Sleep quality commonly deteriorates in people receiving chemotherapy for breast cancer (BC). We aimed to determine feasibility and acceptability of telehealth-delivered cognitive behaviour therapy for insomnia (CBT-I) in people with early BC receiving (neo)adjuvant chemotherapy. Multi-centre, single arm, phase 2 feasibility trial. People with stage I-III BC received 4 sessions of telehealth CBT-I over 8 weeks, during chemotherapy. Participants completed Pittsburgh Sleep Quality Index (PSQI) and other Patient Reported Outcome Measures (PROMs) at baseline, post-program (week 9) and post-chemotherapy (week 24); and an Acceptability Questionnaire at week 9. Primary endpoint was proportion completing 4 sessions of telehealth CBT-I. In total, 41 participants were recruited: mean age 51 years (range 31–73). All 4 CBT-I sessions were completed by 35 (85

WinPro: A window of opportunity study of endocrine therapy with and without prometrium in postmenopausal women with early-stage hormone receptor-positive breast cancer Authors Teesha Downton1,2,3, Davendra Segara3, Andrew Ong4, Janne Bingham5, Emma-Kate Carson4, Julia Chen1,2,3, Kate Middleton3, Geoffrey Lindeman6, Andrew Parker3, Elgene Lim1,2,3. Affiliations 1Garvan Institute of Medical Research, Darlinghurst NSW, Australia; 2School of Clinical Medicine, St Vincent’s Healthcare Clinical Campus, Faculty of Medicine and Health, University of New South Wales Sydney, Australia; 3St Vincent’s Hospital Sydney, Darlinghurst NSW, Australia; 4Campbelltown Hospital, Campbelltown NSW, Australia; 5Royal Adelaide Hospital, Adelaide SA, Australia; 6Walter & Eliza Hall Institute of Medical Research, Parkville VIC, Australia Disclosures T. Downton: None. D. Segara: None. A. Ong: None. J. Bingham: None. E. Carson: None. J. Chen: None. K. Middleton: None. G. Lindeman: None. A. Parker: None. E. Lim: Advisory Board for Pfizer, Astra Zeneca, Lilly, Roche, Novartis, Gilead Australia. Research Funding from Pfizer, Novartis, Bayer. Abstract Background: Preclinical studies have observed that progesterone has inhibitory effects on the estrogen-stimulated growth of estrogen receptor (ER)-positive, progesterone receptor (PR)-positive breast cancer. Mohammed H et al. (Nature 2015) identified that activated PR associates with the ER and modulates the interactions of the ER with chromatin, with a shift towards the transcription of genes associated with apoptosis and differentiation, and away from genes associated with proliferation. We hypothesize that the addition of prometrium, a microionized progesterone, may enhance the anti-proliferative effects of standard endocrine therapy in women with ER-positive PR-positive breast cancer. Trial Design: WinPro (NCT03906669) is an ongoing multicenter, phase II, randomized, open-label, window of opportunity study comparing the effect on standard endocrine therapy with or without prometrium on breast cancer cell proliferation. The study population is postmenopausal women with early-stage operable breast cancer where the tumor is ≥5mm on imaging, ER ≥10%, PR≥10%, and HER2-negative. Patients currently on hormone replacement therapy or the oral contraceptive pill, or who have a history of endometrial cancer or venous thromboembolism are not eligible. Patients are randomized 1:1:1 to letrozole 2.5mg daily, letrozole 2.5mg + prometrium 300mg daily, or tamoxifen 20mg + prometrium 300mg daily. Allocated treatment is taken for 14 days prior to surgery. Primary surgery and adjuvant treatment is as per standard of care. Objectives: The primary objective is to compare the geometric mean suppression of centrally assessed Ki67 between the diagnostic biopsy sample (pre-treatment) and the surgical sample (post-treatment). The secondary objective is to evaluate safety and tolerability. Tertiary objectives include defining genes predictive of a reduction in Ki67, and evaluating the changes in ER, PR, AR, FoxA1, Cyclin D1, and apoptotic markers in breast tumors post-intervention. Accrual: This study opened in February 2018 and as of 13 July 2022, 164 patients have been enrolled. Target accrual is 200 patients. Contact information: This study is led at St Vincent’s Hospital Sydney, Australia, and funded by the Cancer Council of NSW and the NHMRC Translational Breast Cancer Project grant. Contact: Elgene Lim MBBS FRACP PhD at e.lim@garvan.org.au. Citation Format: Teesha Downton, Davendra Segara, Andrew Ong, Janne Bingham, Emma-Kate Carson, Julia Chen, Kate Middleton, Geoffrey Lindeman, Andrew Parker, Elgene Lim. WinPro: A window of opportunity study of endocrine therapy with and without prometrium in postmenopausal women with early-stage hormone receptor-positive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-01-10.

Endocrine therapy forms the backbone of systemic therapy for the majority of persons with early and late-stage breast cancer. However, the side effects can negatively affect quality of life, and impact treatment adherence and overall oncological outcomes. Adverse effects on cognition are common, underreported and challenging to manage. We aim to describe the nature, incidence, risk factors and underlying mechanisms of endocrine therapy-induced cognitive dysfunction. We conducted a comprehensive literature review of the studies reporting on cognitive dysfunction associated with endocrine therapies for breast cancer. We also summarise prevention and treatment strategies, and ongoing research. Given that patients are taking endocrine therapies for longer durations than ever before, it is essential that these side effects are managed pro-actively within a multi-disciplinary team in order to promote adherence to endocrine therapy and improve patients’ quality of life.

