interquartile range [IQR] = 36–37 weeks) following the initiation of anti-HER2 treatment. At the week 37 visit, the overall median time from chemotherapy completion (IQR) was 38 (25–44) weeks. Premenopausal status was defined as less than six months since the last menstrual period, no prior bilateral ovariectomy, and not on an estrogen replacement, or as biochemical evidence of premenopausal status according to local guidelines. For the purpose of the present analysis, only patients who were premenopausal at random assignment and disease-free at their week 37 visit were included. Premenopausal patients who began treatment with gonadotropin-releasing hormone agonists (GnRHa) or underwent hysterectomy and/or bilateral oophorectomy before their week 37 visit were excluded from the present analysis. If any of these interventions was performed after the week 37 visit, patients were included in the present analysis. Premenopausal patients at random assignment who did not meet the criteria for premenopausal status at the week 37 visit were considered to have developed TRA.
The ALTTO trial was approved by ethics committees/independent review boards of all participating institutions. Written informed consent was obtained from all patients before study entry. The present analysis was approved by the ALTTO Executive and Steering Committees.
Outcomes
The ALTTO primary end point was to compare disease-free survival (DFS) in each of the three lapatinib-containing arms separately with the trastuzumab alone arm (12). Overall survival (OS) was a secondary end point.
The aims of the current analysis were to describe TRA rates after chemotherapy combined with trastuzumab and/or lapatinib and to evaluate the prognostic effect (in terms of DFS and OS) of its occurrence in premenopausal women with hormone receptor–positive and –negative, HER2-positive early breast cancer.
Statistical Methods
Sample size calculations and statistical assumptions on the ALTTO primary objective were previously described (12). The present analysis focusing on risk and prognostic effect of TRA was not preplanned in the study protocol, and the power of the statistical analyses for these end points was not prespecified. The database cutoff date of December 14, 2016, was used for all time-to-event analyses.
TRA risk was analyzed by logistic regression analysis. Unadjusted odds ratios (ORs) with 95% confidence intervals (CIs) for risk factors for TRA were estimated in univariate models. A multivariable model was fitted to test those factors that were statistically significant in the univariate models; adjusted odds ratios and 95% confidence intervals were estimated in the final fitted multivariable model. Selection for multivariable model was achieved through backwards elimination.
DFS and OS were computed using the original definitions of the main ALTTO analysis (12). To reduce the impact of guarantee-time bias (15), DFS and OS probabilities were computed according to the conditional landmark analysis, with 40 weeks prospectively chosen as the landmark to account for variation in the week 37 visit and actual time since random assignment.
ALTTO stratification factors (timing of chemotherapy, central hormone receptor status, and lymph node status) were included in all survival models for effect of TRA on DFS and OS. Univariate models tested the effect of individual variables of interest on DFS and OS. Multivariable models for the survival end points were fitted with TRA and adjusted for variables that were statistically significant in the univariate analyses, treatment, and the ALTTO stratification factors; the final model was achieved by stepwise selection. Likelihood ratio test considered whether there was evidence of an interaction between treatment and TRA, and hormone receptor status and TRA. Data were presented using Kaplan-Meier survival plots. Given the size of the week 37 visit window, a time-dependent Cox regression model was also fitted, using the intention-to-treat (ITT) population as a supplemental analysis to confirm the conclusions from the landmark analysis (15).
All statistical tests were two-sided, and P values of less than .05 were considered statistically significant.
Results
Characteristics of the Included Patients
Between June 2007 and July 2011, 8381 patients were randomly assigned in the ALTTO trial. A total of 2862 women were eligible for the present analysis, 2099 (73.3%) in the TRA cohort and 763 (26.7%) in the no TRA cohort (Figure 1). The overall median age was 43 (IQR = 38–47) years.
Figure 1.
CONSORT flow diagram. *Patients who underwent hysterectomy and/or bilateral oophorectomy before their week 37 visit. ALTTO = Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization; DFS = disease-free survival; GnRHa = gonadotropin releasing hormone agonist; ITT = intention-to-treat; OS = overall survival; TRA = treatment-related amenorrhea.
