NCIC CTG MA.17: Intent to treat analysis (ITT) of randomized patients after a median follow-up of 54 months

Abstract #1134 Background: The selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene reduce the risk of ER+ (but not ER-) invasive breast cancers in healthy women at high risk for developing breast cancer. Aromatase inhibitors (AIs) given as adjuvant therapy to treatment-naïve or post-tamoxifen patients significantly reduce the risk of in-breast recurrences (IBRs) and contralateral breast cancers (CBCs) and are currently in clinical trials for breast cancer prevention (NCIC CTG MAP.3 and IBIS-II). It is hypothesized that SERMS inhibit promotion of ER+ breast cancer whereas AIs may reduce both ER+ and ER- breast cancer by inhibiting both tumor initiation and promotion. Little is known about the characteristics of IBRs and CBCs that arise on AI therapy. We present the ER/PR expression and clinicopathologic features of IBRs and CBCs that occurred on MA.17.
 Methods: We examined ER/PR status of IBRs and CBCs that arose on letrozole vs. placebo among women enrolled in MA.17, a placebo-controlled (PLAC) trial of letrozole (LET) following 5 years of tamoxifen in postmenopausal women with early stage breast cancer.
 Results: Seventy-one patients (pts) developed an IBR and 87 developed a CBC on trial. Consistent with results previously reported, fewer IBRs (LET 20 vs PLAC 51) and CBCs (LET 35 vs PLAC 52) were observed in the LET group. ER and PR status is currently available on 35 women with an IBR and 39 with a CBC. The majority of IBRs were ER+ in both the LET and PLAC groups (10/11 [91%] vs 18/24 [75%], respectively; p=NS) but numbers of both ER+ and – IBRs were less in LET group, suggesting that letrozole may decrease both ER+ and ER- IBRs. CBCs that arose on PLAC were more likely to be ER+ than on LET (16/22 [73%] vs 6/19 pts [32%], respectively; p=0.01), suggesting that letrozole predominantly prevents ER+ CBCs. Discordance in ER expression between primary breast cancer and IBRs among women randomized to LET vs. PLAC was observed in 1/11 [9%] and 6/24 [26%] women respectively (p=NS) and between primary breast cancer and CBCs in 12/18 pts [67%] vs. 6/21 [29%] women respectively (p=0.01). Other clinicopathologic characteristics such as grade, tumor size, PR, HER-2/neu, and nodal status of IBRs and CBCs will be presented at the meeting.
 Conclusion: Extended adjuvant endocrine therapy with letrozole results in fewer IBRs and CBCs compared with placebo as previously reported. Our data suggests that letrozole may decrease both ER+ and ER- IBRs. Letrozole appears to prevent ER+ CBCs but has little or no apparent effect on the development of ER- CBCs. These results need confirmation in the primary prevention trials of AIs.
 
 Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1134.

Intent-to-treat analysis of the placebo-controlled trial of letrozole for extended adjuvant therapy in early breast cancer: NCIC CTG MA.17

