Tamoxifen Arm Research Articles

ETHAN: A phase II study comparing different endocrine therapies for male breast cancer.

TPS632 Background: Male breast cancer is a rare disease, and most cases are hormone receptor-positive (HR+). Due to a lack of clinical trials, male breast cancer has historically been treated based on data extrapolated from women. However, there are substantial knowledge gaps in the comparative efficacy, safety, and patient-reported outcomes of endocrine therapies for male breast cancer. While tamoxifen is the current standard of care, additional data are warranted for aromatase inhibitors (AI), gonadal suppression, and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Methods: This is an open-label, multicenter, randomized, phase II trial designed to evaluate different endocrine therapies in men with HR+ and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. A total of 60 men will be enrolled across nine (9) sites within the Translational Breast Cancer Research Consortium (TBCRC). Key eligibility criteria include male sex and stage I, II, or III HR+/HER2- breast cancer before surgical resection of the primary tumor and axillary nodes. Key exclusion criteria include prior anti-cancer therapy for the current breast cancer or any other malignancy within the past 12 months, and inflammatory breast cancer. The trial has two phases. The first phase is a window of opportunity component in which newly diagnosed men are randomized 1:1:1 to either tamoxifen (Arm A), anastrozole (Arm B), or anastrozole plus degarelix (Arm C) given for three weeks. The primary endpoint for the window phase is Ki-67 reduction from the baseline diagnostic biopsy to the research biopsy at the end of the window phase. The second phase consists of neoadjuvant treatment, in which the tamoxifen group is randomized 1:1 to tamoxifen (Arm D) versus tamoxifen plus abemaciclib (Arm E), and the anastrozole alone (Arm B) and anastrozole plus degarelix (Arm C) groups are merged and then randomized 1:1 to anastrozole plus degarelix (Arm F) versus anastrozole plus degarelix plus abemaciclib (Arm G). The duration of the neoadjuvant phase is four (4) months, and the primary endpoint of this phase is residual cancer burden (RCB) index at time of surgery. The trial is powered for the RCB endpoint in a 2 x 2 factorial design to detect a 0.6 unit decrease in RCB index with 80% power and alpha=10%. For the Ki-67 endpoint, we assume an approximately 50% reduction in Arms A and B; Arm C will be of interest if it leads to ≥80% reduction in Ki-67. Secondary endpoints include: estradiol and testosterone levels at baseline, end of window, and during neoadjuvant phase; preoperative endocrine prognostic index (PEPI) score at surgery; adverse events; and patient-reported outcomes (including quality of life). Tumor tissue will be collected for correlative analyses. The study opened to enrollment at Dana-Farber in October 2023, and additional sites will open in 2024. Clinical trial information: NCT05501704 .

Radiotherapy versus low-dose tamoxifen following breast-conserving surgery for low-risk and estrogen receptor-positive breast ductal carcinoma in situ: an international open-label randomized non-inferiority trial (TBCC-ARO DCIS Trial)

BackgroundRadiotherapy (RT) following breast-conserving surgery (BCS) is mainly used to decrease the rate of ipsilateral breast tumor recurrence (IBTR) in women with breast ductal carcinoma in situ (DCIS). Recent studies have demonstrated that low-dose tamoxifen significantly reduces IBTR in breast DCIS. Here, we aim to determine whether the administration of low-dose tamoxifen is non-inferior to RT in preventing IBTR in patients with low-risk characteristics of breast DCIS.Methods/designThis is a prospective, international, open-label, randomized, non-inferiority trial. Patients with low-risk clinicopathologic features (> 40 years old, low risk of breast cancer susceptibility gene (BRCA) 1 and BRCA2 mutations, mammographically detected unicentric and non-mass lesions, low- or intermediate-grade without comedo or necrosis, measuring < 2.5 cm with margins ≥ 3 mm, and estrogen receptor-positive status) of DCIS who underwent BCS will be randomized at a 1:1 ratio to either receive tamoxifen (5 mg/day) for 5 years or undergo RT with conventional fractions (50 Gy in 25 fractions) or hypofractionations (40.05 Gy in 15 fractions). Randomization will be stratified by the Taiwan Breast Cancer Consortium. As approximately 5% of patients cannot tolerate the side effects of low-dose tamoxifen and will receive RT, we estimate that 405 patients will be randomized to a low-dose tamoxifen arm and 405 patients to the RT arm, according to a non-inferiority margin within 5% of IBTR difference and 90% β-power noticing non-inferiority. The primary endpoints are breast tumor recurrence, including ipsilateral, regional, contralateral, and distant recurrence of breast DCIS or invasive cancer. The secondary endpoints are overall survival and adverse effects of RT and tamoxifen. Translational studies will also be conducted for this trial.DiscussionThis is the first non-inferiority trial on breast DCIS. This study will provide an important recommendation for clinical physicians on whether to use low-dose adjuvant tamoxifen for patients with low-risk breast DCIS who do not want to receive adjuvant RT.Trial registrationClinicalTrials.gov, ID: NCT04046159, Registered on April 30, 2019.

