Breast Cancer After Use of Estrogen Plus Progestin and Estrogen Alone

Analyses of Data From 2 Women's Health Initiative Randomized Clinical Trials

Rowan T. Chlebowski, Thomas E. Rohan, Jo Ann E Manson, Aaron K. Aragaki, Andrew Kaunitz, Marcia L. Stefanick, Michael S. Simon, Karen C. Johnson, Jean Wactawski-Wende, Mary J. O'Sullivan, Lucile L. Adams-Campbell, Rami Nassir, Lawrence S. Lessin, Ross L. Prentice

Research output: Contribution to journalArticle

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Abstract

IMPORTANCE: The use of menopausal hormone therapy (HT) continues in clinical practice, but reports are conflicting concerning the longer-term breast cancer effects of relatively short-term use.

OBJECTIVE: To report the longer-term influence of menopausal HT on breast cancer incidence in the 2 Women's Health Initiative (WHI) randomized clinical trials.

DESIGN, SETTING, AND PARTICIPANTS: A total of 27,347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers from 1993 to 1998 and followed up for a median of 13 years through September 2010.

INTERVENTIONS: A total of 16,608 women with a uterus were randomized to conjugated equine estrogens (0.625 mg/d [estrogen]) plus medroxyprogesterone acetate (2.5 mg/d [progestin]) (E + P) or placebo with a median intervention duration of 5.6 years, and 10,739 women with prior hysterectomy were randomized to conjugated equine estrogens alone (0.625 mg/d) or placebo with a median intervention duration of 7.2 years.

MAIN OUTCOMES AND MEASURES: Time-specific invasive breast cancer incidence rates and exploratory analyses of breast cancer characteristics by intervention and postintervention phases in the 2 HT trials.

RESULTS: In the E + P trial, hazard ratios (HRs) for the influence of combined HT on breast cancer were lower than 1 for 2 years (HR, 0.71; 95% CI, 0.47-1.08) and steadily increased throughout intervention, becoming significantly increased for the entire intervention phase (HR, 1.24; 95% CI, 1.01-1.53). In the early postintervention phase (within 2.75 years from intervention), there was a sharp decrease in breast cancer incidence in the combined HT group, though the HR remained higher than 1 (HR, 1.23; 95% CI, 0.90-1.70). During the late postintervention phase (requiring patient re-consent), the HR for breast cancer risk remained higher than 1 through 5.5 years (median) of additional follow-up (HR, 1.37; 95% CI, 1.06-1.77). In the estrogen alone trial, the HR for invasive breast cancer risk was lower than 1 throughout the intervention phase (HR, 0.79; 95% CI, 0.61-1.02) and remained lower than 1 in the early postintervention phase (HR, 0.55; 95% CI, 0.34-0.89), but risk reduction was not observed during the late postintervention follow-up (HR, 1.17; 95% CI, 0.73-1.87). Characteristics of breast cancers diagnosed during early and late postintervention phases differed in both trials.

CONCLUSIONS AND RELEVANCE: In the E + P trial, the higher breast cancer risk seen during intervention was followed by a substantial drop in risk in the early postintervention phase, but a higher breast cancer risk remained during the late postintervention follow-up. In the estrogen alone trial, the lower breast cancer risk seen during intervention was sustained in the early postintervention phase but was not evident during the late postintervention follow-up.

Original languageEnglish (US)
Pages (from-to)296-305
Number of pages10
JournalJAMA oncology
Volume1
Issue number3
DOIs
StatePublished - Jun 1 2015

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Women's Health
Progestins
Estrogens
Randomized Controlled Trials
Breast Neoplasms
Hormones
Conjugated (USP) Estrogens
Incidence
Placebos
Medroxyprogesterone Acetate
Risk Reduction Behavior
Therapeutics
Group Psychotherapy
Hysterectomy
Uterus

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Breast Cancer After Use of Estrogen Plus Progestin and Estrogen Alone : Analyses of Data From 2 Women's Health Initiative Randomized Clinical Trials. / Chlebowski, Rowan T.; Rohan, Thomas E.; Manson, Jo Ann E; Aragaki, Aaron K.; Kaunitz, Andrew; Stefanick, Marcia L.; Simon, Michael S.; Johnson, Karen C.; Wactawski-Wende, Jean; O'Sullivan, Mary J.; Adams-Campbell, Lucile L.; Nassir, Rami; Lessin, Lawrence S.; Prentice, Ross L.

In: JAMA oncology, Vol. 1, No. 3, 01.06.2015, p. 296-305.