491 Background: CheckMate 274 demonstrated a significant improvement in disease-free survival (DFS) with nivolumab (NIVO) versus placebo (PBO) both in the intent-to-treat population (hazard ratio [HR], 0.70; 98.22% confidence interval [CI], 0.55–0.90; P < 0.001) and in patients (pts) with tumor programmed death ligand 1 (PD-L1) expression ≥ 1% assessed by the tumor proportion score (TPS) (HR, 0.55; 98.72% CI, 0.35–0.85; P < 0.001). An exploratory subgroup analysis showed a trend toward a DFS benefit with NIVO in pts with TPS < 1% (0.82; 95% CI, 0.63–1.06). To further characterize the relationship between PD-L1 expression and NIVO efficacy, we report an analysis of DFS based on PD-L1 expression in both tumor and immune cells using the combined positive score (CPS). Methods: CheckMate 274 is a phase 3, randomized, double-blind, multicenter trial of NIVO versus PBO in pts with high-risk muscle-invasive urothelial carcinoma after radical surgery. Pts were randomized 1:1 to NIVO 240 mg or PBO every 2 weeks intravenously for 1 year of adjuvant treatment. The primary endpoints of the study are DFS in the intent-to-treat population and in pts with TPS ≥ 1%. The Dako PD-L1 IHC 28-8 pharmDx assay was used to evaluate TPS. CPS was determined retrospectively from previously stained immunohistochemistry slides using the CPS algorithm. CPS was calculated as the number of both PD-L1 positive tumor and immune cells divided by the number of viable tumor cells in the evaluable tumor area, multiplied by 100; TPS was similarly calculated with the number of PD-L1 positive tumor cells as the numerator. This analysis only included pts with both quantifiable CPS and TPS. Results: Of the 629 pts with quantifiable TPS and CPS, 249 (40%) had TPS ≥ 1% (NIVO, n = 124; PBO, n = 125), 380 (60%) had TPS < 1% (NIVO, n = 191; PBO, n = 189), 557 (89%) had CPS ≥ 1 (NIVO, n = 281; PBO, n = 276), and 72 (11%) had CPS < 1 (NIVO, n = 34; PBO, n = 38). Within TPS < 1% pts, 81% (n = 309) had CPS ≥ 1. The number of pts and the DFS outcomes in pts with TPS ≥ 1% and CPS ≥ 1 are shown in the Table. In pts with TPS < 1% who also had CPS ≥ 1, median DFS (95% CI) was 19.2 (15.6–33.4) months with NIVO versus 10.1 (8.2–19.4) months with PBO. The HR for NIVO versus PBO in these pts was 0.73 (95% CI, 0.54–0.99). Conclusions: This exploratory analysis of PD-L1 expression by CPS showed a higher proportion of pts with CPS ≥ 1 than TPS ≥ 1%, and that most pts with TPS < 1% had CPS ≥ 1. In the CPS ≥ 1 subgroup, median DFS with NIVO was more than double that with placebo. These results support the conclusion that pts with TPS < 1% also benefit from adjuvant NIVO. Clinical trial information: NCT02632409. [Table: see text]

550 Background: 5187 postmenopausal women were originally randomized to NCIC CTG MA.17 to receive letrozole (LET) or placebo (PLAC) after 5 years of tamoxifen. The hazard ratio (HR) for disease-free survival (DFS) was 0.58 (0.450.76, p=0.00004) after a median follow-up of 30 months (mo). The trial was unblinded in October 2003 after the first interim analysis. Women randomized to PLAC were offered LET at the time of unblinding. The goal of this analysis was to determine whether women switching from PLAC to LET benefit in terms of disease outcome and to evaluate treatment related toxicities. Methods: LET and PLAC-LET have been compared to PLAC, based on the hazard ratio and adjusting for baseline patient and disease variables including, among others, tumor size, nodal status and prior adjuvant chemotherapy. Results: Information about their follow-up treatment after unblinding was available on 2268 women originally assigned to PLAC and who were free of recurrence and alive at the time of unblinding. Among them, 1655 crossed over from PLAC to LET while 613 elected no treatment. With 54 mo f/up the HR for DFS was 0.31 (0.18, 0.55: p<0.0001) favoring patients who crossed over to LET compared to those who stayed on no treatment. The treatment switch was well tolerated with no significant difference in bone fractures or cardiovascular events. An updated analysis of DFS, DDFS and OS by nodal and tumor receptor status, prior chemotherapy, menopausal status at the start of tamoxifen, and duration of prior tamoxifen therapy will be presented at the meeting. Conclusion: Women with hormone dependent breast cancer prescribed LET after a prolonged delay from completing tamoxifen experienced a significant improvement in outcome (DFS, DDFS, OS) and should be considered for this therapy. [Table: see text]