Palbociclib (P) plus tamoxifen (TAM) ± goserelin in women with hormone receptor-positive (HR+)/HER2-negative (HER2−) advanced breast cancer (ABC): Primary results of NCCH1607/PATHWAY, an Asian international double-blind randomized phase 3 trial.

LBA1068 Background: In Asian countries, BC incidence rates are rising, with a higher proportion of pre/perimenopausal (pre/peri-M) patients (pts). Data on treatment options for pre/peri-M pts are limited. Adding P to endocrine therapy (ET), such as aromatase inhibitor or fulvestrant, has improved progression-free survival (PFS) in phase 3 studies. However, the efficacy and safety of P in combination with TAM are still unclear in pts with HR+/HER2− ABC regardless of M status. This combination was investigated in PATHWAY (NCT03423199): a double-blind randomized phase 3 trial conducted in Japan, Korea, Taiwan and Singapore. The study was conducted as a Clinical Research Collaboration with the National Cancer Center Hospital being the regulatory sponsor and Pfizer providing drug and financial support. Methods: Women with HR+/HER2− ABC were randomly assigned 1:1 to receive either P (125 mg once daily, days 1-21 of a 28-day cycle) or placebo in combination with TAM (20 mg once daily, continuously) as 1st or 2nd line treatment for ABC. Pre/peri-M women received concurrent ovarian function suppression with goserelin. Pts were stratified by 1st vs 2nd line ET and M status. The primary endpoint was PFS as assessed by investigators. Secondary endpoints include overall survival (OS), objective response, safety, and patient-reported outcomes. Results: A total of 184 pts were assigned to P + TAM (91 pts) and placebo + TAM (93 pts). At data cutoff date (Sep 15, 2022), 138 PFS events had occurred. Median follow-up was 40.9 months for censored pts. Median PFS was 24.4 months (95% CI: 13.1, 32.4) with P + TAM and 11.1 months (95% CI: 7.4, 14.6) with placebo + TAM (hazard ratio [HR]: 0.602 [95% CI: 0.428, 0.848], 1-sided p-value from stratified log rank test: 0.002). The HRs for PFS of the subgroups by stratification factors were as follows: for pts with 1st line ET (HR: 0.521 [95% CI: 0.332, 0.817]) or with 2nd line ET (HR: 0.707 [95% CI: 0.421, 1.189]), and for pre/peri-M pts (HR: 0.378 [95% CI: 0.192, 0.742]) or post-M pts (HR: 0.677 [95% CI: 0.456, 1.005]). While OS data were still immature, the primary analysis showed a 27% reduction in overall risk of death (median OS: not reached in both arms, HR: 0.73 [95% CI: 0.442, 1.207]). 93.4% of pts with P + TAM vs. 20.4% of pts with placebo + TAM had grade (G) ≥3 treatment-emergent adverse events (TEAEs). The most frequently observed G ≥3 TEAE was neutropenia (89.0% in P + TAM arm and 1.1% in placebo + TAM arm). There were no G5 TEAEs in either arm. Conclusions: The study achieved its primary endpoint, demonstrating a significant and clinically meaningful improvement in PFS for P + TAM compared with placebo + TAM for pts with HR+/HER2− ABC. Early OS data with P+TAM is encouraging. TEAEs were generally consistent with the known safety profile of P and ET. Clinical trial information: NCT03423199 .

Randomized Placebo Controlled Trial of Low-Dose Tamoxifen to Prevent Recurrence in Breast Noninvasive Neoplasia: A 10-Year Follow-Up of TAM-01 Study.

