- RxPONDER (SWOG S1007):
- Changed adjuvant decision-making for patients with HR-positive, HER2-negative early breast cancer with 1 to 3 positive axillary nodes:
- By showing that the value of chemotherapy depends heavily on menopausal status:
- When the 21-gene recurrence score (Oncotype DX RS) is 0 to 25
- By showing that the value of chemotherapy depends heavily on menopausal status:
- The key practice-changing message is that postmenopausal women with RS 0 to 25:
- Generally do not benefit from adjuvant chemotherapy:
- Whereas premenopausal women with the same RS range do appear to benefit
- Generally do not benefit from adjuvant chemotherapy:
- Changed adjuvant decision-making for patients with HR-positive, HER2-negative early breast cancer with 1 to 3 positive axillary nodes:
- Trial design:
- RxPONDER was a prospective randomized phase III trial enrolling more than 5,000 women with HR-positive, HER2-negative breast cancer, 1 to 3 positive lymph nodes, and an RS of 25 or lower
- Patients were randomized to endocrine therapy alone or chemoendocrine therapy
- The central goal was to determine whether recurrence score could identify node-positive patients who could safely avoid chemotherapy
- Main result:
- In the overall study population, the effect of chemotherapy differed by menopausal status:
- Among postmenopausal women:
- Adding chemotherapy did not improve invasive disease–free survival
- Among premenopausal women:
- Chemotherapy did improve invasive disease–free survival and distant relapse–free survival:
- This interaction is the most important clinical takeaway from the study
- Chemotherapy did improve invasive disease–free survival and distant relapse–free survival:
- Among postmenopausal women:
- Postmenopausal patients:
- For postmenopausal patients with 1 to 3 positive nodes and RS 0 to 25:
- Chemotherapy can usually be omitted without compromising outcomes:
- This is the group in which RxPONDER most clearly supports de-escalation
- For the surgeon, this means that limited nodal positivity alone no longer automatically implies a chemotherapy recommendation in HR-positive / HER2-negative disease
- Chemotherapy can usually be omitted without compromising outcomes:
- For postmenopausal patients with 1 to 3 positive nodes and RS 0 to 25:
- Premenopausal patients:
- For premenopausal patients with 1 to 3 positive nodes and RS 0 to 25:
- Chemotherapy was associated with a statistically significant benefit
- The trial did not prove whether that benefit came from cytotoxic therapy itself, chemotherapy-induced ovarian suppression, or both:
- So multidisciplinary interpretation remains important
- Current NCCN educational guidance reflects this nuance:
- Noting that in premenopausal patients the assay may help frame discussion of alternatives such as ovarian function suppression, but chemotherapy and ovarian suppression are not yet proven interchangeable
- For premenopausal patients with 1 to 3 positive nodes and RS 0 to 25:
- In the overall study population, the effect of chemotherapy differed by menopausal status:
- What it means for the surgical oncologist:
- RxPONDER matters because it directly affects postoperative counseling after lumpectomy or mastectomy when final pathology shows 1 to 3 positive nodes
- The surgeon should anticipate genomic testing in appropriate ER-positive / HER2-negative patients and should understand that:
- Node-positive does not automatically mean chemotherapy
- Menopausal status is central to interpretation:
- In postmenopausal patients with RS 0 to 25:
- Chemotherapy can often be avoided
- In premenopausal patients with RS 0–25:
- Chemotherapy is still generally recommended unless the medical oncology discussion supports a different endocrine-based strategy
- In postmenopausal patients with RS 0 to 25:
- Practical surgical takeaway:
- For a surgical oncologist:
- RxPONDER shifts the conversation from “How many nodes are positive?” to “What is the biology, and is the patient premenopausal or postmenopausal?”
- In modern breast practice, a patient with 1 to 3 positive nodes and favorable genomics may still avoid chemotherapy if she is postmenopausal:
- But a similar premenopausal patient usually still merits strong consideration of chemotherapy
- For a surgical oncologist:
- Bottom line:
- RxPONDER showed that for HR-positive, HER2-negative early breast cancer with 1 to 3 positive nodes and Oncotype DX RS 0 to 25, postmenopausal women do not derive meaningful chemotherapy benefit, while premenopausal women do:
- That is the key message that should guide surgical counseling and multidisciplinary adjuvant planning
- RxPONDER showed that for HR-positive, HER2-negative early breast cancer with 1 to 3 positive nodes and Oncotype DX RS 0 to 25, postmenopausal women do not derive meaningful chemotherapy benefit, while premenopausal women do:
- Key references:
- Kalinsky K, Barlow WE, Gralow JR, et al. 21-Gene Assay to Inform Chemotherapy Benefit in Node-Positive Breast Cancer. N Engl J Med. 2021;385:2336-2347.
- NCCN educational update on biomarkers in early-stage breast cancer, summarizing current use of the 21-gene assay in node-positive disease.
Rodrigo Arrangoiz MS, MD, FACS, FSSO 