Baseline patient and tumor characteristics were similar between the two cohorts except for older age at diagnosis (P < .001), node-positive (P = .008) and hormone receptor–positive (P < .001) tumors in the TRA cohort (Table 1). Overall, 1679 (58.7%) patients had hormone receptor–positive disease.
Table 1.
Patient and tumor baseline characteristics
| Characteristics | TRA cohort (n = 2099) | No TRA cohort (n = 763) | P* |
|---|---|---|---|
| Age median (IQR), y | 45 (41–48) | 38 (34–42) | <.001 |
| Age, No. (%) | |||
| ≤30 y | 44 (2.1) | 86 (11.3) | <.001 |
| 31–40 y | 504 (24.0) | 443 (58.1) | |
| 41–45 y | 687 (32.7) | 167 (21.9) | |
| ≥46 y | 864 (41.2) | 67 (8.8) | |
| BMI, No. (%) | |||
| Underweight (<18.5 kg/m2) | 52 (2.5) | 17 (2.2) | .21 |
| Normal (18.5–24.9 kg/m2) | 1095 (52.2) | 432 (56.6) | |
| Overweight (25.0–29.9 kg/m2) | 618 (29.4) | 211 (27.7) | |
| Obese (≥30 kg/m2) | 329 (15.7) | 103 (13.5) | |
| Missing | 5 (0.2) | 0 (0.0) | |
| Histology, No. (%) | |||
| Ductal carcinoma | 1955 (93.1) | 715 (93.7) | .85 |
| Lobular carcinoma | 35 (1.7) | 11 (1.4) | |
| Other/missing | 109 (5.2) | 37 (4.9) | |
| Tumor size, No. (%) | |||
| pT1 | 809 (38.5) | 336 (44.0) | .11 |
| pT2 | 959 (45.7 | 313 (41.0) | |
| pT3–pT4 | 149 (7.1) | 49 (6.4) | |
| Not applicable (NACT) | 176 (8.4) | 62 (8.1) | |
| Missing | 6 (0.3) | 3 (0.4) | |
| Nodal status, No. (%) | |||
| pN0 | 765 (36.5) | 331 (43.4) | .008 |
| pN1 | 666 (31.7) | 212 (27.8) | |
| pN2–pN3 | 492 (23.4) | 158 (20.7) | |
| Not applicable (NACT) | 176 (8.4) | 62 (8.1) | |
| Tumor grade, No. (%) | |||
| G1 | 57 (2.7) | 15 (2.0) | .74 |
| G2 | 814 (38.8) | 294 (38.5) | |
| G3 | 1158 (55.2) | 420 (55.1) | |
| GX (cannot be assessed) | 68 (3.2) | 26 (3.4) | |
| Missing | 2 (0.1) | 8 (1.1) | |
| Hormone receptor status, No. (%) | |||
| Positive | 1315 (62.7) | 364 (47.7) | <.001 |
| Negative | 784 (37.4) | 399 (52.3) | |
P values were calculated by excluding missing data; two-sided t test for continuous variables or chi-square test (k-1 degrees of freedom, where k is the number of levels) for categorical variables. BMI = body mass index; G = tumor grade; IQR = interquartile range; NACT = neoadjuvant chemotherapy; N = nodal status; T = tumor size; TRA = treatment-related amenorrhea.
There was an association between timing of chemotherapy and TRA cohort (P < .001) and between type of chemotherapy and TRA cohort (P < .001): more patients in the TRA cohort received concurrent non-TCH chemotherapy (design 2) and the addition of taxanes to an anthracycline-based regimen (either design 1 or design 2) (Table 2). Median durations of chemotherapy were 21.1 and 20.3 weeks in the TRA and no TRA cohorts, respectively (P = .006).
Table 2.