Five-year data of the phase III trial TAM-01 showed that low-dose tamoxifen at 5 mg once daily administered for 3 years in women with intraepithelial neoplasia (IEN) reduced by 52% the recurrence of invasive breast cancer or ductal carcinoma in situ (DCIS), without additional adverse events over placebo. Here, we present the 10-year results. We randomly assigned 500 women with breast IEN (atypical ductal hyperplasia, lobular carcinoma in situ [LCIS], or hormone-sensitive or unknown DCIS) to low-dose tamoxifen or placebo after surgery with or without irradiation. The primary end point was the incidence of invasive breast cancer or DCIS. The TAM-01 population included 500 women (20% atypical ductal hyperplasia, 11% LCIS, and 69% DCIS). The mean (±SD) age at the start of treatment was 54 ± 9 years, and 58% of participants were postmenopausal. After a median follow-up of 9.7 years (IQR, 8.3-10.9 years), 66 breast cancers (15 in situ; 51 invasive) were diagnosed: 25 in the tamoxifen group and 41 in the placebo group (annual rate per 1,000 person-years, 11.3 with tamoxifen v 19.5 with placebo; hazard ratio [HR], 0.58; 95% CI, 0.35 to 0.95; log-rank P = .03). Most recurrences were invasive (77%) and ipsilateral (59%). Regarding contralateral breast cancer incidence, there were six events in the tamoxifen arm and 16 in the placebo arm (HR, 0.36; 95% CI, 0.14 to 0.92; P = .025). The number needed to be treated to prevent one case of breast event with tamoxifen therapy was 22 in 5 years and 14 in 10 years. The benefit was seen across all patient subgroups. There was a significant 50% reduction of recurrence with tamoxifen in the DCIS cohort, which represents 70% of the overall population (HR, 0.50; 95% CI, 0.28 to 0.91; P = .02). No between-group difference in the incidence of serious adverse events was reported during the prolonged follow-up period. Tamoxifen 5 mg once daily for 3 years significantly prevents recurrence from noninvasive breast cancer after 7 years from treatment cessation without long-term adverse events.

Abstract PD15-12: PD15-12 A pre-surgical window trial of oral tamoxifen versus transdermal 4-hydroxytamoxifen gel in women with estrogen receptor positive duct carcinoma in situ (DCIS)

Abstract Background: Adjuvant oral tamoxifen (TAM) benefits women with DCIS, but toxicity concerns have limited its acceptance. Transdermal therapy with 4-hydroxy tamoxifen (4-OHT) gel applied to the breast skin is a possible solution. Previous pilot data suggest equivalent anti-proliferative efficacy of TAM and 4-OHT gel, but minimal systemic exposure with transdermal therapy. We report a prospective double blinded randomized phase 2 trial comparing TAM to 4-OHT gel in women with DCIS. Methods: 107 women with estrogen receptor positive (≥10%) DCIS were randomized to TAM (20 mg/day + placebo gel) or 4-OHT gel (2mg 4-OHT gel/breast, bilaterally + oral placebo), for 4-10 weeks prior to surgery. The primary endpoint was reduction in DCIS Ki67 labeling index (LI). Secondary endpoints included the 12-gene DCIS Score assay (Exact Sciences), breast tissue and plasma concentrations of 4-OHT and endoxifen, TAM-responsive circulating proteins, and patient reported symptoms (Breast Eight Symptom Scale). We estimated that 80 evaluable participants would provide 80.5% power to establish non-inferiority of 4-OHT, defined as relative Ki67-LI decline &amp;gt;35% and absolute decline &amp;gt;2.6%, with one-sided 𝛼=0.10. Non-inferiority of 4-OHT gel for Ki67-LI reduction was tested using an ANCOVA model. Statistical comparisons within- and between-arms were calculated with paired t-test and Welch Two Sample t-test, respectively. Results: 72 of 87 women adhered to the protocol, and were evaluable for the primary endpoint (39 TAM and 33 4-OHT gel). Mean treatment duration was 47 days for TAM and 44 days for 4-OHT gel (p=0.2). The median absolute decline in Ki67 labeling index was significant in the oral TAM (-3.7%, p&amp;lt; 0.001) but not in 4-OHT gel arm (-1.3%, p=0.2) (p=0.002). Ki67 results following menopausal stratification also favored the TAM arm: (-1.3%; p=0.06 in 37 premenopausal women and -3.7%; p=0.02 in 35 postmenopausal women). Similarly, DCIS score showed a significantly greater reduction in the TAM (-14, p&amp;lt; 0.001) but not in the 4-OHT gel arm (-4, p=0.1). Tissue 4-OHT concentrations were non-significantly higher in the TAM arm and were similar between superficial and deep sampling locations (superficial 6.1 and 4.2 ng/g for TAM and 4-OHT gel, respectively, p= 0.55; deep 5.7 and 3.8 ng/g, respectively, p= 0.06), whereas plasma 4-OHT concentration was markedly lower in the gel group (2 ng/mL and 0.24 ng/mL for TAM and 4-OHT gel, respectively, P &amp;lt; 0.001). Endoxifen was abundant in plasma (11 ng/mL) and deep tissue (13 ng/g) of the TAM arm, but present in trace amounts in the 4-OHT gel arm (undetectable in plasma and 0.31 ng/g in tissue; p &amp;lt; 0.001). Circulating TAM responsive markers (insulin like growth factor 1, sex hormone binding globulin, von Willebrand factor, and protein S total) and vasomotor symptoms were significantly and unfavorably modulated by TAM, but not by 4-OHT gel therapy. Conclusions: The non-inferiority of transdermal 4-OHT gel to Tam in terms of anti-proliferative effect in DCIS lesions was not demonstrated at the doses used for this study. DCIS Score analysis gave similar results. Tissue 4-OHT concentration in 4-OHT gel and Tam-treated subjects was roughly similar. However, endoxifen exposure was higher with oral TAM therapy and may partially explain the observed differences in major endpoints. In future studies, use of higher 4-OHT gel doses, longer duration of treatment, or different formulation may overcome these. Citation Format: Oukseub Lee, Xinlei Mi, Yanfei Xu, Luis Blanco, Azza M. Akasha, Kelly Benante, Shanshan Zhang, Carissa LaBoy, Thomas Helland, Melissa Pilewskie, Amy Degnim, Zahraa Al-Hilli, Amanda L. Amin, E Shelley Hwang, Joseph M. Guenther, Simon Steinar Hustad, Demirkan B. Gursel, Masha Kocherginsky, Gunnar Mellgren, Eileen Dimond, Marjorie Perloff, Brandy M. Heckman-Stoddard, Seema Khan. PD15-12 A pre-surgical window trial of oral tamoxifen versus transdermal 4-hydroxytamoxifen gel in women with estrogen receptor positive duct carcinoma in situ (DCIS) [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 PD15-12.