658 Background: In the phase 3, randomized, double-blind CheckMate 274 trial, adjuvant NIVO demonstrated statistically significant and clinically meaningful disease-free survival (DFS) benefit vs PBO in pts with high-risk MIUC after radical surgery (RS) ± prior neoadjuvant cisplatin-based chemotherapy (NAC). With extended 3-y median follow-up, continued improvements in DFS were seen with NIVO vs PBO in the primary efficacy populations (intent-to-treat [ITT], tumor programmed death ligand 1 [PD-L1] expression ≥ 1%) and in pts with MIBC. Early trends in interim OS favored NIVO vs PBO in ITT and tumor PD-L1 ≥ 1% pts. Here we report additional efficacy outcomes for pts with MIBC. Methods: Pts were randomized 1:1 to NIVO 240 mg every 2 wk or PBO for ≤ 1 y of adjuvant treatment, stratified by tumor PD-L1 expression, nodal status, and prior NAC. Primary endpoints were DFS in ITT and tumor PD-L1 expression ≥ 1% pts. OS in ITT and PD-L1 ≥ 1% pts was a secondary endpoint. Analysis of MIBC pts was exploratory. MIBC OS data are from preplanned interim analyses of ITT and PD-L1 ≥ 1% pts. OS follow-up is ongoing as the prespecified statistical boundaries for significance in ITT and PD-L1 ≥ 1% pts were not crossed at the time of these analyses. Results: Of 709 randomized pts (ITT), 560 (79%) had MIBC (NIVO, n = 279; PBO, n = 281); 284 (51%) of MIBC pts had prior NAC. With median follow-up of 36.1 mo (ITT), DFS improvement with NIVO vs PBO was consistent between all pts with MIBC (hazard ratio [HR] 0.63) and those with (HR 0.58) and without prior NAC (HR 0.69; Table). For OS, HRs favored NIVO vs PBO in all pts with MIBC (HR 0.70) and the tumor PD-L1 ≥ 1% subgroup (HR 0.48), as well as in pts with MIBC with (HR 0.74) and without prior NAC (HR 0.67). Safety was consistent with previous data in ITT pts; no new safety signals were identified. Conclusions: With 3-y median follow-up, consistent benefit in DFS was observed with NIVO vs PBO in all MIBC pts and across prior NAC subgroups. The HR for OS favored NIVO in all MIBC pts, in those with PD-L1 ≥ 1%, and regardless of prior NAC status. These results continue to support adjuvant NIVO as a standard of care for high-risk MIUC and MIBC, potentially providing an opportunity for a curative outcome. Clinical trial information: NCT02632409 . NIVOn NIVOMedian(95% CI), mo PBOn PBOMedian(95% CI), mo HR (95% CI) DFS All MIBC 279 25.6 (19.2–41.8) 281 8.5 (7.3–13.7) 0.63 (0.51–0.78) With prior NAC 142 19.6 (15.6–48.2) 142 8.3 (5.6–11.2) 0.58 (0.43–0.79) No prior NAC 137 25.9 (19.2–51.5) 139 13.7 (7.8–22.1) 0.69 (0.50–0.94) OS All MIBC 279 NR (45.0–NE) 281 39.9 (29.8–52.1) 0.70 (0.55–0.90) PD-L1 ≥ 1% 113 NR (NE–NE) 117 37.6 (26.9–NE) 0.48 (0.29–0.77) With prior NAC 142 55.2 (41.8–NE) 142 40.2 (28.8–53.7) 0.74 (0.53–1.03) No prior NAC 137 NR (40.7–NE) 139 37.7 (28.7–65.2) 0.67 (0.47–0.95) NE, not estimable; NR, not reached.