Treatment characteristics
| Characteristics | TRA cohort (n = 2099) | No TRA cohort (n = 763) | P* |
|---|---|---|---|
| Treatment arm, No. (%) | |||
| Trastuzumab | 513 (24.4) | 194 (25.4) | .64 |
| Lapatinib | 518 (24.7) | 182 (23.9) | |
| Trastuzumab→lapatinib | 538 (25.6) | 208 (27.3) | |
| Trastuzumab+lapatinib | 530 (25.3) | 179 (23.5) | |
| Timing of chemotherapy, No. (%) | |||
| Sequential (design 1) | 1011 (48.2) | 461 (60.4) | <.001 |
| Concurrent non-TCH (design 2) | 992 (47.3) | 271 (35.5) | |
| Concurrent TCH (design 2B) | 96 (4.6) | 31 (4.1) | |
| Time from end of chemotherapy to week 37 visit, median (IQR) | |||
| Sequential (design 1) | 43.3 (40.7–46.9) | 43.3 (40.7–46.4) | .78 |
| Concurrent non-TCH (design 2) | 25.0 (24.3–26.0) | 25.0 (24.6–26.6) | .21 |
| Concurrent TCH (design 2B) | 21.0 (20.1–21.2) | 20.7 (19.9–21.0) | .17 |
| Type of chemotherapy, No. (%) | |||
| Anthracycline-based | 399 (19.0) | 227 (29.8) | <.001 |
| Anthracycline- and taxane-based | 1604 (76.4) | 505 (66.2) | |
| Taxane-based (design 2B) | 96 (4.6) | 31 (4.1) | |
| Type of taxane†, No. (%) | |||
| Paclitaxel | 287 (53.5) | 967 (56.9) | .39 |
| Docetaxel | 242 (45.2) | 714 (42.0) | |
| Paclitaxel and docetaxel | 19 (1.1) | 7 (1.3) | |
| Duration of chemotherapy, median (IQR), weeks | 21.1 (15.7–24.3) | 20.3 (15.3–24.0) | .006 |
| Cumulative dose of anthracyclines, median (IQR), mg | 480 (400–600) | 500 (416–600) | .07 |
| Cumulative dose of cyclophosphamide, median (IQR), mg | 4000 (3400–4500) | 4000 (3445–4740) | .08 |
| Adjuvant endocrine therapy‡, No. (%) | |||
| Administered | 1233 (93.8) | 316 (86.8) | <.001 |
| Not administered | 82 (6.2) | 48 (13.2) | |
| Type of adjuvant endocrine therapy§, No. (%) | |||
| SERM | 859 (69.7) | 272 (86.1) | <.001 |
| SERM + GnRHa | 21 (1.7) | 16 (5.1) | |
| SERM and AI (± GnRHa), any sequence | 353 (28.6) | 28 (8.9) | |
Two-sided t test for continuous variables or chi-square test (k-1 degrees of freedom, where k is the number of levels) for categorical variables. AI = aromatase inhibitor; GnRHa = gonadotropin releasing hormone agonist; IQR = interquartile range; SERM = selective estrogen receptor modulator; TCH = docetaxel and carboplatin; TRA = treatment-related amenorrhea.
Percentages calculated on the total number of patients who received taxanes.
Percentages calculated on the total number of patients with hormone receptor–positive disease.
Percentages calculated on the total number of patients with hormone receptor–positive disease who received adjuvant endocrine therapy (patients who started GnRHa before their week 37 visit were excluded from the present analysis [n = 296] [Figure 1]; patients who started GnRHa after their week 37 visit were included in the present analysis [n = 55]).
Associations were also observed between the TRA cohort and administration of adjuvant endocrine therapy (P < .001) and between the TRA cohort and type of adjuvant endocrine therapy used (P < .001): more patients in the TRA cohort received adjuvant endocrine therapy, and aromatase inhibitors were more likely to be included (Table 2).
Risk of Developing TRA
The incidence of TRA in the four treatment arms according to patients’ baseline and treatment characteristics is reported in Table 3. TRA rates were 72.6%, 74.0%, 72.1%, and 74.8% in the trastuzumab, lapatinib, trastuzumab→lapatinib, and trastuzumab+lapatinib arms, respectively (P = .64). As compared with trastuzumab alone, no difference in TRA risk was observed with lapatinib (OR = 1.13, 95% CI = 0.90 to 1.43, P = .29), trastuzumab→lapatinib (OR = 0.99, 95% CI = 0.79 to 1.24, P = .91), and trastuzumab+lapatinib (OR = 1.19, 95% CI = 0.94 to 1.51, P = .14) (Supplementary Table 1, available online).
