Turning scientific serendipity into discoveries in breast cancer research and treatment: a tale of PhD students and a 50-year roaming tamoxifen team

Purpose This retrospective, about a single “mobile” laboratory in six locations on two continents, is intended as a case study in discovery for trainees and junior faculty in the medical sciences. Your knowledge of your topic is necessary to expect the unexpected. Historical method In 1972, there was no tamoxifen, only ICI 46, 474, a non-steroidal anti-estrogen with little chance of clinical development. No one would ever be foolish enough to predict that the medicine, 20 years later, would achieve legendary status as the first targeted treatment for breast cancer, and millions of women would benefit from long-term adjuvant tamoxifen therapy. The secret of tamoxifen’s success was a translational research strategy proposed in the mid 1970’s. This strategy was to treat only patients with estrogen receptor (ER)-positive breast cancer and deploy 5 or more years of adjuvant tamoxifen therapy to prevent recurrence. Additionally, tamoxifen prevented mammary cancer in animals. Could the medicine prevent breast cancer in women? Results Tamoxifen and the failed breast cancer drug raloxifene became the first selective estrogen receptor modulators (SERMs): a new drug group, discovered at the University of Wisconsin, Comprehensive Cancer Center. Serendipity can play a fundamental role in discovery, but there must be a rigorous preparation for the investigator to appreciate the possibility of a pending discovery. This article follows the unanticipated discoveries when PhD students “get the wrong answer.” The secret of success of my six Tamoxifen Teams was their technical excellence to create models, to decipher mechanisms, that drove the development of new medicines. Summary of advances Discoveries are listed that either changed women’s health or allowed an understanding of originally opaque mechanisms of action of potential therapies. These advances in women’s health were supported entirely by government-sponsored peer-reviewed funding and major philanthropy from the Lynn Sage Breast Cancer Foundation, the Avon Foundation, and the Susan G. Komen Breast Cancer Foundation. The resulting lives saved or extended, families aided in a time of crisis and the injection of billions of dollars into national economies by drug development, is proof of the value of Federal or philanthropic investment into unencumbered research aimed at saving millions of lives.

Prognostic impact of co-expression of LLCL2 and SLC7A5 in ERα-positive breast cancer patients

Background Lethal giant larvae homolog 2 (LLGL2) functions as a promoter of tumor growth and localizes at cell junctions and membranes with solute carrier family 7 member 5 (SLC7A5) in estrogen receptor α (ERα)-positive breast cancer. LLGL2 and SLC7A5 have been reported to be involved in resistance to endocrine therapy. This study aimed to assess the effects of LLGL2/SLC7A5 co-expression in predicting prognosis and response to endocrine therapy in ERα-positive breast cancer patients. Methods The associations of clinicopathological factors with LLGL2 and SLC7A5 expression or LLGL2/SLC7A5 co-expression at the mRNA and protein level were assessed in invasive breast cancer patients with long-term follow-up. The median follow-up period was approximately10 years. Survival curves were analyzed using the Kaplan–Meier method and verified by the log-rank test. A Cox proportional hazards regression analysis was used for univariate and multivariate analyses of prognostic values using stepwise linear regression. Results We identified a positive association between low mRNA expression of LLGL2 or SLC7A5 alone and longer disease-free survival (DFS) and overall survival (OS) in ERα-positive breast cancer patients, but not in ERα-negative patients. We also identified that low LLGL2/SLC7A5 mRNA co-expression (LLGL2low/SLC7A5low) was associated with longer survival compared with other combination groups in all breast cancer patients. In ERα-positive breast cancer patients, LLGL2low/SLC7A5low showed longer survival compared with LLGL2high/SLC7A5high and a positive trend of longer survival compared with other combination groups. We also observed that LLGL2low/SLC7A5low showed longer survival compared with LLGL2high/SLC7A5high in ERα-positive breast cancer patients receiving adjuvant tamoxifen therapy. Multivariate analysis demonstrated that LLGL2low/SLC7A5low was an independent favorable prognostic factor of both DFS and OS in ERα-positive breast cancer patients. High co-expression of LLGL2 and SLC7A5 protein showed a positive trend of shorter survival. Conclusions Our study showed that co-expression of LLGL2 and SLC7A5 mRNA is a promising candidate biomarker and suggested that the LLGL2–SLC7A5 axis may be a therapeutic target in early breast cancer patients, especially in those receiving adjuvant tamoxifen therapy.