Most recurrences in women with breast cancer receiving 5 years of adjuvant tamoxifen occur after 5 years. The MA.17 trial, which was designed to determine whether extended adjuvant therapy with the aromatase inhibitor letrozole after tamoxifen reduces the risk of such late recurrences, was stopped early after an interim analysis showed that letrozole improved disease-free survival. This report presents updated findings from the trial. Postmenopausal women completing 5 years of tamoxifen treatment were randomly assigned to a planned 5 years of letrozole (n = 2593) or placebo (n = 2594). The primary endpoint was disease-free survival (DFS); secondary endpoints included distant disease-free survival, overall survival, incidence of contralateral tumors, and toxic effects. Survival was examined using Kaplan-Meier analysis and log-rank tests. Planned subgroup analyses included those by axillary lymph node status. All statistical tests were two-sided. After a median follow-up of 30 months (range = 1.5-61.4 months), women in the letrozole arm had statistically significantly better DFS and distant DFS than women in the placebo arm (DFS: hazard ratio [HR] for recurrence or contralateral breast cancer = 0.58, 95% confidence interval [CI] = 0.45 to 0.76; P < .001; distant DFS: HR = 0.60, 95% CI = 0.43 to 0.84; P = .002). Overall survival was the same in both arms (HR for death from any cause = 0.82, 95% CI = 0.57 to 1.19; P = .3). However, among lymph node-positive patients, overall survival was statistically significantly improved with letrozole (HR = 0.61, 95% CI = 0.38 to 0.98; P = .04). The incidence of contralateral breast cancer was lower in women receiving letrozole, but the difference was not statistically significant. Women receiving letrozole experienced more hormonally related side effects than those receiving placebo, but the incidences of bone fractures and cardiovascular events were the same. Letrozole after tamoxifen is well-tolerated and improves both disease-free and distant disease-free survival but not overall survival, except in node-positive patients.

Prognostic and predictive effects of diabetes, hypertension, and coronary artery disease among women on extended adjuvant letrozole: NCIC CTG MA.17

1578 Background: Contralateral prophylactic mastectomy (CPM) has been shown to reduce the risk of contralateral breast cancer but there is conflicting evidence whether it improves disease-free or overall survival. The objective of the study was to evaluate the clinical benefits of CPM utilizing a large cohort of patients with detailed information available on tumor characteristics, and surgical and systemic treatments. Methods: We included 3,889 female patients with stages I-III breast cancer who were treated at The University of Texas MD Anderson Cancer Center from 1997 to 2009. Cox proportional hazard models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for the associations between CPM and disease-free and overall survival. Results: With a median follow-up time of 4.5 years, CPM was associated with improved disease-free survival (HR 0.75, 95% CI 0.59-0.97) adjusted for stage, nuclear grade, hormone receptor status and chemotherapy. The benefit was seen predominately among the hormone receptor-negative (HR 0.60, 95% CI 0.38-0.95) compared to the hormone receptor-positive patients (HR 0.80, 95% CI 0.58-1.10) but the interaction term was not statistically significant. CPM was also associated with improved overall survival (HR 0.74, 95% CI 0.55-0.99) adjusted for age, race, stage, comorbidities, nuclear grade, hormone receptor status and chemotherapy. Conclusions: CPM was associated with an improvement in breast cancer disease-free and overall survival after controlling for known prognostic factors. The improvement in disease-free survival among the CPM group was largely driven by lower breast cancer deaths and contralateral breast cancers. Further identification of subgroups of patients most likely to benefit from CPM could impact the decision making process for patients and their providers.

Patients with early-stage, hormone receptor-positive breast cancer have considerable residual risk for recurrence after completing 5 years of adjuvant tamoxifen. In May 2001, the National Surgical Adjuvant Breast and Bowel Project (NSABP) initiated accrual to a randomized, placebo-controlled, double-blind clinical trial to evaluate the steroidal aromatase inhibitor exemestane as extended adjuvant therapy in this setting. Postmenopausal patients with clinical T(1-3)N(1)M(0) breast cancer who were disease free after 5 years of tamoxifen were randomly assigned to 5 years of exemestane (25 mg/d orally) or 5 years of placebo. Our primary aim was to test whether exemestane prolongs disease-free survival (DFS). In October 2003, results of National Cancer Institute of Canada (NCIC) MA.17 showing benefit from adjuvant letrozole in this setting necessitated termination of accrual to B-33, unblinding, and offering of exemestane to patients in the placebo group. At the time of unblinding, 1,598 patients had been randomly assigned; 72% in the exemestane group continued on exemestane and 44% in the placebo group elected to receive exemestane. With 30 months of median follow-up, original exemestane assignment resulted in a borderline statistically significant improvement in 4-year DFS (91% v 89%; relative risk [RR] = 0.68; P = .07) and in a statistically significant improvement in 4-year relapse-free survival (RFS; 96% v 94%; RR = 0.44; P = .004). Toxicity, assessed up to time of unblinding, was acceptable for the adjuvant setting. Despite premature closure and crossover to exemestane by a substantial proportion of patients, original exemestane assignment resulted in non-statistically significant improvement in DFS and in statistically significant improvement in RFS.

