Low-Dose Tamoxifen in Noninvasive Breast Neoplasia: Long-Term Results From an Individual-Participant Data Pooled Analysis

Author(s): Sara Gandini, PhD¹; Aliana Guerrieri-Gonzaga, MSc²; Davide Serrano, MD²; Roberta Rizzo, MSc¹; Matteo Lazzeroni, MD²; Matteo Puntoni, PhD³; Tania Buttiron Webber, RN⁴; Gaetano Aurilio, MD, PhD²; Harriet Johansson, MSc²; Alessio Carbone, PhD⁴; Livia Giordano, MD⁵; Maria Digennaro, MD⁶; Laura Cortesi, MD^7,8; Francesco Millo, MD⁹; Katia Cagossi, MD¹⁰; Giuseppe Aprile, MD^11,12; Patrizia Serra, MSc¹³; Elisa Gallerani, MD¹⁴; Marcio Debiasi, MD, PhD¹⁵; Berta Sousa, MD¹⁵; Pedro Gouveia, MD, PhD¹⁵; Bernardo Bonanni, MD²; Andrea DeCensi, MD^4,15;

Source: DOI: 10.1200/JCO-26-00841

Dr. Maen Hussein's Thoughts

Among 1,545 women included with a median follow-up of 9.4 years in postmenopausal women, breast cancer events occurred in 40 of 335 receiving low-dose tamoxifen versus 93 of 401 controls HR, 0.51, with a 10-year absolute reduction of 11.2%. Among premenopausal women, no significant reduction was observed dose was 5mg daily of 10mg every other day in ductal carcinoma in situ (DCIS) and high-risk pts. Less is as good.

PURPOSE

Tamoxifen 20 mg once-daily reduces the risk of breast cancer recurrence after ductal carcinoma in situ (DCIS), but its use is limited by adverse effects. Lower doses may be effective, but benefit durability and differences according to menopausal status and site of recurrence remain uncertain.

METHODS

We conducted an individual-participant pooled analysis of three clinical studies involving women with estrogen receptor–positive or unknown DCIS, microinvasive carcinoma, or high-risk breast lesions. Participants received low-dose tamoxifen (5 mg once daily or 10 mg once-every other day for 2-5 years) or a control intervention. The primary end point was breast cancer–free interval, defined as the first occurrence of any ipsilateral or contralateral invasive breast cancer, DCIS, regional recurrence, or distant recurrence. Hazard ratios (HRs) were estimated with mixed-effects Cox models accounting for between-study variability.

RESULTS

Among 1,545 women included with a median follow-up of 9.4 years, low-dose tamoxifen reduced breast cancer events overall, with evidence of treatment heterogeneity according to menopausal status (P = .01). In postmenopausal women, breast cancer events occurred in 40 of 335 receiving low-dose tamoxifen versus 93 of 401 controls (HR, 0.51 [95% CI, 0.35 to 0.73]), with a 10-year absolute reduction of 11.2%. Among premenopausal women, no significant reduction was observed (HR, 0.90 [95% CI, 0.70 to 1.17]), although contralateral breast cancer was reduced (HR, 0.45 [95% CI, 0.26 to 0.76]). Serious adverse events were infrequent and similar between groups.

CONCLUSION

Low-dose tamoxifen was associated with a sustained reduction in breast cancer events, with differences by menopausal status and site of event. These findings support endocrine dose de-escalation to improve the benefit-risk profile of preventive therapy in DCIS and high-risk lesions.

