Clinical Bottom Line

This systematic review of observational studies provides “Probable” evidence that higher soy isoflavone consumption is associated with a reduced risk of breast cancer recurrence, particularly for postmenopausal and ER-positive survivors. Similarly, it found “Probable” evidence that higher levels of enterolactone (a biomarker of lignan intake) are associated with reduced cancer-specific and all-cause mortality, especially in postmenopausal women.

Evidence for pre-diagnosis green tea intake reducing recurrence was rated “Limited Suggestive”, while no associations were found for cruciferous vegetable intake. Because these findings are from observational studies, they show strong associations but cannot prove causation.

Results

This meta-analysis pooled data from observational studies to assess the association between specific phytonutrients and outcomes in breast cancer survivors.

• Definition of Hazard Ratio (HR): The hazard ratio (HR) estimates the risk of an event (e.g., recurrence or death) in the high-intake group compared to the low-intake group over time. An HR of 0.74, for example, suggests a 26% reduction in the hazard of the event.

• Soy Isoflavones:

  • Recurrence: Associated with a 26% reduced risk of recurrence overall (HR = 0.74, 95% CI = 0.60 to 0.92).

  • Subgroups: The benefit was significant for postmenopausal women (HR = 0.72) and estrogen receptor (ER)-positive survivors (HR = 0.82).

  • Dose-Response: The greatest risk reduction for recurrence was seen at an intake of 60 mg/day, with no further benefit at higher doses.

• Enterolactone (ENL) (biomarker for lignans):

  • Mortality: Associated with a 28% reduced risk of cancer-specific mortality (HR = 0.72, 95% CI = 0.58 to 0.90) and a 31% reduced risk of all-cause mortality (HR = 0.69, 95% CI = 0.57 to 0.83).

  • Subgroups: This association was strongest in postmenopausal women and, for all-cause mortality, in women with node-negative disease.

• Green Tea (Pre-diagnosis intake):

  • Recurrence: Associated with a 44% reduced risk of recurrence only in women with stage I and II breast cancer (HR = 0.56, 95% CI = 0.38 to 0.83).

• Cruciferous Vegetables:

  • No significant associations were found for recurrence, cancer-specific mortality, or all-cause mortality.

Assertive Critical Appraisal

• Certainty of Evidence (GRADE Framework): The authors used the WCRF/AICR adaptation of the GRADE criteria to rate the certainty of the evidence.

  • Probable: The association for soy isoflavones (on recurrence) and enterolactone (on mortality) was graded as “Probable”.

  • Limited Suggestive: Green tea’s effect on recurrence was graded as “Limited Suggestive,” primarily because it was based on only two studies.

  • No Conclusion: The evidence for cruciferous vegetables was graded as “Limited – No Conclusion”

• Heterogeneity: The authors reported the I2 statistic, which estimates the percentage of variation across studies due to real differences in effect rather than just chance.

   

  • The main finding for soy isoflavones and recurrence had an I² = 58.3% indicating moderate heterogeneity and suggesting the included studies had somewhat different results.

  • In contrast, the key analyses for enterolactone, green tea, and cruciferous vegetables all had an I² = 0%, indicating high consistency across the studies in those pools

• Publication Bias: The authors assessed for publication bias using Egger and Begg tests, but only for the soy isoflavone analyses where enough studies were available. They reported no evidence of publication bias for the mortality outcomes. Publication bias is a common threat that can lead to an overestimation of treatment effects, and its absence here (for the soy data) increases confidence in the findings.

• Risk of Bias in Included Studies: The quality of the 32 included observational studies was assessed using the Newcastle-Ottawa Scale (NOS). The authors rated 27 studies as “high quality” and 7 as “moderate quality”. The most commonly neglected criterion in the primary studies was the failure to adjust for essential confounders, particularly treatment type, ER/PR status, and disease stage, which is a key limitation of the underlying evidence.

• Reporting Quality Assessment (PRISMA): This review adheres to high reporting standards. The authors state they followed PRISMA guidelines. Crucially, they include a complete PRISMA flow diagram (Figure 1) that transparently shows the study selection process, and they describe the full search strategy for MEDLINE. This transparency strengthens the reproducibility and validity of the review.

Research Objective

The review’s objective was to evaluate evidence from observational studies on the impact of soy, lignans, cruciferous vegetables, and green tea on breast cancer recurrence, breast cancer-specific mortality, and all-cause mortality, with a specific focus on effective dosages and intake time frames.

Study Design

This was a systematic review and meta-analysis of prospective and retrospective observational studies. The authors searched MEDLINE, EMBASE, CINAHL, Cochrane Library, and trial registries through October 2023. A random-effects model was used to pool hazard ratios, and nonlinear dose-response analyses were also conducted.

Setting and Participants

The review included 32 articles (representing 34 individual studies). The final meta-analyses included 22 of these studies. The total number of participants was large, for example:

• Soy Isoflavones: 11 studies with 34,567 participants (all-cause mortality analysis)

• Enterolactone: 3 studies with 3,864 participants

• Green Tea: 2 studies with 1,632 participants

   

Bibliographic Data

• Title: Phytonutrients and outcomes following breast cancer: a systematic review and meta-analysis of observational studies

• Authors: M. Diana van Die, PhD; Kerry M. Bone, BSc (Hons); Kala Visvanathan, MD, MHS; Cecile Kyrø, PhD; Dagfinn Aune, PhD; Carolyn Ee, PhD; Channing J. Paller, MD

• Journal: JNCI Cancer Spectrum

• Year: 2023

• DOI: 10.1093/jncics/pkad104