Background: MONALEESA-2 (ML-2) recently reported a statistically significant overall survival (OS) benefit with first-line ribociclib (RIB) + letrozole (LET) over placebo (PBO) + LET in postmenopausal patients with HR+/HER2- advanced breast cancer (ABC) (median, 63.9 vs 51.4 months; hazard ratio, 0.76; 95% CI, 0.63-0.93; P = .004). Understanding OS outcomes in clinically relevant subgroups of patients is important for improving personalized care and prognosis. Here, we report the results of a prespecified exploratory OS analysis in select patient subgroups by baseline location and number of metastatic sites.. Methods: Postmenopausal patients with HR+/HER2− ABC were randomized 1:1 to receive first-line RIB or PBO with LET. Prespecified exploratory OS analyses were performed for subgroups of special interest by baseline location (bone only [yes or no], liver involvement [yes or no], liver or lung involvement [yes or no]) and number of metastatic sites (&amp;lt; 3 or ≥ 3). The data are hypothesis generating since this analysis was exploratory and not powered for statistical significance.. Results: A total of 668 patients were included in the analysis. A consistent improvement in OS was observed with RIB + LET vs PBO + LET in all subgroups regardless of baseline metastatic site (Table). RIB + LET demonstrated an OS benefit over PBO + LET in clinically relevant subgroups by baseline location and number of metastatic sites, including subgroups of patients with liver metastases, liver or lung metastases, and ≥ 3 metastatic sites, who generally have a worse prognosis.. Conclusion: Consistent with the intent-to-treat population of ML-2, the results of this prespecified exploratory analysis demonstrated an OS benefit with RIB + LET independent of the site and number of metastatic lesions. TableTreatment Arm (n)HR (95% CI)Bone-only metastasisYesRIB + LET (69)0.78 (0.50-1.21)PBO + LET (79)NoRIB + LET (265)0.77(0.61-0.96)PBO + LET (255)Liver involvementYesRIB + LET (59)0.81 (0.54-1.24)PBO + LET (72)NoRIB + LET (275)0.77 (0.62-0.97)PBO + LET (262)Liver or lung involvementYesRIB + LET (182)0.81(0.62-1.05)PBO + LET (190)NoRIB + LET (152)0.71 (0.53-0.96)PBO + LET (144)No. of metastatic sites&amp;lt; 3RIB + LET (220)0.78(0.61-1.00)PBO + LET (222)≥ 3RIB + LET (114)0.71(0.51-0.98)PBO + LET (112) Citation Format: Joyce O'Shaughnessy, Salomon M Stemmer, Howard A Burris, Yoon-Sim Yap, Gabe Sonke, Lowell Hart, Mario Campone, Katarina Petrakova, Eric P Winer, Wolfgang Janni, Pierfranco Conte, David A Cameron, Fabrice André, Carlos Arteaga, Juan Pablo Zarate, Arunava Chakravartty, Tetiana Taran, Fabienne Le Gac, Paolo Serra, Gabriel N Hortobagyi. Overall survival subgroup analysis by metastatic site from the phase 3 MONALEESA-2 study of first-line ribociclib + letrozole in postmenopausal patients with advanced HR+/HER2− breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS2-01.