Three inhibitors of CDK4/6 kinases were recently FDA approved for use in combination with endocrine therapy, and they significantly increase the progression-free survival of patients with advanced estrogen receptor-positive (ER+) breast cancer in the first-line treatment setting. As the new standard of care in some countries, there is the clinical emergence of patients with breast cancer that is both CDK4/6 inhibitor and endocrine therapy resistant. The strategies to combat these cancers with resistance to multiple treatments are not yet defined and represent the next major clinical challenge in ER+ breast cancer. In this review, we discuss how the molecular landscape of endocrine therapy resistance may affect the response to CDK4/6 inhibitors, and how this intersects with biomarkers of intrinsic insensitivity. We identify the handful of pre-clinical models of acquired resistance to CDK4/6 inhibitors and discuss whether the molecular changes in these models are likely to be relevant or modified in the con text of endocrine therapy resistance. Finally, we consider the crucial question of how some of these changes are potentially amenable to therapy.

BACKGROUND:Breast cancer is the most common cancer in women in Australia. Breast cancer is a heterogeneous disease; subtypes are defined by their biology with prognostic and therapeutic implications. Advancements in treatment have led to improved survival and quality of life for patients with advanced breast cancer.OBJECTIVE:The aim of this article is to provide a concise update regarding the current systemic management of advanced breast cancer, including novel treatment options.DISCUSSION:The aim of treatment in advanced breast cancer is to prolong life, manage symptoms and improve quality of life. The general practitioner is an important member of the patient’s multidisciplinary team.

Window of opportunity therapies, which involve short-term administration of systemic therapy between cancer diagnosis and surgery, have raised significant interest in recent years as a mean of assessing the sensitivity of a patient's cancer to therapy prior to surgery. There is now compelling evidence that in patients with early stage hormone-receptor positive breast cancer, a 2-week preoperative treatment with standard hormone therapies in a preoperative window period provides important prognostic information, which in turn helps to aid decision-making regarding treatment options. Changes in short-term biomarker endpoints such as cell proliferation measured by Ki-67 can act as surrogate markers of long-term outcomes. Paired tissues obtained pre- and post-investigational treatment, without having to subject the patient to additional biopsies, can then be used to conduct translational research to investigate predictive biomarkers and pharmacodynamics. In this review, we will examine the utility and challenges of window of opportunities therapies in breast cancer in the current literature, and the current Australian and international trial landscape in this clinical space.

Abstract Background: There is bidirectional interplay between PR and ER in human breast cancers (Lim, Endo Rel Can 2016). Evidence in breast cancer cell lines suggests that dual treatment with estrogen and progesterone compared to estrogen alone leads to reprogramming of ER chromatin binding sites via regulation of 470 genes (Mohammed, Nature 2015). Importantly, there was an additive anticancer effect in preclinical breast cancer models when natural progesterone was combined with standard endocrine therapy; we hypothesize that this combination has activity in women with breast cancer.Trial design: We are conducting a phase II multi-center, randomised, open-label, three-arm study in which 200 postmenopausal women with early-stage ER-positive (ER ≥10%), PR-positive (PR ≥10%), HER2-negative breast cancer will be randomised 1:1:1 to letrozole 2.5mg daily (arm 1); letrozole 2.5mg and prometrium 300mg PO daily (arm 2); or tamoxifen 20mg and prometrium 300mg PO daily (arm 3). Surgery will occur on day 14 after treatment initiation. Eligible subjects must have tumor size ≥10mm on imaging, no history of uterine cancer or venous thromboembolism, and no receipt of other preoperative therapies. The primary objective is to assess the reduction in proliferative marker Ki67 following treatment in either combination arm compared to letrozole alone.Methods: Blood will be collected at baseline and at end of treatment. Tissue samples will be collected from the diagnostic biopsy and at the time of surgery. The primary endpoint is geometric mean reduction of centrally assessed Ki67 expression after two weeks of treatment compared with baseline. Given the expected geometric mean reduction of 76% for aromatase inhibitor alone (Dowsett, J Natl Can Inst 2007) and allowing 4% dropouts, 200 patients provides 80% power to detect an improvement in Ki67 suppression to 92% in either experimental arm with p-value 0.025 for each comparison.The secondary endpoint of safety and tolerability will be assessed (NCI-CTCAE v4.0). Translational endpoints include definition of a predictive gene set biomarker for Ki67 reduction; tumor biomarkers after treatment, including apoptotic markers Bcl-2 and cleaved-caspase3, as well as protein and mRNA expression of ER, PR, AR, FoxA1, and CyclinD1; and levels of estrone, estradiol, E2, progesterone, testosterone, DHT, and DHEAS in serum and finger prick dried blood spot after treatment.Accrual: Enrolment commenced in February 2018 and 70 patients have been randomized from 7 sites to date (1 July 2020). Target accrual is 200 patients enrolled from 8 sites.Contact information: This study is led at The Kinghorn Cancer Centre, St Vincent’s Sydney Hospital Sydney, Australia, and funded by the Cancer Council of NSW and the NHMRC Translational Breast Cancer Project grant. Contact Elgene Lim MBBS FRACP PhD at e.lim@garvan.org.au. Citation Format: Brandon Lau, Davendra Segara, Andrew Ong, Janne Bingham, Belinda Kiely, Emma-Kate Carson, Julia Chen, Cindy Mak, Sanjay Warrier, Mun Hui, Kate Middleton, Andrew Parker, Bruce Mann, Geoffrey Lindeman, Wayne Tilley, Elgene Lim. Winpro: A window of opportunity study of endocrine therapy with and without prometrium in postmenopausal women with early stage hormone receptor-positive breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-09-07.