 UNIRAD (NCT01805271): Safety Study of Adding Everolimus to Adjuvant Hormone Therapy in Women With High Risk of Relapse, ER+ and HER2- Primary Breast Cancer, Free of Disease After Receiving at Least One Year of Adjuvant Hormone Therapy (Official Title: Randomized, Double Blind, Multicentric Phase III Trial Evaluating the Safety and Benefit of Adding Everolimus to Adjuvant Hormone Therapy in Women With High Risk of Relapse, ER+ and HER2- Primary Breast Cancer Who Remain Free of Disease After Receiving at Least 1 Year of Adjuvant Hormone Therapy)
EBioMedicine. 2024 May 7;104:105141. IF: 11.1 Association between endocrine adjuvant therapy intake timing and disease-free survival in patients with high-risk early breast cancer: results of a sub-study of the UCBG-UNIRAD trial. Sylvie Giacchetti, Enora Laas, Thomas Bachelot, Jérome Lemonnier, Fabrice André, David Cameron, Judith Bliss, Sylvie Chabaud, Anne-Claire Hardy-Bessard, Magali Lacroix-Triki, Jean-Luc Canon, Marc Debled, Mario Campone, Paul Cottu, Florence Dalenc, Annabelle Ballesta, Frederique Penault-Llorca, Bernard Asselain, Elise Dumas, Fabien Reyal, Paul Gougis, Francis Lévi, Anne-Sophie Hamy. Hopital Saint Louis, Paris, France; Paris-Saclay University, Villejuif, France; Institut Curie, Universite Paris Cite, Paris, France; Centre Leon Berard, Lyon, France; R&D Unicancer, Paris, France; Gustave Roussy, Villejuif, France; CARIO, Plerin, France; Institut Bergonie, Bordeaux, France; Institut Cancerologie de l’Ouest, Saint Herblain, France; Oncopole Claudius Regaud, IUCT, Toulouse, France; Institut Curie, Saint Cloud, France; Centre Jean Perrin, Université Clermont Auvergne, Clermont Ferrand, France; Arcagy-Gineco, Paris, France; Universite Paris Cité, Paris, France; The Institute of Cancer Research, London, United Kingdom; Western General Hospital, Edinburgh, United Kingdom; Grand Hopital de Charleroi, Charleroi, Belgium; Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. BACKGROUND: Circadian rhythms regulate cellular physiology and could influence the efficacy of endocrine therapy (ET) in breast cancer (BC). We prospectively tested this hypothesis within the UNIRAD adjuvant phase III trial (NCT01805271). METHODS: 1278 patients with high-risk hormonal receptor positive (HR+)/HER2 negative (HER2-) primary BC were randomly assigned to adjuvant ET with placebo or everolimus. Patients prospectively reported in a diary the daily timing of ET intake among four 6-h slots (06:00-11:59 (morning), 12:00-17:59 (afternoon), 18:00-23:59 (evening), or 24:00-05:59 (nighttime). The association between ET timing and disease-free survival (DFS) was a prespecified secondary endpoint of the trial and the results of this observational study are reported here. FINDINGS: ET timing was recorded by 855 patients (67.2%). Patients declaring morning (n = 465, 54.4%) or afternoon (n = 45, 5.4%) ET intake were older than those declaring evening (n = 339, 39.6%) or nighttime (n = 5, 0.6%) intake. With a median follow-up of 46.7 months, 118 patients had a local (n = 30) or metastasis relapse (n = 84), and 41 patients died. ET intake timing was not associated with DFS in the whole population (HR = 0.77, 95% CI [0.53-1.12]). The association between ET intake timing and DFS according to the stratification factors revealed interactions with ET agent (tamoxifen versus Aromatase inhibitors (AI) with an increased DFS in the group of evening/nighttime versus morning/afternoon tamoxifen intake (HR = 0.43, 95% CI [0.22-0.85]), while no association was found for AI intake (HR = 1.07, 95% CI [0.68-1.69]). The interaction between ET intake timing and ET agent remained in multivariable analysis (HR = 0.38 [0.16-0.91]). INTERPRETATION: Tamoxifen intake in the evening/nighttime could be recommended in patients with high-risk HR+/HER2- BC while awaiting for results from further ET timing studies. FUNDING: UNIRAD was Supported by a grant from the French Ministry of Health PHRC 2012 and received funding from La Ligue contre le Cancer, Cancer Research-UK, Myriad Genetics, and Novartis. EVIDENCE BEFORE THIS STUDY: 'Endocrine therapy (ET) has remained the cornerstone for the treatment of patients with HR + BC since the 80's. In the adjuvant setting, nearly 20% of the patients relapse despite the daily oral intake of tamoxifen or aromatase inhibitors. The timing of medications can largely moderate tolerability and efficacy, as shown for cancer chemotherapy, radiotherapy and immunotherapy. However, the possible relevance of ET daily timing for efficacy is largely unknown, despite the timing of ET intake is a frequent question asked to their physicians by the patients with breast cancer. ADDED VALUE OF THIS STUDY: Considering the scarcity of data on the influence of timing of ET intake as adjuvant treatment for patients with HR+/HER2-breast cancer, we investigated this issue through a pre-planned ancillary ET intake timing study within a large prospective randomized controlled UNIRAD trial (NCT01805271). Between June 2013 and March 2020, 1278 patients with HR+/HER2-high-risk early BC patients were randomized to receive ET with placebo or everolimus, a mammalian target of rapamycin (mTOR) inhibitor. The patients were asked to prospectively record the timing of ET intakes in a daily diary during their expected 2-year participation in the trial. The UNIRAD study did not demonstrate any therapeutic benefit of the combination of Everolimus with ET. Of the 855 patients who participated in this preplanned sub study, only 1% of the patients changed ET intake timing during the planned 2 years of their participation. Strikingly, tamoxifen intake in the evening or at night was independently associated with a significant prolongation of Disease-Free Survival as compared to morning or afternoon intake with a Hazard Ratio of 0.43 [95% CI, 0.22-0.85]. In contrast, no timing effect was found for aromatase inhibitors efficacy. Our results for tamoxifen are consistent with the larger metastatic potential of circulating breast cancer cells at night, and the frequent dampening of circadian rhythms in older women. IMPLICATIONS OF ALL THE AVAILABLE EVIDENCE: In the absence of any current guidelines, tamoxifen oral intake could be recommended in the evening for patients with HR+/HER2- breast cancer, especially in the younger women. This prospective and hypothesis-generating timing study stresses the need for further chronotherapeutic trials testing endocrine therapies in patients with breast cancer and for elucidating the circadian mechanisms at work. KEYWORDS: Breast cancer, Endocrine therapy, Tamoxifen, Aromatase inhibitors, Circadian rhythm, Intake timing, Chronotherapy DOI: 10.1016/j.ebiom.2024.105141    |
|
|
