The Most Important Step Toward Chemotherapy-Free Breast Cancer Treatment in Postmenopausal Women

Chemotherapy can now be avoided with greater confidence in patients with early-stage breast cancer. The large phase-3 trial presented at the 2020 San Antonio Breast Cancer Symposium (SABCS), RxPONDER, attracted considerable attention. An interim analysis with a median follow-up of 5 years was presented at the symposium.

Summarizing the study, the researchers reported that, among women with a low-risk Oncotype Dx gene score, node-positive, hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) postmenopausal breast cancer, adding chemotherapy to hormone suppression therapy did not improve disease outcomes compared with hormonal therapy alone.

Note: Oncotype Dx test results are reported between 0 and 100 as a Recurrence Score. A low score indicates a low likelihood of cancer recurrence, and a high score indicates a high likelihood. The score also gives patients and doctors important information about the potential benefit of adding chemotherapy to hormone therapy. 

The results of RxPONDER are similar to those obtained in the TAILORx trial. Results from this trial were first presented in 2018, and practice changed for women with no lymph node involvement and early-stage disease (see How do we identify patients who will not receive chemotherapy after breast cancer surgery?)

Treatment of breast cancer with lymph node metastasis has changed

RxPONDER has taken its place in oncology history as a practice-changing study. Data from RxPONDER are the most important clinical data presented at this year’s San Antonio Breast Cancer Symposium.

The study’s lead author Dr. Kevin Kalinsky, emphasized that the study presented many challenges: it also included premenopausal women with the same disease characteristics who were found to benefit from chemotherapy.

It was unclear whether the benefit in these younger women came from chemotherapy’s cytotoxicity (cell-killing effect) or its hormonal effects / ovarian suppression (limiting production of estrogen, which stimulates breast cells). However, many experts argued that the effect most likely came from ovarian suppression. There are, nevertheless, less toxic ways than chemotherapy to suppress ovarian function.

Although the data are quite clear for postmenopausal node-positive women, they may be insufficient for premenopausal women. Nevertheless, it is difficult to say that all premenopausal patients [with a low gene score and positive nodes] should receive chemotherapy.

RxPONDER patients will be followed for 15 years, so additional data and insights will also be followed.

Treatment decisions should be reviewed for patients with a small number of positive lymph nodes

RxPONDER, also known as SWOG S1007, included women with HR+, HER2-negative breast cancer and one to three positive lymph nodes — more than 5000 women. Their results from the 21-tumor-gene expression test (Oncotype Dx) were low risk, meaning a recurrence score ≤25.

Metastatic disease was absent in these women with HR+, HER2- breast cancer, approximately 20% of whom have one to three involved lymph nodes. In Turkey, this proportion corresponds to a decision affecting approximately 2 to 3 thousand women every year.

Study results

• Participants were randomly assigned to receive standard chemotherapy plus hormonal therapy or hormonal therapy alone. Follow-up averaged 5 years before the current preplanned analysis.
• At a median follow-up of 5.1 years, 447 disease-free survival events were observed. This chosen primary endpoint represents 54% of the number expected in the final analysis.
• Across the entire patient group, adding chemotherapy to hormonal therapy was associated with improved disease-free survival, 92.4% versus 91.0% ( P = .026).
• However, in postmenopausal women no such improvement was seen. The 5-year disease-free survival rate was 91.6% with chemotherapy plus hormonal therapy and 91.9% with hormonal therapy alone ( P = .82).
• Improved disease-free survival was reported among premenopausal women. The 5-year rate was 94.2% with chemotherapy plus hormonal therapy versus 89.0% with hormonal therapy alone ( P = .0004).
• These differences were reflected in overall survival outcomes. Among postmenopausal women, 5-year overall survival rates did not differ (96.2% versus 96.1%).
• In contrast, there was a significant difference in 5-year overall survival among premenopausal women (98.6% versus 97.3%; P=.032).
• Stratifying patients by Oncotype Dx recurrence score, 0-13 versus 14-25, and by one versus two to three positive lymph nodes was said to have no significant impact on the results. It was also noted that future analyses would include quality of life.

More information about hormonal therapy in RxPONDER

Premenopausal women in RxPONDER were said to have "almost always" been prescribed tamoxifen.

However, the current standard treatment approach for this age group is not tamoxifen alone; it is ovarian suppression plus an aromatase inhibitor or tamoxifen. Combination treatments with ovarian suppression are now known to be superior to tamoxifen alone.

Note: In premenopausal patients, ovarian suppression is achieved by one of these 3 methods: surgical removal of the ovaries, radiotherapy to the ovaries, or monthly injections.

Adjuvant chemotherapy suppresses ovarian function in many premenopausal patients, so these patients should subsequently be regarded as having received ovarian suppression plus tamoxifen, rather than tamoxifen alone in the group not receiving chemotherapy.

Of course, we cannot know at present whether the difference in outcomes in this subgroup is due to chemotherapy’s hormonal effects.

The difference in chemotherapy benefit in premenopausal women could also arise from possible biological differences between premenopausal tumors and tumors in postmenopausal women.

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Conclusion

Assessing the genetic makeup of the patient/tumor is becoming increasingly important in cancer treatment decisions. In conclusion, the RxPONDER study shows that chemotherapy can safely be avoided in postmenopausal women with hormone-positive, HER2-negative breast cancer and 1-3 positive lymph nodes if their tumor’s Oncotype Dx recurrence score is low risk.