ASCO 2014 - Abstract LBA505

ASCO 2014. Abstract LBA505. Phase III trial (Prevention of Early Menopause Study [POEMS]-SWOG S0230) of LHRH analog during chemotherapy (CT) to reduce ovarian failure in early-stage, hormone receptor-negative breast cancer: An international Intergroup trial of SWOG, IBCSG, ECOG, and CALGB (Alliance).

Halle C. F. Moore, Joseph M. Unger, Kelly-Anne Phillips, Frances M. Boyle, Erika Hitre, David James Porter, Prudence A. Francis, Lori M. Minasian, Richard D. Gelber, Lori J. Goldstein, Henry Leonidas Gomez, Carlos Vallejos, Ann H. Partridge, Shaker R. Dakhil, Silvana Martino, William E. Barlow, Carol J. Fabian, Frank L. Meyskens, Gabriel N. Hortobagyi, Kathy S. Albain; Cleveland Clinic, Cleveland, OH; SWOG Statistical Center, Seattle, WA; Peter MacCallum Cancer Center, Melbourne, Australia; The Mater Hospital, Sydney, Australia; National Institute of Oncology, Budapest, Hungary; Department of Oncology, Auckland City Hospital, Auckland, New Zealand; Peter MacCallum Cancer Centre, East Melbourne, Australia; National Cancer Institute, Bethesda, MD; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA; Fox Chase Cancer Center, Philadelphia, PA; Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru; ONCOSALUD, Lima, Peru; Dana-Farber Cancer Institute, Boston, MA; Wichita Community Clinical Oncology Program, Wichita, KS; The Angeles Clinic and Research Institute, Santa Monica, CA; Cancer Research and Biostatistics, Seattle, WA; University of Kansas Medical Center, Kansas City, KS; Chao Family Comprehensive Cancer Center, Orange, CA; The University of Texas MD Anderson Cancer Center, Houston, TX; Loyola University Medical Center, Maywood, IL

Background: Premature ovarian failure (POF) is a common toxicity of CT. Risk depends on type and amount of CT, age, and perhaps ovarian cycling at the time of CT. POEMS is a SWOG coordinated phase III randomized study to evaluate whether LHRH analog administration with CT for early-stage breast cancer (BC) would reduce POF.

Methods: Premenopausal patients (PT) age<50 with stage I-IIIA ER/PR-negative BC to be treated with CT were randomized to receive standard cyclophosphamide-containing CT with or without monthly goserelin (GN) 3.6 mg SQ starting 1 week prior to the first CT dose. The primary endpoint is 2-year POF, defined as amenorrhea for the prior 6 months and post-menopausal FSH. Other endpoints include pregnancies and survival. Endpoints were analyzed in multivariable regression adjusting for stratification factors (age and CT regimen).

Results: Between 2/04 and 5/11, 257 PT enrolled. Among 218 evaluable PT, 62% had complete primary endpoint data. Dropouts (n=83) were mostly due to deaths (n=14) or lack of FSH data. There was no strong evidence of informative missing data by arm according to stratification factors (p>.05). POF rates were 22% in the standard arm and 8% in the GN arm (OR=0.30, 95% CI: 0.10-0.87, p=.03 [unadjusted analysis]; OR= 0.36, 95%CI: 0.11-1.14, p=0.08 [adjusted logistic regression analysis]). In a sensitivity analysis defining 2-year POF more liberally as either amenorrhea or elevated FSH, 45% in the standard arm and 20% in the GN arm had POF (OR=0.29, 95% CI: 0.12-0.70, p=.006). There were 13 pregnancies in the standard arm and 22 in the GN arm (OR=2.22, 95% CI: 1.00-4.92, p=.05). DFS and OS were better in the GN arm (Cox regression, including stage: HR=0.49, 95% CI: 0.24-0.97, p=.04; HR= 0.43, 95% CI: 0.18-1.00, p=.05, respectively).

Conclusions: LHRH analog administration with CT was associated with less POF and more pregnancies. In an exploratory analysis, GN use in premenopausal ER-negative BC was associated with improved DFS and OS. 

• Approximately 25% of breast cancer patients are diagnosed under the age of 50. The consequences of chemotherapy induced premature ovarian failure (sub/infertility, menopausal symptoms, access/referral to fertility consultants and resultant potential delays in adjuvant treatment) only further compounds to the overall distress of the initial breast cancer diagnosis and treatment

• Compared to historical controls, other smaller studies reported potential ovarian protection with concomitant LHRH analog. Previous smaller randomized studies reported mixed results and commonly only used return of menses as an endpoint with few data on pregnancy outcomes.

• The POEMS study1 is the largest phase III study that demonstrates the benefit of LHRH analog therapy for potential ovarian protection (and pregnancy outcomes) in this breast cancer patient population with the main benefit seen at year 2. An expected increase in vasomotor symptoms was noted while on LHRH treatment with no other unexpected serious events.

• Of note, the trial was closed prior to full accrual (original target 416 patients) due to slow accrual and loss of drug funding, and post-hoc power calculations were required. Endpoint data was also missing for 38% and patients were not stratified for other disease risk factors (stage, HER2, nodal status), however stage adjustment did not significantly alter DFS or OS.

• Intriguingly, in a planned exploratory analysis the investigators reported an improvement in 4yDFS (78% → 89%) for those receiving LHRH analog therapy (HR 0.47, p=0.04) and a trend in OS as well. But one has to remember that this was a secondary endpoint of the trial with immature follow-up and methodologic issues as noted above.

• Although not definitive, given the overall risk-benefit profile in this ER negative patient population, clinicians should at least discuss and patients should consider the option of concomitant LHRH analog therapy during chemotherapy for potential ovarian protection. This approach, for ovarian preservation purposes however, cannot be translated to patients with ER+ disease. The potential therapeutic role of ovarian suppression in ER+ breast cancer patients (TEXT/SOFT2) was also presented at ASCO 2014 and is the subject of another CARE Faculty Commentary.
— The CARE Breast Cancer Faculty

References:

  1. Phase III trial (Prevention of Early Menopause Study [POEMS]-SWOG S0230) of LHRH analog during chemotherapy (CT) to reduce ovarian failure in early-stage, hormone receptor-negative breast cancer: An international Intergroup trial of SWOG, IBCSG, ECOG, and CALGB (Alliance). H.C.F Moore et al.   J Clin Oncol 32:5s, 2014 (suppl; abstr LBA505)
     
  2. Randomized comparison of adjuvant aromatase inhibitor (AI) exemestane (E) plus ovarian function suppression (OFS) vs tamoxifen (T) plus OFS in premenopausal women with hormone receptor-positive (HR+) early breast cancer (BC): Joint analysis of IBCSG TEXT and SOFT trials. O Pagani et al. J Clin Oncol 32:5s, 2014 (suppl; abstr LBA1)