What is the RxPONDER Trial in Breast Cancer?

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • Full name:
    • “Rx for Positive Node, Endocrine Responsive Breast Cancer”:
      • SWOG S1007
  • Population:
    • Women with hormone receptor (HR)-positive, HER2-negative breast cancer:
      • With 1 to 3 positive axillary lymph nodes:
        • Who have had surgery
    • All had a 21-gene Recurrence Score (RS) of:
      • ≤ 25
  • Key question:
    • Among patients with 1 to 3 positive nodes and RS ≤ 25:
      • Which patients benefit from adding adjuvant chemotherapy to endocrine therapy vs endocrine therapy alone? 
  • Trial Design:
    • Multi-center trial:
      • 632 sites across 9 countries (USA, Canada, Mexico, Colombia, Ireland, France, Spain, South Korea, Saudi Arabia):
        • Enrolled over 5,000 women
    • Enrollment:
      • ~ 5,083 women assigned
      • ~ 5,015 analyzed
      • Approximately two-thirds were postmenopausal
      • One-third premenopausal
    • Treatment arms:
      • Randomized to endocrine therapy alone vs chemotherapy + endocrine therapy
    • Chemotherapy regimens included:
      • Taxane and / or anthracycline
    • Recurrence Score stratifications within ≤ 25:
      • RS categories 0 to 13 vs 14 to 25 used for some analyses
    • Also stratified by menopausal status, number of nodes (1 vs 2 to 3), tumor size / grade
    • Follow-up:
      • Median ≈ 5.1 years for primary results

RxPONDER (SWOG S1007): Five-Year Outcomes
HR-positive / HER2-negative, 1 to 3 positive nodes, Recurrence Score ≤ 25
  • Other data:
    • Overall survival at 5 years among premenopausal women:
      • 98.6% with chemotherapy + endocrine therapy vs 97.3% endocrine therapy only (absolute ~ 1.3%) – HR ~ 0.47; P ≈ 0.032
    • Among postmenopausal women, OS was virtually identical:
      • 96.2% vs 96.1% (chemo vs no chemo) – HR ~ 0.96; not statistically significant
    • Also:
      • The benefit in premenopausal women:
        • Was consistent across RS levels (0 to 13 and 14 to 25):
          • Though absolute benefit tended to be larger in those with RS 14 to 25
      • The benefit was also seen irrespective of number of positive nodes (1 vs 2 to 3):
        • But, again, the magnitude of benefit varied
  • Secondary / Extended Analyses and Modeling:
    • A modeling study (Wojcik et al., 2024) simulated 10-year distant recurrence-free survival, life-years, and quality-adjusted life-years (QALYs) for women like those in RxPONDER:
      • In premenopausal women:
        • 10-year distant RFS ~ 85.3% with chemo-endocrine therapy vs 80.1% endocrine therapy alone (absolute benefit ~ 5.6%) in the simulation
      • In postmenopausal women:
        • No meaningful benefit; distant RFS practically the same between arms
      • Modeled life-years gained:
        • ~ 2.1 years for premenopausal women; no gain or even small losses for postmenopausal receiving chemotherapy (due to toxicity and side effects) when weighed
    • Another RxPONDER analysis looked at racial / ethnic outcomes:
      • Non-Hispanic Black women had worse 5-year IDFS and DRFS compared to non-Hispanic White women despite similar RS, node numbers, and treatment:
        • Asian women had somewhat better outcomes
      • But chemotherapy efficacy didn’t differ significantly by race
  • Implications / Guidelines Impact:
    • For postmenopausal women with HR+ / HER2- disease, 1 to 3 positive nodes, and RS ≤ 25:
      • Chemotherapy can generally be omitted without compromising IDFS:
        • Endocrine therapy alone is acceptable in most
    • For premenopausal women in the same category:
      • Chemotherapy + endocrine therapy provides meaningful benefit:
        • Omission risks worse IDFS
    • The decision should consider absolute benefit, potential side effects, and patient preferences
    • Also – it is not completely certain how much of the
    • Recurrence Score:
      • Remains a useful tool in node-positive disease (for nodes 1 to 3) to stratify risk and guide therapy
    • Previously, Oncotype DX was used more in node-negative disease (TAILORx):
      • But RxPONDER expands its utility
    • The data supports more personalized treatment – sparing many postmenopausal women unnecessary chemotherapy, reducing overtreatment and its toxicities
  • Things to Remember / Caveats:
    • Follow-up duration:
      • Median ~ 5 years:
        • Longer-term data (10+ years) may reveal differential distant recurrence or survival effects:
          • Especially in HR+ disease which often has late recurrences
    • Chemotherapy regimens, adherence, patient comorbidities:
      • The trial setting may not fully reflect “real world” in all respects – e.g. older women with comorbidity may suffer more chemotherapy toxicity
    • Menopausal status matters:
      • Distinct differences in benefit. Also, in premenopausal women, part of chemotherapy’s benefit may be mediated via ovarian suppression (or ablation), which was not fully controlled for
    • Patient preferences are key:
      • Absolute benefit for many is modest; potential chemotherapy toxicities (short-term and long-term) need weighing
    • RS >25 were excluded – standard indications for chemotherapy remain for high RS or more nodes, etc
  • Key Points:
    • No significant chemotherapy benefit in postmenopausal women:
      • Absolute IDFS gain only ~ 0.6 % at 5 years, hazard ratio ~1.0
    • Clear benefit in premenopausal women:
      • Absolute IDFS gain ~ 4% to 5 %, distant recurrence reduction ~ 3 %, and a small OS improvement (~ 1 %)
      • Benefit was consistent across Recurrence Score 0 to 13 vs 14 to 25 and for 1 vs 2 to 3 positive nodes
  • Clinical implication:
    • Postmenopausal patients with RS ≤ 25 and 1 to 3 positive nodes:
      • Can usually omit adjuvant chemotherapy
    • Premenopausal patients in the same setting should be offered chemotherapy:
      • As the IDFS and DRFS advantages are clinically meaningful
  • Primary source:
    • Kalinsky K et al. N Engl J Med 2021;385:2336-2347 【NEJM doi:10.1056/NEJMoa2108873】
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Published by Rodrigo Arrangoiz MS, MD, FACS, FSSO