Table 3.
Treatment-related amenorrhea rates in the four anti-HER2 treatment arms according to patient and treatment characteristics
| Characteristics | Trastuzumab (n = 707) No. (%)* | Lapatinib (n = 700) No. (%)* | Trastuzumab→lapatinib (n = 746) No. (%)* | Trastuzumab+lapatinib (n = 709) No. (%)* | P† |
|---|---|---|---|---|---|
| Age, y | |||||
| ≤30 | 11 (29.7) | 12 (40.0) | 11 (36.7) | 10 (30.3) | .54 |
| 31–40 | 127 (57.2) | 127 (52.5) | 125 (49.8) | 125 (53.9) | |
| 41–45 | 172 (76.8) | 165 (84.6) | 176 (75.2) | 174 (82.5) | |
| ≥46 | 203 (90.6) | 214 (91.8) | 226 (93.8) | 221 (94.8) | |
| BMI, kg/m2 | |||||
| Underweight (<18.5) | 14 (100) | 10 (66.7) | 16 (66.7) | 12 (75.0) | .67 |
| Normal (18.5–24.9) | 292 (72.8) | 265 (72.2) | 277 (69.1) | 261 (72.9) | |
| Overweight (25.0–29.9) | 137 (69.5) | 158 (77.5) | 156 (75.0) | 167 (75.9) | |
| Obese (≥30) | 70 (73.7) | 83 (74.1) | 86 (78.2) | 12 (75.0) | |
| Type of chemotherapy | |||||
| Anthracycline-based | 89 (57.4) | 96 (66.2) | 102 (63.4) | 112 (67.9) | .61 |
| Anthracycline- and taxane-based | 399 (76.4) | 401 (75.8) | 408 (74.6) | 411 (77.5) | |
| Taxane-based (design 2B) | 25 (83.3) | 21 (80.8) | 28 (73.7) | 22 (66.7) | |
| Timing of chemotherapy | |||||
| Sequential (design 1) | 246 (67.4) | 250 (68.7) | 262 (68.8) | 253 (69.9) | .64 |
| Concurrent non-TCH (design 2) | 242 (77.6) | 247 (79.7) | 248 (75.8) | 255 (81.2) | |
| Concurrent TCH (design 2b) | 25 (83.3) | 21 (80.8) | 28 (73.7) | 22 (66.7) | |
| Type of taxanes | |||||
| No taxane | 89 (57.4) | 96 (66.2) | 102 (63.4) | 112 (67.9) | .61 |
| Docetaxel | 177 (77.0) | 184 (74.8) | 189 (74.1) | 164 (72.9) | |
| Paclitaxel | 241 (76.8) | 236 (76.9) | 243 (75.5) | 247 (79.4) | |
| Paclitaxel and docetaxel | 6 (75.0) | 2 (100) | 4 (50.0) | 7 (87.5) | |
| Hormone receptor status | |||||
| Positive | 318 (77.2) | 328 (80.4) | 352 (77.2) | 317 (78.7) | .52 |
| Negative | 195 (66.1) | 190 (65.1) | 186 (64.1) | 213 (69.6) | |
| Use of adjuvant endocrine therapy‡ | |||||
| Yes | 296 (78.5) | 309 (82.0) | 329 (78.7) | 299 (79.3) | .67 |
| No | 22 (62.9) | 19 (61.3) | 23 (60.5) | 18 (69.2) | |
Percentages calculated on the number of patients within each subgroup of the respective anti-HER2 treatment arm. BMI = body mass index; HER2 = human epidermal growth factor receptor 2; TCH = docetaxel and carboplatin.
Chi-square test (k-1 degrees of freedom, where k is the number of levels) for difference in treatment-induced amenorrhea between arms.
Including only patients with hormone receptor–positive disease.