Adverse effects of adjuvant tamoxifen treatment on bone mineral density in premenopausal breast cancer patients: A systematic review and meta-analysis.

e12500 Background: It is well known that adjuvant tamoxifen treatment for breast cancer in postmenopausal women decreases bone loss. However, the adverse effect of adjuvant tamoxifen therapy for bone mineral density (BMD) in premenopausal breast cancer patients remains uncertain. This meta-analysis aimed to assess the effects of adjuvant tamoxifen therapy on BMD changes in premenopausal women with primary breast cancer. Methods: Through April 2020, studies reporting BMD changes of lumbar spine or hip in premenopausal women with primary breast cancer treated with adjuvant tamoxifen were collected from EMBASE and PubMed. The pooled analysis was performed using random effects model of the standardized mean difference (SMD) of BMD in patients. Results: A total of 1,432 premenopausal patients from eight studies were included in the pooled analysis. After 3 years of median follow up, adjuvant tamoxifen therapy decreased BMD by as much as SMD of -0.79 [95% confidence interval (CI); -1.25 to -0.33, P < 0.01] at lumbar spines and -0.38 at hip (95%CI; -0.88 to 0.12, P > 0.05). Compared with patients received tamoxifen alone, patients who received combination therapy with chemotherapy or ovarian function suppression (OFS) showed decreased bone loss at lumbar spine (SMD -1.17 with 95%CI -1.59 to -0.75, -0.43 with 95%CI -2.26 to 1.40, and -0.75 with 95%CI -1.38 to -0.13, respectively). Conclusions: Our meta-analysis revealed that premenopausal women who received adjuvant tamoxifen treatment showed significant bone loss over a period of time, especially at lumbar spine. However, tamoxifen attenuated bone loss in those who received tamoxifen after chemotherapy or along with OFS.[Table: see text]

Efficacy of AI and palbociclib in ER+ HER2- advanced breast cancer patients relapsing during adjuvant tamoxifen: An exploratory analysis of the PADA-1 trial.

1070 Background: In PADA-1 (NCT03079011), a phase III trial testing the clinical utility of ESR1mut detection, ER+ HER2- advanced breast patients (ABC pts) received Aromatase Inhibitor (AI) and Palbociclib (Pal) +/- LHRH agonist as first line therapy. PADA-1 was open to “AI-sensitive” pts, including those with de novo stage IV disease or metastatic relapse after adjuvant endocrine therapy but also pts with metastatic relapses during adjuvant tamoxifen (TAM). In this subsidiary analysis, we report the efficacy of AI+PAL as first line therapy in patients relapsing on adjuvant TAM. Methods: Main inclusion criteria in PADA-1 are: pre- or post-menopausal pts with ER+ HER2- ABC, who did not receive any prior therapy for ABC and who had no adjuvant AI or completed adjuvant AI for > 12 months or who had disease recurrence while on adjuvant TAM. Results: From 04/2017 to 01/2019, 1017 ABC pts have been included in PADA-1, of which 115 (11.3%) had a metastatic relapse while on adjuvant TAM (TAM only (N = 112) or TAM+GnRH agonist (N = 3)). Median age at inclusion was 46 years (range 25-81), and 58 (50.4%) patients had visceral disease. The median PFS under AI+PAL was 20.4 months (95%CI16.1;27.8) in patients relapsing during adjuvant TAM. In contrast, median PFS in patients with de novo metastatic disease and metastatic relapses after the completion of adjuvant endocrine therapy were 30.6 months (95%CI26.7;Not reached) and 27.8 months (95%CI24.1;30.)], respectively. A subgroup analysis among patients relapsing on adjuvant TAM showed that those relapsing during the first two years of adjuvant TAM had a shorter PFS (11.4 months 95%CI[8.7;20.7]) than those relapsing after 2 years of adjuvant TAM (23.8 months 95%CI[20.2;Not reached]). Conclusions: To our knowledge, these are the first data on first line AI+CDK4/6 inhibitor in patients relapsing on adjuvant TAM. While PFS on AI + PAL appears primarily driven by endocrine resistance status, our data show that AI+PAL is a valuable option also in patients relapsing during adjuvant TAM. Clinical trial information: NCT03079011 .