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Differing Patterns of Breast Cancer Risk After Hormone Therapy With Estrogen Plus Progestin or Estrogen Alone

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Key Points

  • Among patients receiving estrogen plus progestin, risk was reduced early during intervention, but increased later in intervention and in the postintervention period.
  • Among patients receiving estrogen alone, risk was reduced during intervention and the early postintervention period, but increased thereafter.

In an analysis of Women’s Health Initiative (WHI) trials reported in JAMA Oncology, Chlebowski et al found differing patterns of breast cancer risk among women receiving menopausal hormone therapy with estrogen plus progestin or estrogen alone. Women receiving estrogen plus progestin had reduced early risk, with risk subsequently increasing throughout treatment and during postintervention follow-up. Women receiving estrogen alone had reduced risk during intervention and early postintervention, with risk increasing thereafter.

Study Details

The study included data from 27,347 postmenopausal women aged 50 to 79 years who were enrolled in two WHI trials at 40 U.S. centers from 1993 to 1998 and followed for a median of 13 years through September 2010. In one trial, 16,608 women with a uterus were randomly assigned to estrogen plus progestin (n = 8,506) or placebo (n = 8,102) with a median intervention duration of 5.6 years. In the other, 10,739 women with prior hysterectomy were randomly assigned to estrogen alone (n = 5,310) or placebo (n = 5,429) with a median intervention duration of 7.2 years.

Risk in Estrogen-Plus-Progestin Trial

In the estrogen-plus-progestin trial, risk of invasive breast cancer was reduced during the first 2 years of intervention (hazard ratio [HR] = 0.71, 95% confidence interval [CI] = 0.47–1.08) but increased during the subsequent two 2-year intervals during intervention (HR = 1.36, 95% CI = 0.95–1.94, and HR = 1.65, 95% CI = 1.17–2.32), resulting in a significantly increased risk for the entire intervention period (HR = 1.24, 95% CI = 1.01–1.53).

For the entire postintervention period of follow-up, risk was significantly increased (HR = 1.32, 95% CI = 1.08–1.61), including nonsignificantly increased risk during the early postintervention period (within 2.75 years; HR = 1.23, 95% CI = 0.90–1.70) and significantly increased risk in later follow-up (through a median of 5.5 years; HR = 1.37, 95% CI = 1.06–1.77).

Risk in Estrogen-Alone Trial

In the estrogen-alone trial, risk of invasive breast cancer risk was nonsignificantly reduced throughout the intervention period (HR = 0.79, 95% CI = 0.61–1.02). Risk was significantly reduced during the early postintervention period (HR = 0.55, 95% CI = 0.34–0.89) but not during the late postintervention period (HR = 1.17, 95% CI = 0.73–1.87), yielding overall nonsignificantly reduced risk during the entire postintervention period (HR = 0.80, 95% CI = 0.58–1.11). The hazard ratio crossed 1 at approximately 4.5 years postintervention.

Differences in Early vs Late Postintervention Periods

Characteristics of breast cancers diagnosed during the early vs late postintervention periods differed in both trials. Among patients receiving estrogen plus progestin, the early vs late period was characterized by increased risk of larger tumors (HR = 2.67, 95% CI = 1.19–6.00, vs HR = 0.97, 95% CI = 0.57–1.65; P = .04) and progesterone receptor–negative tumors (HR = 2.67, 95% CI = 1.25–5.73, vs HR = 0.93, 95% CI = 0.54–1.59; P = .004), as well as somewhat increased risk for triple-negative tumors (HR = 2.20, 95% CI = 0.68–7.15, vs HR = 1.08, 95% CI = 0.44-2.67). Among patients receiving estrogen alone, there was increased risk of HER2-positive tumors (HR = 1.79, 95% CI = 0.43–7.49, vs HR = 0.25, 95% CI = 0.03–2.23; P = .007) and reduced frequency of moderately differentiated tumors (HR = 0.24, 95% CI = 0.10–0.59, vs HR = 1.99, 95% CI = 0.96–4.10; P = .008) for early vs late postintervention periods.

The investigators concluded: “In the [estrogen-plus-progestin] trial, the higher breast cancer risk seen during intervention was followed by a substantial drop in risk in the early post-intervention phase, but a higher breast cancer risk remained during the late post-intervention follow-up. In the estrogen alone trial, the lower breast cancer risk seen during intervention was sustained in the early post-intervention phase but was not evident during the late post-intervention follow-up.”

They noted: “With longer follow-up of the 2 WHI hormone therapy trials, a complex pattern of changing year-to-year influences on breast cancer was observed. The ongoing influences on breast cancer after stopping hormone therapy in the WHI trials require recalibration of breast cancer risk and benefit calculation for both regimens, with greater adverse influence for estrogen and progestin use and somewhat greater benefit for use of estrogen alone.”

Rowan T. Chlebowski, MD, PhD, of Harbor-UCLA Medical Center, is the corresponding author for the JAMA Oncology article.

The WHI program is supported by the National Heart, Lung, and Blood Institute, National Institutes of Health. Dr. Chlebowski reported being a consultant for AstraZeneca, Novartis, Amgen, Genomic Health, and Novo Nordisk; receiving funding support from Amgen; and serving on the speaker’s bureau for Novartis and Genentech.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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