In the multivariable analysis (Table 4), the only factors that remained statistically significantly associated with higher risk of TRA were older age at diagnosis (adjusted OR = 2.84, 95% CI = 1.93 to 4.17, P < .001), addition of taxanes to anthracycline-based chemotherapy (adjusted OR = 1.92, 95% CI = 1.44 to 2.56, P < .001), administration of TCH (design 2B) regimen (adjusted OR = 2.24, 95% CI = 1.18 to 4.27, P = .01), and use of adjuvant endocrine therapy (adjusted OR = 2.84, 95% CI = 1.85 to 4.35, P < .001).
Table 4.
Risk factors for the development of treatment-related amenorrhea (multivariable analysis)*
| Risk factor | OR (95% CI) | P† |
|---|---|---|
| Age, y | ||
| ≤30 | 0.11 (0.06 to 0.20) | <.001 |
| 31–40 | 0.27 (0.20 to 0.37) | <.001 |
| 41–45 | 1.00 (reference) | – |
| ≥46 | 2.84 (1.93 to 4.17) | <.001 |
| Type of chemotherapy | ||
| Anthracycline-based regimens | 1.00 (reference) | – |
| Anthracycline- and taxane-based regimens | 1.92 (1.44 to 2.56) | <.001 |
| Taxane-based regimens (design 2B) | 2.24 (1.18 to 4.27) | .01 |
| Use of adjuvant endocrine therapy | ||
| Yes | 2.84 (1.85 to 4.35) | <.001 |
| No | 1.00 (reference) | – |
C-value (area under the curve) of the final model from the logistic regression analysis = 0.78. CI = confidence interval; OR = odds ratio.
Chi-square test (k-1 degrees of freedom, where k is the number of levels).
Prognostic Effect of TRA
Median follow-up time was 6.9 (IQR = 6.6–7.0) years; out of 2844 patients in the landmark population, 481 (16.9%) and 199 (7.0%) patients experienced DFS and OS events, respectively (Figure 1). A statistically significant interaction was observed between TRA and hormone receptor status for both DFS (Pinteraction = .007) and OS (Pinteraction = .003).
In patients with hormone receptor–positive disease, six-year DFS was 86.6% (95% CI = 84.6% to 88.4%) in the TRA cohort and 78.0% (95% CI = 73.3% to 82.0%) in the no TRA cohort (adjusted HR = 0.58, 95% CI = 0.45 to 0.76) (Figure 2A). In patients with hormone receptor–negative disease, six-year DFS was 81.7% (95% CI = 78.9% to 84.3%) in the TRA cohort and 78.9% (95% CI = 74.4% to 82.6%) in the no TRA cohort (adjusted HR = 0.92, 95% CI = 0.70 to 1.20) (Figure 2B). A statistically significantly better DFS was observed in patients who received anthracycline- and taxane-based regimen and concurrent administration, whereas DFS was worse in patients treated in the lapatinib arm (Supplementary Tables 2 and 3, available online).
Figure 2.
Disease-free survival in patients with hormone receptor–positive (A) and hormone receptor–negative (B) disease. Conditional landmark analysis (40-week landmark), Kaplan-Meier curves are shown; time (in years) is from randomization and the numbers of patients at risk in each group at various time points are shown below the graphs. CI = confidence interval; DFS = disease-free survival; HR = hazard ratio; TRA = treatment-related amenorrhea.
In patients with hormone receptor–positive disease, six-year OS was 95.6% (95% CI = 94.3% to 96.6%) in the TRA cohort and 92.2% (95% CI = 88.8% to 94.5%) in the no TRA cohort (adjusted HR = 0.63, 95% CI = 0.40 to 0.99) (Figure 3A). In patients with hormone receptor–negative disease, six-year OS was 91.2% (95% CI = 88.9% to 93.1%) in the TRA cohort and 90.2% (95% CI = 86.8% to 92.8%) in the no TRA cohort (adjusted HR = 1.03, 95% CI = 0.68 to 1.56) (Figure 3B). A statistically significantly better OS was observed in patients who received a anthracycline- and taxane-based regimen, whereas OS was worse in patients treated in the lapatinib arm (Supplementary Tables 4 and 5, available online).
Figure 3.
