by Valentina Guarneri, MD, PhD

The article “Adjuvant capecitabine for early breast cancer: 15-year overall survival results from a randomized trial”, by Joensuu and colleagues, reported the protocol-scheduled analysis of overall survival (OS) at 15-year follow-up of the FinXX trial, which was designed to evaluate the role of incorporating capecitabine into sequential anthracycline/taxane-based chemotherapy for patients with node positive or high-risk node negative early breast cancer (EBC).¹ The results of the primary end point, recurrence-free survival (RFS), were published in 2009 after an interim analysis triggered by events, showing a significant reduction in the risk of relapse for the capecitabine-containing arm.² These results were observed after 35 months of median follow-up. The final analysis, after a median follow-up time of 59 months, did not confirm the RFS benefit for capecitabine in the ITT population.³ However, exploratory analyses suggested improved RFS and breast cancer-specific survival in patients with triple-negative (TN) disease and in patients with more than three positive nodes.³ Now, after approximately 15 years of median follow-up, the authors have reported a significant OS benefit, which was more marked, and possibly more meaningful, in estrogen receptor (ER)-negative, human epidermal growth factor receptor 2 (HER2)-negative, and TN subgroups.

The FinXX study is based on a strong biological background, is robust from a methodological standpoint, and now has enough mature follow-up data to be considered definitive. However, are these results going to impact the current scenario of adjuvant treatment of EBC? Probably not. In the past decade, a number of new strategies have progressively set new standards in all biological breast cancer subtypes. Dose-dense scheduling of standard anthracycline/taxane regimens significantly reduced the risk of recurrence and death from breast cancer without increasing mortality from other causes, and is endorsed by current guidelines as one of the options for intermediate-high risk patients.⁴ With 12% of HER2-positive patients only receiving adjuvant trastuzumab, the data from this subset have been overcome by later data. Besides trastuzumab, current standards now include dual HER2 blockade with trastuzumab-pertuzumab in combination with chemotherapy, as well as the post-neoadjuvant strategy with T-DM1 in patients without pathologic complete response.^5,6 In hormone receptor (HR)-positive disease, enhancing endocrine targeting with ovarian function suppression in premenopausal women, or prolonging treatment beyond 5 years is now routinely discussed with intermediate-high risk patients. More recently, abemaciclib combined with standard endocrine treatment significantly reduced disease-free survival (DFS) and distant-DFS in high-risk EBC.⁷ Given the role of endocrine manipulation in luminal subtypes, we can assume a resizing of the impact of escalation on chemotherapy. Even in the TN subtype, where the OS benefit described by the FinXX study is more pronounced, the optimal adjuvant strategy has recently been totally redefined. Given the paramount prognostic relevance of response to neoadjuvant therapy, the stage threshold for offering preoperative chemotherapy has progressively reduced over time. The possibility of offering post-neoadjuvant therapy to sub-optimal responders, as demonstrated with capecitabine in the create-X trial, has further increased the proportion of TN patients who are offered a neoadjuvant strategy aiming at a more personalized approach.⁸ More recently, adding pembrolizumab to a chemotherapy backbone including platinum salts significantly increased pathologic complete response as well as DFS.⁹ Last but not least, the Olympia trial demonstrated DFS and OS benefit for adjuvant olaparib in patients with gBRCA-mutant HER2-negative tumors.¹⁰

Nonetheless, the results of this study remain important for the oncology community. Indeed, the constant improvement in cancer care is paralleled by a constant increase in the financial burden, and disparities in drug access will inevitably increase. The new strategies described above will, unfortunately, only be available for a limited proportion of breast cancer patients diagnosed worldwide. Therefore, incorporating capecitabine into the chemotherapy plan will probably save a lot of lives.

 

References

1. Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, et al. Adjuvant Capecitabine for Early Breast Cancer: 15-year Overall Survival Results from a Randomized Trial. J Clin Oncol 2022;40(10):1051-8.
2. Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, et al. Adjuvant capecitabine in combination with docetaxel and cyclophosphamide plus epirubicin for breast cancer: an open-label, randomised controlled trial. Lancet Oncol 2009;10(12):1145–51.
3. Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, et al. Adjuvant capecitabine, docetaxel, cyclophosphamide, and epirubicin for early breast cancer: Final analysis of the randomized FinXX trial. J Clin Oncol 2012;30(1):11-8.
4. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Increasing the dose intensity of chemotherapy by more frequent administration or sequential scheduling: a patient-level meta-analysis of 37298 women with early breast cancer in 26 randomised trials. Lancet 2019;393(10179):1440–52.
5. von Minckwitz G, Procter M, de Azambuja E, et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med 2017;377(2):122-131.
6. von Minckwitz G, Huang CS, Mano MS, et al. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N Engl J Med 2019;380(7):617-628.
7. Harbeck N, Rastogi P, Martin M, et al. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study. Ann Oncol 2021;32(12):1571-81.
8. Masuda N, Lee SJ, Ohtani S, et al. Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy. N Engl J Med 2017;376(22):2147-59.
9. Schmid P, Cortes J, Dent R, et al. Event-free Survival with Pembrolizumab in Early Triple-Negative Breast Cancer. N Engl J Med 2022;386(6):556-67.
10. Tutt ANJ, Garber J, Gelber RD, et al. Pre-specified event driven analysis of overall survival (OS) in the Olympia Phase III trial of adjuvant olaparib (OL) in germline BRCA1/2 mutation (gBRCAm) associated breast cancer. ESMO virtual plenar 2022.