Abstract GS4-08: 10-year results of a phase 3 trial of low-dose tamoxifen in non-invasive breast cancer

Abstract We have previously shown in a phase 3 trial that tamoxifen 5 mg/day for 3 years decreased by 52% the incidence of recurrence of invasive breast cancer or DCIS after a median follow-up of 5.1 years in women with excised non invasive breast disease, including atypical ductal hyperplasia, DCIS or LCIS (DeCensi et al. JCO 2019; 37:1629). Toxicity was negligible with only an extra hot flash per day in the tamoxifen arm compared with the placebo arm. These findings were incorporated into the ASCO clinical practice guidelines for breast cancer risk reduction as an alternative option to standard doses and duration of tamoxifen or aromatase inhibitors in women with non-invasive disease (Visvanathan et al. JCO 2019; 37:3152). In the present study we update the findings on breast cancer recurrence after a median of 9.14 years (interquartile range, IQR, 7.16-10.73) and a total of 10.57 person years of follow up to see if the treatment effect is retained with more events and after a median of approximately 6 years from treatment cessation. We conducted a national multicenter randomized trial of tamoxifen, 5 mg/d or placebo administered for 3 years after surgery in women with hormone-sensitive or unknown breast intraepithelial neoplasia, including atypical ductal hyperplasia and lobular or ductal carcinoma in situ. The primary end point was the incidence of invasive breast cancer or ductal carcinoma in situ. Between November 1, 2008, and March 31, 2015, 1,160 women were screened and 500 aged 75 years of age or younger were included in the study. Women with high-grade or comedo/necrotic DCIS received adjuvant radiotherapy of 50 Gy in 25 courses. The mean age was 54 years (standard deviation, 9 years), and 55% of participants were postmenopausal. The mean (SD) body mass index, kg/m2, was 25.7 (4.8) on tamoxifen and 25.3 (4.2) on placebo. Twenty percent had ADH, 11% had LCIS, and the remaining 69% had DCIS. After a median follow-up of 9.14 years, there were 22 neoplastic events (invasive breast cancer or DCIS) with tamoxifen and 37 with placebo (annual rate 11.09, 95% CI, 7-30-16.84 on T vs 19.71, 95% CI, 14.28-27.21 on P per 1,000 person-years; hazard ratio, 0.56; 95% CI, 0.33 to 0.95; P = .03), which resulted in a 5-year number needed to treat of 18. Overall, 71% of the recurrences were invasive breast cancer. The follow-up was updated with the most recent visit within 12 months in two thirds of the participants, so an update of all participants will be performed by Sept 30th with full analysis of neoplastic events, annual risk rate ratio, serious adverse events and deaths. Moreover, an updated analysis of potential effect modifiers will be conducted, including menopausal status, baseline estradiol levels, menopausal symptoms, BMI, smoking status and Ki-67 of the primary lesion. In conclusion, our findings indicate that low dose tamoxifen given for 3 years still significantly prevents recurrences from non-invasive breast cancer after a median of 6 years from treatment cessation, providing a valid prevention/interception option in this disease group. Supported by Ente Ospedaliero Ospedali Galliera, Genova, Italy, the Italian Ministry of Health (RFPS-2006-1-339898), the Italian Association for Cancer Research (IG 2008 Grant No. 5611), and the Italian League against Cancer (LILT 7-08). Citation Format: Andrea De Censi, Matteo Lazzeroni, Matteo Puntoni, Luca Boni, Aliana Guerrieri Gonzaga, Tania Buttiron Webber, Marianna Fava, Irene Maria Briata, Livia Giordano, Maria Digennaro, Laura Cortesi, Fabio Falcini, Franca Avino, Francesco Millo, Katia Cagossi, Elisa Gallerani, Alessia De Simone, Anna Cariello, Giuseppe Aprile, Maria Renne, Bernardo Bonanni. 10-year results of a phase 3 trial of low-dose tamoxifen in non-invasive 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 GS4-08.

