Wednesday, March 29, 2023

Until now, we have focused on the contributions made by Bernie Fisher and his colleagues to the surgical management of breast cancer. But there was another dimension to how breast cancer was to be treated as well. It was recognized that even with surgery, recurrence was common. This occurred because dissemination of disease may have already occurred prior to surgical resection and thus microscopic deposits of tumor may be endangering the future prognosis of the post-surgical patient.

Systemic chemotherapy was utilized for the treatment of metastatic disease in breast cancer. It was clear that it could be efficacious in shrinking visible disease and prolonging life. However, it was equally clear that it was not capable of eliminating metastatic disease altogether and curing the patient. However, there was a theoretical belief that chemotherapy administered for microscopic metastatic disease could be more effective in the eradication of a minimal tumor burden than it was for a visible tumor. Furthermore, while it was already known that combination chemotherapy regimens were generally more effective than single drugs, perhaps a single drug in the adjuvant setting could be effective. If so, subsequent studies could evaluate more complex regimens.

This all led to the initiation of a randomized trial in 1972 that was conducted at 82 institutions across the U.S. and Canada. To be eligible for inclusion in this study, women had to have undergone a mastectomy for localized breast cancer and to have at least one positive lymph node. According to the initial report, published in the New England Journal of Medicine in 1975, 103 women were randomized to L-phenylalanine mustard (L-PAM), an alkylating agent, while 108 women were randomized to a placebo. The risk of recurrence after 16 months was 22% in the placebo group versus 9.7% in the L-PAM group, p=0.01, a greater than 50% reduction in the recurrence rate. The benefits varied depending on the menopausal status of the women, but later studies confirmed chemotherapy benefits for both pre- and postmenopausal patients.

This study demonstrated the proof-of-concept that adjuvant chemotherapy could reduce the risk of recurrence after breast cancer surgery. Over the ensuing 40 years, other chemotherapy drugs have replaced L-PAM, such as Cytoxan (cyclophosphamide), a different alkylating agent, and more elaborate and complex chemotherapy regimens which are more efficacious in reducing risk. But this initial study by Fisher and the NSABP was the first one; in parallel, an Italian group, led by Gianni Bonadonna in Milan, confirmed this concept using a multi-drug regimen known as CMF. Later studies have led to more elaborate and complex regimens, like dose-dense chemotherapy, the current standard of care.

It has also been long recognized that about two-thirds of breast cancers are sensitive to hormones, such as estrogens or progesterone. These breast cancers can be recognized by the presence on their surface of proteins known as estrogen receptor and/or progesterone receptor proteins. Breast cancers that have these proteins on their surfaces and are hormone sensitive can be treated with certain hormonal agents with great success.

A drug that became particularly popular for this purpose was tamoxifen, an anti-estrogenic hormone. It was very effective in the treatment of women with metastatic hormone-responsive breast cancer. Because of this, Fisher and the NSABP initiated a study in 1981 to evaluate the use of tamoxifen as an adjuvant therapy. To be eligible for the trial (protocol B-13), women had to have undergone surgery for an axillary node-negative, estrogen receptor-positive breast cancer. The paper published in the New England Journal of Medicine in 1989 reports that 2644 women were randomized to receive either five years of tamoxifen or placebo. The paper reported that, at four years of follow-up, the tamoxifen group had recurrence in 17% while the placebo group had recurrence in 23%, a 26% reduction in recurrence. Later studies demonstrated that these benefits persisted with further follow-up and that prolongation of tamoxifen out to 10 years was also beneficial.

Additional studies by Fisher and the NSABP demonstrated that adjuvant hormonal therapy was also beneficial for those who were node-positive, that aromatase inhibitors (a different type of hormonal therapy) could be utilized, and that the benefits of combined adjuvant chemotherapy and hormonal therapy could be cumulative. Further studies extended the benefits of adjuvant hormonal therapy to women diagnosed with breast ductal carcinoma in-situ, so this treatment is now standard of care in that setting as well.

The end-result of all these studies is that women with non-metastatic breast cancer are now managed for the most part with limited surgery that is usually followed by adjuvant radiation therapy and some combination of systemic chemotherapy and/or hormonal therapy, depending on the cancer’s hormone receptor status. Another wrinkle is added by the more recent HER2-neu oncogene marker in 20% of patients, a marker that predicts whether they should receive trastuzumab, yet another highly effective addition to the breast cancer adjuvant pharmacopoeia, again studied by NSABP. The disease-free survival and mortality benefits to women with breast cancer, while preserving better quality of life, has been incalculable. And an extraordinary part of the credit has to go to Fisher and the NSABP.

Alfred I. Neugut, MD, PhD, is a medical oncologist and cancer epidemiologist at Columbia University Irving Medical Center/New York Presbyterian and Mailman School of Public Health in New York.

This article is for educational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment, and does not constitute medical or other professional advice. Always seek the advice of your qualified health provider with any questions you may have regarding a medical condition or treatment.

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