Retrospective Study
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World J Clin Oncol. Dec 10, 2014; 5(5): 1088-1096
Published online Dec 10, 2014. doi: 10.5306/wjco.v5.i5.1088
Competing risks of death in younger and older postmenopausal breast cancer patients
Judy-Anne W Chapman, Kathleen I Pritchard, Paul E Goss, James N Ingle, Hyman B Muss, Susan F Dent, Ted A Vandenberg, Brian Findlay, Karen A Gelmon, Carolyn F Wilson, Lois E Shepherd, Michael N Pollak
Judy-Anne W Chapman, NCIC Clinical Trials Group, Queen’s University, Kingston, ON, K7L 3N6, Canada
Kathleen I Pritchard, Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, M4N 3M5, Canada
Paul E Goss, Massachusetts General Hospital, Harvard University, Boston, MA 02114, United States
James N Ingle, Mayo Clinic, Rochester, MN 55902, United States
Hyman B Muss, Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, United States
Susan F Dent, Ottawa Hospital Cancer Center, University of Ottawa, Ottawa, ON, K1H 8L6, Canada
Ted A Vandenberg, London Health Sciences Centre, University of Western Ontario, London, ON, N6G 2V4, Canada
Brian Findlay, Niagara Health System, McMaster University, St. Catharines, ON, L2R 2Z4, Canada
Karen A Gelmon, BC Cancer Agency, University of British Columbia, Vancouver, BC, V5Z 1L3, Canada
Carolyn F Wilson, Lois E Shepherd, NCIC Clinical Trials Group, Queen’s University, Kingston, Ontario, K7L 3N6, Canada
Michael N Pollak, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, H3T 1E2, Canada
Author contributions: Chapman JAW designed the research; Goss PE, Ingle JN, Muss HB, Shepherd LE and Pollak MN contributed to conception; Pritchard KI, Goss PE, Dent SF, Vandenberg TA, Findlay B, Gelmon KA, Wilson CF, Shepherd LE and Pollak MN contributed to data; Chapman JAW analyzed the data; Chapman JAW drafted the article with critical content review and revision by all other authors; all authors approved the version submitted for publication.
Supported by the Canadian Cancer Society through a grant to the NCIC Clinical Trials Group from the Canadian Cancer Society Research Institute; Novartis provided the NCIC CTG MA.14 drug octreotide LAR
Correspondence to: Judy-Anne W Chapman, PhD, Senior Biostatistician, NCIC Clinical Trials Group, Queen’s University, 10 Stuart Street, Kingston, ON, K7L 3N6, Canada. jachapma@aol.com
Telephone: +1-613-5336430 Fax: +1-613-5332941
Received: December 22, 2013
Revised: April 30, 2014
Accepted: July 12, 2014
Published online: December 10, 2014
Processing time: 354 Days and 8 Hours
Abstract

AIM: To show a new paradigm of simultaneously testing whether breast cancer therapies impact other causes of death.

METHODS: MA.14 allocated 667 postmenopausal women to 5 years of tamoxifen 20 mg/daily ± 2 years of octreotide 90 mg, given by depot intramuscular injections monthly. Event-free survival was the primary endpoint of MA.14; at median 7.9 years, the tamoxifen+octreotide and tamoxifen arms had similar event-free survival (P = 0.62). Overall survival was a secondary endpoint, and the two trial arms also had similar overall survival (P = 0.86). We used the median 9.8 years follow-up to examine by intention-to-treat, the multivariate time-to-breast cancer-specific (BrCa) and other cause (OC) mortality with log-normal survival analysis adjusted by treatment and stratification factors. We tested whether baseline factors including Insulin-like growth factor 1 (IGF1), IGF binding protein-3, C-peptide, body mass index, and 25-hydroxy vitamin D were associated with (1) all cause mortality, and if so and (2) cause-specific mortality. We also fit step-wise forward cause-specific adjusted models.

RESULTS: The analyses were performed on 329 patients allocated tamoxifen and 329 allocated tamoxifen+octreotide. The median age of MA.14 patients was 60.1 years: 447 (82%) < 70 years and 120 (18%) ≥ 70 years. There were 170 deaths: 106 (62.3%) BrCa; 55 (32.4%) OC, of which 24 were other malignancies, 31 other causes of death; 9 (5.3%) patients with unknown cause of death were excluded from competing risk assessments. BrCa and OC deaths were not significantly different by treatment arm (P = 0.40): tamoxifen patients experienced 50 BrCa and 32 OC deaths, while tamoxifen + octreotide patients experienced 56 BrCa and 23 OC deaths. Proportionately more deaths (P = 0.004) were from BrCa for patients < 70 years, where 70% of deaths were due to BrCa, compared to 54% for those ≥ 70 years of age. The proportion of deaths from OC increased with increasing body mass index (BMI) (P = 0.02). Higher pathologic T and N were associated with more BrCa deaths (P < 0.0001 and 0.002, respectively). The cumulative hazard plot for BrCa and OC mortality indicated the concurrent accrual of both types of death throughout follow-up, that is the existence of competing risks of mortality. MA.14 therapy did not impact mortality (P = 0.77). Three baseline patient and tumor characteristics were differentially associated with cause of death: older patients experienced more OC (P = 0.01) mortality; patients with T1 tumors and hormone receptor positive tumors had less BrCa mortality (respectively, P = 0.01, P = 0.06). Additionally, step-wise cause-specific models indicated that patients with node negative disease experienced less BrCa mortality (P = 0.002); there was weak evidence that, lower C-peptide (P = 0.08) was associated with less BrCa mortality, while higher BMI (P = 0.01) was associated with worse OC mortality.

CONCLUSION: We demonstrate here a new paradigm of simultaneous testing of therapeutics directed at multiple diseases for which postmenopausal women are concurrently at risk. Octreotide LAR did not significantly impact breast cancer or other cause mortality, although different baseline factors influenced type of death.

Keywords: Breast cancer; Postmenopausal; Hormone receptor positive; Competing risks; Tamoxifen; Octreotide LAR

Core tip: With earlier detection and improved therapies, patients with early breast cancer simultaneously face multiple health risks; 54% of women ≥ 70 years at diagnosis died from other causes. Octreotide LAR, an early drug targeting the insulin pathway, might have affected both breast and other cause mortality. We demonstrated a method of jointly assessing the impact of therapy and baseline patient characteristics on multiple causes of death. Older patients with higher body mass index experienced more other cause mortality, while women with smaller hormone receptor positive tumours and less lymph node involvement were less likely to die from breast cancer.