Regorafenib or Tamoxifen for platinum-sensitive recurrent ovarian cancer with rising CA125 and no evidence of clinical or RECIST progression: A GINECO randomized phase II trial (REGOVAR)

ObjectiveTo evaluate the efficacy and safety of regorafenib versus tamoxifen in platinum-sensitive ovarian cancer biological recurrence, defined by CA-125 increase without radiological (RECIST criteria) or symptomatic evidence of progression. Patients and methods116 patients with platinum-sensitive ovarian cancer presenting an isolated increase of CA-125 were planned to be randomized. Regorafenib was administered orally at 160 or 120 mg daily, 3 weeks on/1 week off or tamoxifen at 40 mg daily, until disease progression or development of unacceptable toxicity. The primary endpoint was Progression-Free Survival, assessed by progression according to RECIST 1.1 or death (by any cause). Secondary endpoints included Overall Survival, Best Response and CA-125 response rate. Results68 patients were randomized. Median age was 67 years (range: 30–87). Primary site of cancer was ovarian for most patients (92.6%). Tumors were predominantly serous / (89.7%), high grade (83.6%) and initial FIGO staging was III for 69.6% of the patients. Most (79.4%) patients were included after the first line of platinum-based treatment. After a median follow-up of 32 months, there was no difference of progression-free survival (PFS) between regorafenib and tamoxifen groups (p = 0.72), with median PFS of 5.6 months (CI 90%: 3.84–7.52) for the tamoxifen arm and 4.6 months (CI 90%: 3.65–7.33) for the regorafenib arm. There was also no difference in term of overall survival, best response or CA-125 response, delay to next therapy. Regorafenib presented a less favorable safety profile than tamoxifen, with grade 3/4 events occurring for 90.9% of the patients compared to 54.3% for tamoxifen. The most frequent were cutaneous, digestive, and biological events. Notably, hand-foot syndrome occurred in 36.4% of these patients. ConclusionRegorafenib presented an unfavorable toxicity profile compared to tamoxifen, with no superior efficacy in this population of patients.

An open label randomized controlled trial of tamoxifen combined with amphotericin B and fluconazole for cryptococcal meningitis.

Cryptococcal meningitis has high mortality. Flucytosine is a key treatment but is expensive and rarely available. The anticancer agent tamoxifen has synergistic anti-cryptococcal activity with amphotericin in vitro. It is off-patent, cheap, and widely available. We performed a trial to determine its therapeutic potential. Open label randomized controlled trial. Participants received standard care - amphotericin combined with fluconazole for the first 2 weeks - or standard care plus tamoxifen 300 mg/day. The primary end point was Early Fungicidal Activity (EFA) - the rate of yeast clearance from cerebrospinal fluid (CSF). Trial registration https://clinicaltrials.gov/ct2/show/NCT03112031. Fifty patients were enrolled (median age 34 years, 35 male). Tamoxifen had no effect on EFA (-0.48log10 colony-forming units/mL/CSF control arm versus -0.49 tamoxifen arm, difference -0.005log10CFU/ml/day, 95% CI: -0.16, 0.15, p=0.95). Tamoxifen caused QTc prolongation. High-dose tamoxifen does not increase the clearance rate of Cryptococcus from CSF. Novel, affordable therapies are needed. The trial was funded through the Wellcome Trust Asia Programme Vietnam Core Grant 106680 and a Wellcome Trust Intermediate Fellowship to JND grant number WT097147MA.

Abstract PD11-07: Use of low-dose tamoxifen to increase screening sensitivity in mammography of premenopausal women