Overall survival in patients with hormone receptor–positive (A) and hormone receptor–negative (B) disease. Conditional landmark analysis (40-week landmark), Kaplan-Meier curves are shown; time (in years) is from randomization and the numbers of patients at risk in each group at various time points are shown below the graphs. CI = confidence interval; HR = hazard ratio; OS = overall survival; TRA = treatment-related amenorrhea.
Similar results were observed by performing a sensitivity analysis excluding patients (n = 55) who started GnRHa after their week 37 visit (Supplementary Table 6, available online) or by repeating the analyses with the time-dependent Cox regression model in the ITT population (data not shown).
Discussion
This is the largest analysis that described TRA rates after chemotherapy combined with trastuzumab and/or lapatinib and the first to specifically address the prognostic effect of its occurrence in HER2-positive early breast cancer patients. No difference in TRA rates was observed between the four anti-HER2 treatment arms. TRA was associated with statistically significantly improved DFS and OS in patients with hormone receptor–positive disease.
During oncofertility counseling in premenopausal breast cancer patients, TRA risk with the proposed anticancer treatments should be discussed as early as possible after diagnosis (16,17). Hence, knowing the gonadotoxicity of anticancer agents to correctly estimate this risk is crucial. So far, only two retrospective studies including 39 and 64 patients have evaluated TRA rate with the use of chemotherapy combined with trastuzumab (18,19). Trastuzumab did not seem to increase TRA risk, but the numbers are very scarce to draw solid conclusions. No data exist for lapatinib or dual anti-HER2 blockade. In our analysis (n = 2862), no difference in TRA rates among the four anti-HER2 treatment arms was observed. Although the lack of gonadotoxicity for trastuzumab and/or lapatinib cannot be claimed from our analysis due to the unavailability of a treatment arm without anti-HER2 therapy, the absence of higher TRA rate in the dual blockade arm as compared with single-agent arms may suggest the gonadal safety of these agents. Chemotherapy and dual anti-HER2 blockade with trastuzumab plus pertuzumab has been recently approved for high-risk HER2-positive early breast cancer patients (20,21). Hence, studies addressing the gonadotoxicity of this combination should be considered a research priority.
The large sample size of our study allowed also the investigation of other factors impacting TRA risk. Older age, use of cyclophosphamide-containing chemotherapy, and administration of adjuvant endocrine therapy are the three main known risk factors for TRA in breast cancer patients (5,6). Our study confirmed the statistically significant impact of age with a 19% higher TRA risk per every year of increased age. More than twofold increased risk of TRA with the use of endocrine therapy was observed; nevertheless, it remains unclear whether endocrine therapy has an additional independent or possibly synergistic gonadotoxic mechanism beyond the effect of chemotherapy (22,23). Our findings add to the body of knowledge in this area, with more insights on the controversial gonadotoxic potential of taxanes. A recent meta-analysis of eight studies (n = 2124) investigating the addition of taxanes to anthracycline-based chemotherapy showed no statistically significantly increased likelihood of TRA (adjusted OR = 1.45, 95% CI = 0.94 to 2.23) (24). With a larger sample size (n = 2737), we observed a statistically significantly increased TRA risk for women receiving taxanes in addition to anthracycline-based chemotherapy, with no apparent difference between docetaxel and paclitaxel. Regarding non-anthracycline-based regimens in premenopausal patients with HER2-positive disease, a weekly regimen of paclitaxel and trastuzumab has a low TRA rate (28%) (19). Our study is the first to report on the gonadotoxicity of TCH chemotherapy. This regimen showed a 75.6% TRA rate and a higher risk as compared with anthracycline-based chemotherapy (adjusted OR = 2.24, 95% CI = 1.18 to 4.27). However, this result should be interpreted with caution. Besides the possible added gonadotoxicity of carboplatin, it should be noted that menopausal status in patients receiving TCH was evaluated earlier (approximately 21 weeks after the end of chemotherapy) than in women receiving anthracycline-based chemotherapy with or without taxanes (between 25 and 43 weeks). Therefore, TCH-treated patients had a shorter time for menstrual function recovery.