Research output: Contribution to journalArticle

Chlebowski, RT, Rohan, TE, Manson, JAE, Aragaki, AK, Kaunitz, A, Stefanick, ML, Simon, MS, Johnson, KC, Wactawski-Wende, J, O'Sullivan, MJ, Adams-Campbell, LL, Nassir, R, Lessin, LS & Prentice, RL 2015, 'Breast Cancer After Use of Estrogen Plus Progestin and Estrogen Alone: Analyses of Data From 2 Women's Health Initiative Randomized Clinical Trials', JAMA oncology, vol. 1, no. 3, pp. 296-305. https://doi.org/10.1001/jamaoncol.2015.0494
Chlebowski, Rowan T. ; Rohan, Thomas E. ; Manson, Jo Ann E ; Aragaki, Aaron K. ; Kaunitz, Andrew ; Stefanick, Marcia L. ; Simon, Michael S. ; Johnson, Karen C. ; Wactawski-Wende, Jean ; O'Sullivan, Mary J. ; Adams-Campbell, Lucile L. ; Nassir, Rami ; Lessin, Lawrence S. ; Prentice, Ross L. / Breast Cancer After Use of Estrogen Plus Progestin and Estrogen Alone : Analyses of Data From 2 Women's Health Initiative Randomized Clinical Trials. In: JAMA oncology. 2015 ; Vol. 1, No. 3. pp. 296-305.
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abstract = "IMPORTANCE: The use of menopausal hormone therapy (HT) continues in clinical practice, but reports are conflicting concerning the longer-term breast cancer effects of relatively short-term use.OBJECTIVE: To report the longer-term influence of menopausal HT on breast cancer incidence in the 2 Women's Health Initiative (WHI) randomized clinical trials.DESIGN, SETTING, AND PARTICIPANTS: A total of 27,347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers from 1993 to 1998 and followed up for a median of 13 years through September 2010.INTERVENTIONS: A total of 16,608 women with a uterus were randomized to conjugated equine estrogens (0.625 mg/d [estrogen]) plus medroxyprogesterone acetate (2.5 mg/d [progestin]) (E + P) or placebo with a median intervention duration of 5.6 years, and 10,739 women with prior hysterectomy were randomized to conjugated equine estrogens alone (0.625 mg/d) or placebo with a median intervention duration of 7.2 years.MAIN OUTCOMES AND MEASURES: Time-specific invasive breast cancer incidence rates and exploratory analyses of breast cancer characteristics by intervention and postintervention phases in the 2 HT trials.RESULTS: In the E + P trial, hazard ratios (HRs) for the influence of combined HT on breast cancer were lower than 1 for 2 years (HR, 0.71; 95{\%} CI, 0.47-1.08) and steadily increased throughout intervention, becoming significantly increased for the entire intervention phase (HR, 1.24; 95{\%} CI, 1.01-1.53). In the early postintervention phase (within 2.75 years from intervention), there was a sharp decrease in breast cancer incidence in the combined HT group, though the HR remained higher than 1 (HR, 1.23; 95{\%} CI, 0.90-1.70). During the late postintervention phase (requiring patient re-consent), the HR for breast cancer risk remained higher than 1 through 5.5 years (median) of additional follow-up (HR, 1.37; 95{\%} CI, 1.06-1.77). In the estrogen alone trial, the HR for invasive breast cancer risk was lower than 1 throughout the intervention phase (HR, 0.79; 95{\%} CI, 0.61-1.02) and remained lower than 1 in the early postintervention phase (HR, 0.55; 95{\%} CI, 0.34-0.89), but risk reduction was not observed during the late postintervention follow-up (HR, 1.17; 95{\%} CI, 0.73-1.87). Characteristics of breast cancers diagnosed during early and late postintervention phases differed in both trials.CONCLUSIONS AND RELEVANCE: In the E + P trial, the higher breast cancer risk seen during intervention was followed by a substantial drop in risk in the early postintervention phase, but a higher breast cancer risk remained during the late postintervention follow-up. In the estrogen alone trial, the lower breast cancer risk seen during intervention was sustained in the early postintervention phase but was not evident during the late postintervention follow-up.",
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T1 - Breast Cancer After Use of Estrogen Plus Progestin and Estrogen Alone

T2 - Analyses of Data From 2 Women's Health Initiative Randomized Clinical Trials

AU - Chlebowski, Rowan T.

AU - Rohan, Thomas E.

AU - Manson, Jo Ann E

AU - Aragaki, Aaron K.

AU - Kaunitz, Andrew

AU - Stefanick, Marcia L.

AU - Simon, Michael S.

AU - Johnson, Karen C.

AU - Wactawski-Wende, Jean

AU - O'Sullivan, Mary J.

AU - Adams-Campbell, Lucile L.

AU - Nassir, Rami

AU - Lessin, Lawrence S.

AU - Prentice, Ross L.