847 Background: Over half of recurrences and two thirds of deaths from hormone dependent breast cancer occur after completion of 5 years of adjuvant tamoxifen. We previously reported an improvement in disease free survival in women receiving extended adjuvant treatment with L after tamoxifen. Toxicities reported up until February 2003, 8 months prior to unblinding of the study medication, were low grade and included vasomotor symptoms, arthritis, joint and muscle pain. Hypercholesterolemia and cardiovascular events were similar in both arms and while new patient-reported diagnoses of osteoporosis were slightly more common (5.8% vs 4.5% L vs P), clinical fracture rate was unchanged by L. Methods: The study database was locked as of August 2003 for analysis of events in disease free survival (DFS) which were local or distant recurrence or new contralateral breast cancer. A subset analysis of outcome according to nodal status was performed. A full and updated analysis of all study endpoints, including safety and quality of life, as of the date of unblinding the trial (October 9 2003) will be conducted in mid-January 2004. Results: 5187 patients were randomized. Demonstration of an improvement in DFS was achieved earlier than anticipated (P = 0.00008 at the first interim analysis) with a hazard rate of 0.57, indicating a 43% reduction in risk. L decreased the risk of events by 53% and 40% for node negative and node positive patients respectively. This translated into an absolute improvement in 3-year disease free survival of 3% and 7% in node negative and node positive patients, respectively. Conclusions: Letrozole is indicated as extended adjuvant therapy for the majority of breast cancer patients completing about 5 years of tamoxifen regardless of nodal status. Further data from the updated analysis will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis; Pfizer Novartis; Pfizer AstraZeneca; Novartis

847 Background: Over half of recurrences and two thirds of deaths from hormone dependent breast cancer occur after completion of 5 years of adjuvant tamoxifen. We previously reported an improvement in disease free survival in women receiving extended adjuvant treatment with L after tamoxifen. Toxicities reported up until February 2003, 8 months prior to unblinding of the study medication, were low grade and included vasomotor symptoms, arthritis, joint and muscle pain. Hypercholesterolemia and cardiovascular events were similar in both arms and while new patient-reported diagnoses of osteoporosis were slightly more common (5.8% vs 4.5% L vs P), clinical fracture rate was unchanged by L. Methods: The study database was locked as of August 2003 for analysis of events in disease free survival (DFS) which were local or distant recurrence or new contralateral breast cancer. A subset analysis of outcome according to nodal status was performed. A full and updated analysis of all study endpoints, including safety and quality of life, as of the date of unblinding the trial (October 9 2003) will be conducted in mid-January 2004. Results: 5187 patients were randomized. Demonstration of an improvement in DFS was achieved earlier than anticipated (P = 0.00008 at the first interim analysis) with a hazard rate of 0.57, indicating a 43% reduction in risk. L decreased the risk of events by 53% and 40% for node negative and node positive patients respectively. This translated into an absolute improvement in 3-year disease free survival of 3% and 7% in node negative and node positive patients, respectively. Conclusions: Letrozole is indicated as extended adjuvant therapy for the majority of breast cancer patients completing about 5 years of tamoxifen regardless of nodal status. Further data from the updated analysis will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis; Pfizer Novartis; Pfizer AstraZeneca; Novartis

A higher incidence of contralateral breast cancer and ipsilateral recurrence has been reported in familial breast cancer than in sporadic cancer. This study investigated the influence of contralateral cancer and tumour stage on survival in patients with familial non-BRCA1/BRCA2-associated breast cancer. The incidences of contralateral breast cancer, ipsilateral recurrence, distant disease-free and overall survival were assessed in 327 patients from families with three or more breast and/or ovarian cancers, but no BRCA1 or BRCA2 gene mutation (familial non-BRCA1/2), and in 327 control subjects with sporadic breast cancer, matched for year and age at detection. Mean follow-up was 7.3 years for patients with familial-non-BRCA1/2 cancers and 6.5 years for patients with sporadic breast cancer. Tumours were stage T1 or lower in 62.1 per cent of familial non-BRCA1/2 cancers versus 49.9 per cent in sporadic breast cancers (P = 0.003), and node negative in 55.8 versus 52.1 per cent, respectively (P = 0.477). After 10 years the incidence of metachronous contralateral breast cancer was 6.4 per cent for familial non-BRCA1/2 tumours versus 5.4 per cent for sporadic cancers. The rate of ipsilateral recurrence was not significantly increased (17.0 versus 14.2 per cent, respectively, at 10 years; P = 0.132). Tumour size (hazard ratio (HR) 1.02 per mm increase, P = 0.016) and node status (HR 2.6 for three or more involved nodes versus node negative, P = 0.017) were independent predictors of overall survival in the familial non-BRCA1/2 group, and in the whole group, whereas contralateral breast cancer (HR 0.7, P = 0.503) and risk-reducing contralateral mastectomy (HR 0.4, P = 0.163) were not. Stage at detection was a key determinant of prognosis in familial non-BRCA1/2 breast cancer, whereas contralateral cancer was not. Risk-reducing contralateral mastectomy did not significantly improve survival, but early detection can. Decisions on breast-conserving treatment can be made on the same grounds in patients with familial and sporadic breast cancer.