To date, the prognostic impact of TRA in HER2-positive early breast cancer patients is largely unknown. Acquiring this information is of great importance because of its subsequent potential therapeutic implications specifically in women with hormone receptor–positive disease. In the NSABP B-30 trial (n = 1885, yet no information on HER2 status), TRA was associated with improved DFS (HR = 0.51, P < .001) and OS (HR = 0.52, P = .002) only in patients with hormone receptor–positive disease (25). Our analysis (n = 2862) showed that TRA retains a strong prognostic significance also in women with hormone receptor–positive/HER2-positive disease. These findings may explain the subgroup analysis of the SOFT trial (n = 236) showing that adding ovarian function suppression to tamoxifen in patients with hormone receptor–positive breast cancer who did not develop TRA seemed to be of particular benefit in those with HER2-positive disease (HR for DFS = 0.42, 95% CI = 0.22 to 0.80, Pinteraction = .04) (26). Of note, in the NSABP B-30 trial, women with hormone receptor–positive disease received tamoxifen alone as adjuvant endocrine therapy (27); similarly, the majority of premenopausal patients included in the ALTTO trial received tamoxifen alone (67.4%), and only 3.3% received GnRHa as part of treatment. Hence, the potential endocrine effect of chemotherapy may have been underscored in these situations. The results of our analysis strongly support the notion that the choice of the best adjuvant endocrine treatment is crucial also in women with hormone receptor–positive/HER2-positive tumors despite the use of modern chemotherapy regimens and anti-HER2 targeted therapy. Although this is an extrapolation given the important prognostic role of TRA observed in our analysis, the addition of ovarian function suppression as part of adjuvant endocrine therapy may be considered in women with hormone receptor–positive/HER2-positive disease who remain premenopausal after anthracycline-containing or TCH-based chemotherapy.
Some limitations should be considered in the interpretation of our results. First, this is an unplanned analysis relying on an event measured after random assignment. However, definition of menstrual status was clearly detailed in the study protocol and prospectively collected during trial conduct. Second, it is possible that unidentified confounding factors with a potential impact on patients’ baseline ovarian reserve were non–randomly distributed between the two groups. Nevertheless, the large sample size of the current study can be partially reassuring that these factors could not be solely responsible for the results. Third, menopausal status was evaluated at only one fixed time point (ie, the week 37 visit) after a median time from chemotherapy completion of 9.5 months (38 weeks). Although resumption of menses can occur also at longer follow-up, in most of the patients, this happens within the first 12 months after chemotherapy, with lower chances of recovery afterwards (28,29). Hence, in the majority of the studies describing TRA rates, 12 months after chemotherapy was the most widely adopted time point chosen to assess menstrual function recovery. Nevertheless, this 3.5-month difference may explain the higher overall TRA rates observed in our study as compared with prior reports. For the same reason, the different median times from chemotherapy completion among patients who received sequential (design 1) and concurrent (design 2/2B) chemotherapy reduce the reliability of this specific comparison and our ability to interpret possible differences in gonadotoxicity between the TCH- and anthracycline-based regimens. However, these limitations should not influence the overall interpretation of our findings on TRA rates and their prognostic effect in this setting in light of the rigorous methodology applied.
In conclusion, this unplanned analysis of the ALTTO trial suggests that there was no association between TRA rates and type of anti-HER2 treatment in premenopausal patients with HER2-positive early breast cancer. TRA was associated with statistically significant DFS and OS benefits in premenopausal patients with hormone receptor–positive/HER2-positive disease. Our findings may help physicians in counseling premenopausal women with HER2-positive early breast cancer about expected TRA rates with the proposed anticancer treatments. This would facilitate optimal counseling on the pros and cons of the different treatment options, including the possible indication for ovarian function suppression as part of adjuvant endocrine therapy.
Funding
The ALTTO trial received financial support from GlaxoSmithKline (until January 2015), Novartis Pharma AG (as of January 2015), and the National Cancer Institute of the National Institutes of Health (Grant No. U10CA180821 and U10CA180882 to the Alliance for Clinical Trials in Oncology and Grant No. CA025224 to the legacy North Central Cancer Treatment Group). The present analysis did not receive additional funding.
The funders and sponsors had no role in the design or conduct of the study; in the collection, analysis, or interpretation of the data; or in the preparation, review, or approval of the manuscript.