PY - 2015/6/1

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N2 - IMPORTANCE: The use of menopausal hormone therapy (HT) continues in clinical practice, but reports are conflicting concerning the longer-term breast cancer effects of relatively short-term use.OBJECTIVE: To report the longer-term influence of menopausal HT on breast cancer incidence in the 2 Women's Health Initiative (WHI) randomized clinical trials.DESIGN, SETTING, AND PARTICIPANTS: A total of 27,347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers from 1993 to 1998 and followed up for a median of 13 years through September 2010.INTERVENTIONS: A total of 16,608 women with a uterus were randomized to conjugated equine estrogens (0.625 mg/d [estrogen]) plus medroxyprogesterone acetate (2.5 mg/d [progestin]) (E + P) or placebo with a median intervention duration of 5.6 years, and 10,739 women with prior hysterectomy were randomized to conjugated equine estrogens alone (0.625 mg/d) or placebo with a median intervention duration of 7.2 years.MAIN OUTCOMES AND MEASURES: Time-specific invasive breast cancer incidence rates and exploratory analyses of breast cancer characteristics by intervention and postintervention phases in the 2 HT trials.RESULTS: In the E + P trial, hazard ratios (HRs) for the influence of combined HT on breast cancer were lower than 1 for 2 years (HR, 0.71; 95% CI, 0.47-1.08) and steadily increased throughout intervention, becoming significantly increased for the entire intervention phase (HR, 1.24; 95% CI, 1.01-1.53). In the early postintervention phase (within 2.75 years from intervention), there was a sharp decrease in breast cancer incidence in the combined HT group, though the HR remained higher than 1 (HR, 1.23; 95% CI, 0.90-1.70). During the late postintervention phase (requiring patient re-consent), the HR for breast cancer risk remained higher than 1 through 5.5 years (median) of additional follow-up (HR, 1.37; 95% CI, 1.06-1.77). In the estrogen alone trial, the HR for invasive breast cancer risk was lower than 1 throughout the intervention phase (HR, 0.79; 95% CI, 0.61-1.02) and remained lower than 1 in the early postintervention phase (HR, 0.55; 95% CI, 0.34-0.89), but risk reduction was not observed during the late postintervention follow-up (HR, 1.17; 95% CI, 0.73-1.87). Characteristics of breast cancers diagnosed during early and late postintervention phases differed in both trials.CONCLUSIONS AND RELEVANCE: In the E + P trial, the higher breast cancer risk seen during intervention was followed by a substantial drop in risk in the early postintervention phase, but a higher breast cancer risk remained during the late postintervention follow-up. In the estrogen alone trial, the lower breast cancer risk seen during intervention was sustained in the early postintervention phase but was not evident during the late postintervention follow-up.

AB - IMPORTANCE: The use of menopausal hormone therapy (HT) continues in clinical practice, but reports are conflicting concerning the longer-term breast cancer effects of relatively short-term use.OBJECTIVE: To report the longer-term influence of menopausal HT on breast cancer incidence in the 2 Women's Health Initiative (WHI) randomized clinical trials.DESIGN, SETTING, AND PARTICIPANTS: A total of 27,347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers from 1993 to 1998 and followed up for a median of 13 years through September 2010.INTERVENTIONS: A total of 16,608 women with a uterus were randomized to conjugated equine estrogens (0.625 mg/d [estrogen]) plus medroxyprogesterone acetate (2.5 mg/d [progestin]) (E + P) or placebo with a median intervention duration of 5.6 years, and 10,739 women with prior hysterectomy were randomized to conjugated equine estrogens alone (0.625 mg/d) or placebo with a median intervention duration of 7.2 years.MAIN OUTCOMES AND MEASURES: Time-specific invasive breast cancer incidence rates and exploratory analyses of breast cancer characteristics by intervention and postintervention phases in the 2 HT trials.RESULTS: In the E + P trial, hazard ratios (HRs) for the influence of combined HT on breast cancer were lower than 1 for 2 years (HR, 0.71; 95% CI, 0.47-1.08) and steadily increased throughout intervention, becoming significantly increased for the entire intervention phase (HR, 1.24; 95% CI, 1.01-1.53). In the early postintervention phase (within 2.75 years from intervention), there was a sharp decrease in breast cancer incidence in the combined HT group, though the HR remained higher than 1 (HR, 1.23; 95% CI, 0.90-1.70). During the late postintervention phase (requiring patient re-consent), the HR for breast cancer risk remained higher than 1 through 5.5 years (median) of additional follow-up (HR, 1.37; 95% CI, 1.06-1.77). In the estrogen alone trial, the HR for invasive breast cancer risk was lower than 1 throughout the intervention phase (HR, 0.79; 95% CI, 0.61-1.02) and remained lower than 1 in the early postintervention phase (HR, 0.55; 95% CI, 0.34-0.89), but risk reduction was not observed during the late postintervention follow-up (HR, 1.17; 95% CI, 0.73-1.87). Characteristics of breast cancers diagnosed during early and late postintervention phases differed in both trials.CONCLUSIONS AND RELEVANCE: In the E + P trial, the higher breast cancer risk seen during intervention was followed by a substantial drop in risk in the early postintervention phase, but a higher breast cancer risk remained during the late postintervention follow-up. In the estrogen alone trial, the lower breast cancer risk seen during intervention was sustained in the early postintervention phase but was not evident during the late postintervention follow-up.

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