Abstract Background. High mammographic density decreases sensitivity of both 2D and 3D mammography. Tamoxifen reduces mammographic density thereby potentially increasing screening sensitivity. We tested if low-dose tamoxifen could be used to increase sensitivity of mammography in premenopausal women. Methods. Mammography screening sensitivity was calculated using the Swedish KARMA prospective screening cohort including 28,282 premenopausal women. Two models were fitted to estimate screening sensitivity and tumor size based on density level at baseline. BI-RADS dependent sensitivity was estimated in each of the four categories (A, B, C, D). The 2.5 mg tamoxifen arm of the KARISMA tamoxifen trial was used to define the change of mammographic density after exposure to low-dose tamoxifen. The models predicted screening sensitivity and tumor size in the KARMA cohort assuming that all women were exposed to 2.5 mg of tamoxifen. Reduction in interval and advanced cancers were estimated in women with mammographic density decrease of 10%, 20%, 30% and 50%. Mammographic density was measured as percent density and a computerized BI-RADS score was estimated using the STRATUS tool. Results. During 8 years of follow-up, 287 (56%) screening detected and 230 (44%) interval cancers were diagnosed in the KARMA cohort. The screening sensitivities, before exposure to tamoxifen, were 77%, 69%, 53%, 46% for BI-RADS categories A, B, C and D, respectively. The mean density decrease after exposure to 2.5 mg of tamoxifen was 17.4% and the BI-RADS category dependent change in sensitivity was 0% (p=0.95), 2% (p=0.01), 4% (p&amp;lt;0.001), and 5% (p&amp;lt;0.001), respectively. A density decrease of ≥20% would reduce the number of interval cancers with 24% (p&amp;lt;0.01) and the probability of identifying &amp;gt;20 mm tumors with 4% (p&amp;lt;0.01). Conclusion. Low-dose tamoxifen has the potential to increase the sensitivity of a screening mammogram and thereby reduce the proportion of interval and advanced cancers. Table. Number of interval cancers per 100,000 age standardized screened women, change in number of interval cancers after tamoxifen exposure, by percentage mammographic density decrease. Density response is presented using density responder cut-offs and is stratified by computer-generated BI-RADS categories A+B, C, D. The normal (unexposed) group is included as the reference.Number of interval cancers (N)NormalDensity responder cut-off (%)group≥10≥20≥30≥50BI-RADS A+B15510710210088BI-RADS C382356339299253BI-RADS D276197180160129BI-RADS A to D combined813660621559470Difference compared to normal group, N (%)BI-RADS A+Bref.-48 (-31)-53 (-34)-55 (-35)-67 (-43)BI-RADS Cref.-26 (-7)-43 (-11)-83 (-22)-129 (-34)BI-RADS Dref.-79 (-29)-96 (-35)-116 (-42)-147 (-53)BI-RADS A to D combinedref.-153 (-19)-192 (-24)-254 (-31)-343 (-42)Number of interval cancers were significantly reduced in each density decrease group, p&amp;lt;0.01. Citation Format: Mikael Eriksson, Kamila Czene, Per Hall. Use of low-dose tamoxifen to increase screening sensitivity in mammography of premenopausal women [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 PD11-07.

Use of Low-Dose Tamoxifen to Increase Mammographic Screening Sensitivity in Premenopausal Women.

Simple SummaryThis is the first study to model the effects of tamoxifen on mammographic density and screening sensitivity. Low-dose tamoxifen reduces mammographic density in premenopausal women by, on average, 20%. Potential outcome analyses suggest that a reduction in mammographic density improves mammography screening sensitivity, reduces the proportion of large tumors, and subsequent interval cancers.Increased breast density decreases mammographic sensitivity due to masking of cancers by dense tissue. Tamoxifen exposure reduces mammographic density and, therefore, should improve screening sensitivity. We modelled how low-dose tamoxifen exposure could be used to increase mammographic sensitivity. Mammographic sensitivity was calculated using the KARMA prospective screening cohort. Two models were fitted to estimate screening sensitivity and detected tumor size based on baseline mammographic density. BI-RADS-dependent sensitivity was estimated. The results of the 2.5 mg tamoxifen arm of the KARISMA trial were used to define expected changes in mammographic density after six months exposure and to predict changes in mammographic screening sensitivity and detected tumor size. Rates of interval cancers and detection of invasive tumors were estimated for women with mammographic density relative decreases by 10–50%. In all, 517 cancers in premenopausal women were diagnosed in KARMA: 287 (56%) screen-detected and 230 (44%) interval cancers. Screening sensitivities prior to tamoxifen, were 76%, 69%, 53%, and 46% for BI-RADS density categories A, B, C, and D, respectively. After exposure to tamoxifen, modelled screening sensitivities were estimated to increase by 0% (p = 0.35), 2% (p < 0.01), 5% (p < 0.01), and 5% (p < 0.01), respectively. An estimated relative density decrease by ≥20% resulted in an estimated reduction of interval cancers by 24% (p < 0.01) and reduction in tumors >20 mm at detection by 4% (p < 0.01). Low-dose tamoxifen has the potential to increase mammographic screening sensitivity and thereby reduce the proportion of interval cancers and larger screen-detected cancers.

Molecular Drivers of Oncotype DX, Prosigna, EndoPredict, and the Breast Cancer Index: A TransATAC Study.