Matteo Lambertini acknowledges support from the European Society for Medical Oncology (ESMO) for a Translational Research Fellowship at Institut Jules Bordet in Brussels (Belgium).
Notes
Affiliations of the authors: Department of Medical Oncology, Institut Jules Bordet and Université Libre de Bruxelles, Brussels, Belgium (ML, MIg, MP, EdA); Frontier Science, Kingussie, UK (CC); Instituto Nacional de Câncer, Rio de Janeiro, Brazil (JB); Breast Cancer Therapeutics, National Cancer Institute, Bethesda, MD (LAK); Novartis Pharma AG, Basel, Switzerland (MIz); Breast International Group, Brussels, Belgium (DF); Department of Medical Oncology, U.O. Sviluppo Terapie Innovative, Policlinico San Martino-IRCCS per l’Oncologia, Department of Internal Medicine and Medical Specialties (DIMI), School of Medicine, University of Genova, Genova, Italy (LDM); Sunnybrook Odette Cancer Centre, the University of Toronto and the NCIC Clinical Trials Group, Toronto, Ontario, Canada (KP); Johns Hopkins School of Medicine, Baltimore, MD (ACW); Department of Gynecology and Obstetrics, Sana Klinikum Offenbach, Offenbach, Germany (CJ); National Institute of Oncology, Budapest, Hungary (IL); Helios Klinikum Berlin Buch, Multidisciplinary Breast Cancer Center, Berlin, Germany (MU); Breast Unit, Royal Marsden Hospital and The Institute of Cancer Research, London, UK (IS); Patricia Ritchie Centre for Cancer Care and Research, The University of Sydney, Mater Hospital, North Sydney, Australia (FB); Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China (BX); Department of Medicine, PUCRS, School of Medicine, Porto Alegre, Brazil (CHB); Memorial Sloan Kettering Cancer Center, New York, NY (JB); Mayo Clinic, Jacksonville, FL (AMA); Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Harvard TH Chan School of Public Health and Frontier Science and Technology Research Foundation, Boston, MA (RDG).
We acknowledge the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization staff of the BrEAST Data Centre at Institut Jules Bordet in Brussels (Belgium) for clinical record online management and Sebastien Guillaume of the BrEAST Data Centre at Institut Jules Bordet in Brussels (Belgium) for administrative support.
None of the individuals named in the acknowledgments received any compensation for their contributions.
Matteo Lambertini served as a consultant for Teva and received a travel grant from Astellas outside the submitted work. Miguel Izquierdo reports employment at Novartis Pharma AG. Lucia Del Mastro received personal fees from Novartis Pharma AG, Roche-Genentech, Ipsen, Astrazeneca, Takeda, and Eli Lilly outside the submitted work. Michail Ignatiadis served as a consultant for Roche-Genentech and received a research grant from Roche-Genentech (to the insitution) outside the submitted work. Martine Piccart received honoraria from Novartis Pharma AG and Roche-Genentech and a research grant from Novartis Pharma AG and Roche-Genentech (to the insitution). Richard D. Gelber received a research grant from Novartis Pharma AG and Roche-Genentech (to institution). Evandro de Azambuja received honoraria from Roche-Genentech, a research grant from Roche–Genentech (to the insitution), and travel grants from Roche-Genentech and GlaxoSmithKline outside the submitted work. Jose Baselga reports non-financial support from Roche/Genentech, during the conduct of the study; personal fees and other from Aura Biosciences, personal fees and other from Northern Biologics (f/k/a Mosaic Biomedicals), personal fees and other from Infinity Pharmaceuticals, other from ApoGen Biotechnologies, personal fees and other from PMV Pharma, personal fees and other from Juno Therapeutics, personal fees and other from TANGO (f/k/a Synthetic Lethal), personal fees and other from Grail, personal fees and other from Varian Medical Systems, other from Foghorn Therapeutics, personal fees and non-financial support from Novartis, personal fees and non-financial support from Eli Lilly, personal fees and other from Bristol Myers Squibb, personal fees and other from Venthera, personal fees and other from Seragon, outside the submitted work. All remaining authors have declared no conflicts of interest.
Supplementary Material
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