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Background <p>Resistance to poly ADP-ribose polymerase (PARP) inhibitors limits durable clinical benefit in breast cancer. The translational relevance of resistance-associated genes to patient prognosis remains poorly characterized. This systematic review and meta-analysis evaluated the clinical prognostic value of homologous recombination repair axis markers and PARP1 expression in breast cancer.</p> Methods <p>PubMed, Embase, and Web of Science were searched from January 2015 to April 2026 for studies reporting survival outcomes associated with PARP inhibitor resistance-associated or homologous recombination repair-related markers. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using a random-effects model, with subgroup, sensitivity, and independent TCGA validation analyses.</p> Results <p>Eighteen studies (13,641 patients) met inclusion criteria. Primary meta-analysis (five studies, <i>n</i> = 909) showed that HR repair axis positivity was associated with reduced mortality risk (HR = 0.508, 95% CI: 0.411–0.627, <i>p</i> &lt; 0.0001; I<sup>2</sup> = 0%), with consistent effects in PARPi-treated (HR = 0.458) and untreated cohorts (HR = 0.557; p for interaction = 0.363). Vote-counting of PARP1 expression (four studies) found three studies reporting high expression as a risk factor, one study protective. TCGA validation suggested an association with worse survival (HR = 1.437, <i>p</i> = 0.013), but this was threshold-dependent and non-significant with an upper-quartile cut-off (<i>p</i> = 0.504). Of note, TCGA assessed mRNA expression, which does not directly measure functional HR deficiency. Evidence for PARP1 as an adverse prognostic marker remains inconclusive. A clinical prioritization framework was developed for HR repair axis markers.</p> Conclusions <p>HR repair axis positivity is associated with reduced mortality risk in breast cancer, independent of PARPi exposure. High PARP1 expression shows an inconclusive prognostic role. These findings support a conceptual distinction between functional HR deficiency and transcriptional biomarker overexpression. However, primary findings are based on limited studies (k = 5) and require prospective validation.</p>

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Clinical prognostic value of homologous recombination repair axis markers and PARP1 expression in breast cancer: a systematic review, meta-analysis, and independent cohort validation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月15日

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  • Kezhen Shen,
  • Lei Cai,
  • Wei Wu

摘要

Background

Resistance to poly ADP-ribose polymerase (PARP) inhibitors limits durable clinical benefit in breast cancer. The translational relevance of resistance-associated genes to patient prognosis remains poorly characterized. This systematic review and meta-analysis evaluated the clinical prognostic value of homologous recombination repair axis markers and PARP1 expression in breast cancer.

Methods

PubMed, Embase, and Web of Science were searched from January 2015 to April 2026 for studies reporting survival outcomes associated with PARP inhibitor resistance-associated or homologous recombination repair-related markers. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using a random-effects model, with subgroup, sensitivity, and independent TCGA validation analyses.

Results

Eighteen studies (13,641 patients) met inclusion criteria. Primary meta-analysis (five studies, n = 909) showed that HR repair axis positivity was associated with reduced mortality risk (HR = 0.508, 95% CI: 0.411–0.627, p < 0.0001; I2 = 0%), with consistent effects in PARPi-treated (HR = 0.458) and untreated cohorts (HR = 0.557; p for interaction = 0.363). Vote-counting of PARP1 expression (four studies) found three studies reporting high expression as a risk factor, one study protective. TCGA validation suggested an association with worse survival (HR = 1.437, p = 0.013), but this was threshold-dependent and non-significant with an upper-quartile cut-off (p = 0.504). Of note, TCGA assessed mRNA expression, which does not directly measure functional HR deficiency. Evidence for PARP1 as an adverse prognostic marker remains inconclusive. A clinical prioritization framework was developed for HR repair axis markers.

Conclusions

HR repair axis positivity is associated with reduced mortality risk in breast cancer, independent of PARPi exposure. High PARP1 expression shows an inconclusive prognostic role. These findings support a conceptual distinction between functional HR deficiency and transcriptional biomarker overexpression. However, primary findings are based on limited studies (k = 5) and require prospective validation.