PURPOSEThe Oncotype DX Recurrence Score (RS), Prosigna Prediction Analysis of Microarray 50 (PAM50) Risk of Recurrence (ROR), EndoPredict (EP), and Breast Cancer Index (BCI) are used clinically for estimating risk of distant recurrence for patients receiving endocrine therapy. Discordances in estimates occur between them. We aimed to identify the molecular features that drive the tests and lead to these differences.PATIENTS AND METHODSAnalyses for RS, ROR, EP, and BCI were conducted by the manufacturers in the TransATAC sample collection that consisted of the tamoxifen or anastrozole arms of the ATAC trial. Estrogen receptor–positive/human epidermal growth factor receptor 2 (HER2)–negative cases without chemotherapy treatment were included in which all four tests were available (n = 785). Clinicopathologic features included in some tests were excluded from the comparisons. Estrogen, proliferation, invasion, and HER2 module scores from RS were used to characterize the respective molecular features. Spearman correlation and analysis of variance tests were applied.RESULTSThere were moderate to strong correlations among the four molecular scores (ρ = 0.63-0.74) except for RS versus ROR (ρ = 0.32) and RS versus BCI (ρ = 0.35). RS had strong negative correlation with its estrogen module (ρ = −0.79) and moderate positive correlation with its proliferation module (ρ = 0.36). RS’s proliferation module explained 72.5% of ROR’s variance, while the estrogen module explained only 0.6%. Most of EP’s and BCI’s variation was accounted for by the proliferation module (50.0% and 54.3%, respectively) and much less by the estrogen module (20.2% and 2.7%, respectively).CONCLUSIONIn contrast to common understanding, RSs are determined more strongly by estrogen-related features and only weakly by proliferation markers. However, the EP, BCI, and particularly ROR scores are determined largely by proliferative features. These relationships help to explain the differences in the prognostic performance of the tests.

Abstract P3-07-05: Correlation between and molecular drivers of oncotype DX, prosigna, EndoPredict and breast cancer index: A TransATAC study

Abstract Background: Oncotype DX Recurrence Score (RS), Prosigna PAM50 ROR score, the EndoPredict score (EP, EPclin) and the Breast Cancer Index (BCI) all provide substantial molecular prognostic information and are used in clinical practice for guiding the treatment for large numbers of patients with primary ER+/HER2- breast cancer. Despite this, there is incomplete information on the concordance between these scores and very little understanding of the molecular features that drive the individual scores. Here we report from a unique database (i) the correlation between all 4 scores when measured by the respective manufacturers in the TransATAC set of samples and (ii) the degree to which each of the scores is driven by proliferation, oestrogen signalling, HER2 signalling and invasive properties insomuch as these are reflected by each component module of the RS test (PM, EM, HM and IM, respectively). Methods: The TransATAC tumour sample set was collected from patients in the tamoxifen or anastrozole arms from the ATAC clinical trial of 5 years of endocrine therapy in postmenopausal patients with primary hormone receptor positive breast cancer. Cases were included if HER2- and all 4 scores were available. None of the patients received adjuvant chemotherapy. EP and ROR both include some clinical features in their final score but components were excluded for the purposes of this study. The RS module scores were provided by the manufacturer. The genes that contribute to the module scores are as follows: PM: Ki67, STK15, Survivin, CCNB1, MYBL2; EM: ER, PGR, BCL2, SCUBE2; HM: GRB7, HER2; IM: MMP11, CTSL2). Spearman rank correlation was used to study the association between molecular components. Results: Data was available for all four molecular scores for 785 TransATAC patients. Correlations were moderate to strong for RS vs EP (r=0.63), ROR vs EP (r=0.68), ROR vs BCI (r=0.74) and EP vs BCI (r=0.67) but were weak for RS vs ROR (r=0.32) and RS vs BCI (r=0.35). The correlation between each score with the RS module scores are shown in the Table. Molecular scoreRS moduleRSROREPBCIPM0.360.860.710.74EM-0.790.00-0.38-0.10HM-0.04-0.14-0.15-0.18IM0.260.380.340.32 The RS had a strong negative correlation with its EM (r= -0.79) and a weak positive correlation with its PM (r= 0.36) although the latter was stronger when the PM was thresholded; 78% of the cases had a PM score below the threshold of 6.5 and were assigned a value of 6.5 in the RS with no correlation between RS and PM in these samples (r=-0.03). ROR showed a very strong correlation with the PM (r=0.86), but none with the EM (r: 0.00). EP and BCI both showed strong correlation with the PM (r= 0.71 and 0.74, respectively) and with low or near absent correlation with EM (r= -0.38 and -0.10, respectively). There was little correlation between the HM with each of the scores while the IM correlation was similar for each score varying from 0.26 to 0.38. Of the two module components of BCI, MGI was strongly associated with the PM (r= 0.84) and not at all with the EM while H/I moderately correlated with PM (r=0.51) and weakly correlated with EM (r= -0.31). Conclusion: EP scores are moderately correlated with each of the other 3 scores while RS scores are dissimilar to those from the ROR and BCI. In contrast to common thinking the RS is driven only weakly by proliferative features and more by those related to ER/PR pathways. The EP, BCI and particularly ROR are dominated by proliferative features. These relationships provide and explanation for the differences that we and others have reported in the prognostic performance of the tests for both early and late recurrence. Citation Format: Richard Buus, Ivana Sestak, Mitch Dowsett, Ralf Kronenwett, Sean Ferree, Catherine Schnabel, Frederick L Baehner, Jack Cuzick. Correlation between and molecular drivers of oncotype DX, prosigna, EndoPredict and breast cancer index: A TransATAC study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-07-05.