My name is Rodrigo Arrangoiz I am a breast surgeon/ thyroid surgeon / parathyroid surgeon / head and neck surgeon / surgical oncologist that works at Center for Advanced Surgical Oncology in Miami, Florida. I was trained as a surgeon at Michigan State University from (2005 to 2010) where I was a chief resident in 2010. My surgical oncology and head and neck training was performed at the Fox Chase Cancer Center in Philadelphia from 2010 to 2012. At the same time I underwent a masters in science (Clinical research for health professionals) at the University of Drexel. Through the International Federation of Head and Neck Societies / Memorial Sloan Kettering Cancer Center I performed a two year head and neck surgery and oncology / endocrine fellowship that ended in 2016. Mi nombre es Rodrigo Arrangoiz, soy cirujano oncólogo / cirujano de tumores de cabeza y cuello / cirujano endocrino que trabaja Center for Advanced Surgical Oncology en Miami, Florida. Fui entrenado como cirujano en Michigan State University (2005 a 2010 ) donde fui jefe de residentes en 2010. Mi formación en oncología quirúrgica y e n tumores de cabeza y cuello se realizó en el Fox Chase Cancer Center en Filadelfia de 2010 a 2012. Al mismo tiempo, me sometí a una maestría en ciencias (investigación clínica para profesionales de la salud) en la Universidad de Drexel. A través de la Federación Internacional de Sociedades de Cabeza y Cuello / Memorial Sloan Kettering Cancer Center realicé una sub especialidad en cirugía de cabeza y cuello / cirugia endocrina de dos años que terminó en 2016.

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