Author Affiliations

¹Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy; ²Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology, IRCCS, Milan, Italy; ³Clinical and Epidemiological Research Unit, University Hospital of Parma, Parma, Italy; ⁴Medical Oncology Unit, EO Ospedali Galliera, Genoa, Italy; ⁵CPO-Piedmont—AOU Città della Salute e della Scienza, Turin, Italy; ⁶IRCCS, Istituto Tumori “Giovanni Paolo II”, Bari, Italy; ⁷Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy; ⁸UOC Oncologia, Azienda USL-IRCCS Reggio Emilia, Reggio Emilia, Italy; ⁹Ospedali Riuniti ASL — Ospedale SS Antonio e Margherita, Tortona (AL), Italy; ¹⁰Oncology and Palliative Care Unit, Civil Hospital Carpi, USL, Carpi, Italy; ¹¹Department of Oncology, San Bortolo General Hospital, Azienda ULSS8 Berica, Vicenza, Italy; ¹²Department of Oncology, Academic Hospital of Udine ASUFC, Udine, Italy; ¹³IRCCS Istituto Romagnolo per lo Studio dei Tumori “Dino Amadori”-IRST S.r.l., Meldola (FC), Italy; ¹⁴Aziende Socio Sanitarie Territoriale dei Sette Laghi, Varese, Italy; ¹⁵Breast Department, Champalimaud Clinical Centre, Lisbon, Portugal

Datopotamab deruxtecan in patients with untreated, advanced triple-negative breast cancer (TROPION-Breast02): a randomised, open-label, international, phase III trial

644 patients who are triple-negative breast cancer (TNBC) not candidates for immunotherapy were randomly assigned to receive Dato-DXd (n = 323) or chemotherapy (n = 321). Median progression-free survival (PFS) was 10.8 months with Dato-DXd and 5.6 months with chemotherapy. Median overall survival (OS) was 23.7 months and 18.7 months with Dato-DXd and chemotherapy, respectively HR 0.79; P = 0.029]. Treatment-related adverse events (TRAEs) of grade ≥3 were reported in 105 (33%) and 89 (29%) patients who received Dato-DXd and chemotherapy, respectively, they were more treatment discontinuation in the chemotherapy arm secondary to treatment related adverse events in 14 (4%) and 23 (7%) patients. There were no treatment-related deaths in either arm. New standard of care? Recall this is on patients not eligible for immunotherapy.

Hypo- Versus Standard Fractionated Locoregional Radiotherapy of Patients With High-Risk Breast Cancer in the Randomized Phase III Trial: The Danish Breast Cancer Group Skagen Trial 1

Less radiation (40Gy vs 50 Gy) was non inferior in preventing locoregional recurrence and distant mets, also lymphedema rates were not worse. Would love feedback from our rad onc, but it seems less is as good.

HER2CLIMB-05: A Phase III Study of Tucatinib Versus Placebo in Combination With Trastuzumab and Pertuzumab as First-Line Maintenance Therapy for HER2+ Metastatic Breast Cancer

Progression-free survival (PFS) was statistically significantly improved with addition of tucatinib versus placebo 24.9 v 16.3 months regardless of the presence/absence of BM or hormone receptor status.

Role of neoadjuvant versus adjuvant chemotherapy, dose density, and treatment schedule in biologically high-risk HR+/HER2- breast cancer: A pooled analysis of the WSG ADAPT-HR+/HER2- and PlanB trials.

1467 pts with RS > 25 and 551 with clinically (neoadjuvant cohort in ADAPT-HR+/HER2-) or pathologically N2, (longer) docetaxel-based CTx showed better distant, invasive disease-free survival in N2-3 pts patients with RS ≤25, OS was also shown in pts with RS>25 anthracycline regimens did not show a significant survival difference in high-risk HR+/HER2 whether used in neoadjuvant or adjuvant setting. So may be no anthracycline for HR+ve pts who are high risk disease.

The Pathologic Response Evaluation and Detection in Circulating Tumor-DNA Study: Ultrasensitive Circulating Tumor-DNA Assessment of Breast Cancer Minimal Residual Disease

Primary objective not met, ctDNA clearance post- neoadjuvant therapy (NAT) cannot reliably predict pathologic complete response (pCR) and shouldn't be used to defer surgery. But the prognostic data are striking: post-NAT ctDNA positivity independently predicted recurrence in triple-negative breast cancer (TNBC) (HR 8.9), and the postsurgical landmark analysis is essentially binary, 100% of ctDNA-positive patients recurred while 94% of ctDNA-negative patients were disease-free at 5 years (HR 128). Not practice-changing yet pending prospective utility trials, but this strongly validates ultrasensitive ctDNA as a prognostic tool and a smart enrollment biomarker for future escalation/de-escalation trials.