Impact of premenopausal status at breast cancer diagnosis in women entered on the placebo-controlled NCIC CTG MA17 trial of extended adjuvant letrozole

Background: Women with early stage breast cancer and DM have poorer survival compared to non-DM women (Lipscombe 2008). Mechanisms include insulin dysregulation and/or DM related comorbidities such as HTN and CAD. MA.17 showed that adjuvant LET after five yrs of TAM reduced the risk of recurrence in women with ER+ early stage breast cancer and improved survival in node +ve disease. We evaluated the impact of DM, HTN, or CAD on prognosis after 5 yrs of TAM and the efficacy of LET in MA.17. Methods: All 5170 women randomized to MA.17 were included. Four year disease free survival (DFS), distant disease free survival (DDFS) and overall survival (OS) were compared using Cox regression model adjusting for other prognostic factors: a) in women treated with placebo (PLAC) based on the presence or absence of baseline DM (n=462), HTN (n=1627), CAD (n=604) or any one of these comorbidities (n=2049), and b) between LET and PLAC groups in each comorbidity. Analyses based on nodal status were also performed. Test for interaction assessed for differential treatment effects in comorbidity groups. Results: Women with DM on PLAC had non-significant lower DFS (89.7 vs. 89.9%, p=0.68), DDFS (92.1 vs 93.9%, p=0.85), and OS (92.1 vs 95.2, p=0.37) than those without DM on PLAC. Treatment effect outcomes were similar between those with and without DM. Women with HTN on PLAC trended toward lower DDFS (92.2 vs 94.4%, HR=1.50, 95%CI: 0.98-2.3, p=0.06) and OS (93.7 vs. 95.5%, HR=1.61, 95%CI: 0.95-2.72, p=0.08) than non-HTN women on PLAC. The interaction between treatment and HTN status was significant for DDFS (p=0.004) with HTN women having significantly better outcome on LET vs PLAC (HR=0.27, 95%CI: 0.13 to 0.54; p=0.0002) compared to non-HTN women on LET vs PLAC (HR=0.82, 95%CI: 0.56-1.20; p=0.31). Women with CAD on PLAC did not have worse outcome, nor did CAD status have a treatment related effect. Women with at least one co-morbidity on PLAC had significantly lower OS (93.6 vs. 95.8%, HR=2.10, 95%CI:1.26-3.51, p=0.004) than those free of comorbidity. For node +ve women, the difference between LET and PLAC in DDFS was greater among women with at least one co-morbidity (HR=0.30, 95%CI:0.15-0.60, p=0.001) compared to those without any co-morbidity (HR=0.72, 95%CI:0.45-1.16, p=0.17) with interaction p=0.04. Conclusions: Having at least one comorbidity was a negative prognostic indicator for OS after 5 yrs of TAM and led to improved DDFS for node +ve women taking LET. DM was not prognostic nor did it predict treatment outcomes. Explanations include not controlling for DM medications; as well, MA.17 enrolled women 5 yrs after TAM with evidence suggesting hyperinsulinemia being a risk for early rather than late recurrence. HTN was a potential risk factor with a trend for worse DDFS and OS. HTN also predicted for treatment benefit: HTN women on LET had improved DDFS compared to non-HTN women on LET. Hypothesis include antihypertensive agents slowing the metabolism of LET; alternatively there may be variations in VEGF levels between groups. HTN predictive effects will be further explored in MA.27 with potential to correlate with VEGF levels. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD03-04.