Using time series analysis to forecast the health-related quality of life of post-menopausal women with non-metastatic ER+ breast cancer: A tutorial and case study.

Time series models are widely used forecasting techniques in health care for long time series and are typically built in commercial statistical packages. However, for short time series data, such as health-related quality of life (HRQoL), guidance on how to select and use appropriate time series models is lacking. This tutorial provides a step-by-step guide adopting a time series analysis framework for HRQoL forecasting. We walk through a case study examining the forecasting of the effects of adjuvant endocrine therapy on the HRQoL of post-menopausal women with non-metastatic ER+breast cancer using data from the HRQoL sub-protocol of the Tamoxifen arm of the Arimidex, tamoxifen, alone or in combination (ATAC) trial. The forecasting of HRQoL consists of four steps: 1) data extraction and accuracy check, 2) forecasting horizon definition and identification of data pattern, 3) forecasting model identification and fitting using five forecasting approaches appropriate for short time series ((i) double exponential smoothing, (ii) double moving average, (iii) fuzzy forecasting, (iv) grey forecasting, and (v) Volterra series), 4) forecasting model selection. A user-friendly visual basic for applications (VBA) Excel add-in is made available to interested users to facilitate the application of the tutorial. The Grey method and Volterra series appeared to be good candidates to forecast the effects of adjuvant endocrine therapy on the HRQoL of post-menopausal women with non-metastatic ER+breast cancer enrolled in the ATAC trial. It is feasible to forecast the effects of treatments on HRQOL even when the time series is short.

Abstract P2-07-02: A newly derived combined clinical treatment score and immunohistochemical-4 prognostic tool

Abstract AIM To determine whether a modified Clinical Treatment Score (CTS) based on continuous tumor size and 5 lymph node categories provided more prognostic information in an independent test set than the original CTS with and without the Immunohistochemical-4 (IHC4) algorithm for prediction of residual distant recurrence risk over 10-years. BACKGROUND Risk of recurrence information in patients with estrogen receptor-positive (ER+), early breast cancer informs decision-making on chemotherapy use. The CTS and IHC4 algorithms provide such information, particularly when used in combination (IHC4+C). Their derivation in the translational cohort of the Arimidex Tamoxifen Alone or in Combination trial (TransATAC) was described by Cuzick et al in 2011. In the original model tumor size and nodal status were each classified into three categories, causing prognostic information to be lost. METHODS We modeled a novel CTSn algorithm on outcome data from patients in the anastrozole and tamoxifen arms in ATAC incorporating tumor size as a continuous variable and sub-dividing nodal status into five categories. IHC4n was re-derived in the TransATAC cohort independent of CTSn. Patients were chemotherapy-naïve. We compared ability to predict risk of residual distant recurrence of the new IHC4n+Cn model with that of the original one when tested in a training cohort and in a validation set of chemotherapy-naïve patients from the Tamoxifen vs. Exemestane Adjuvant Multicentre (TEAM) trial using Cox regression models and the C-index. RESULTS The ATAC training set for CTSn comprised 4056 patients, the TransATAC training set for IHC4n comprised 1125 patients; 2591 patients were in the TEAM validation set. Patients in the TEAM set were older (median age in TransATAC: 63.5, TEAM: 68.3 years), had a higher nodal-burden (node-positive in TransATAC: 29.4%, TEAM: 51.8%) and had more Grade 3 tumors (TransATAC: 18.3%, TEAM: 32.2%). The new IHC4n+Cn was significantly prognostic, and non-significantly more prognostic than the original IHC4+C in both the training and validation cohorts. When assessed using the C-index statistic, IHC4n+Cn had a higher discriminatory ability than the original algorithm (Table 1). Table 1 TransATAC (N=1125)TEAM (N=2591) HR* (95% CI)C-indexHR* (95% CI)C-indexOld Models CTS2.26 (2.01-2.53)0.6811.88 (1.73-2.03)0.650IHC41.67 (1.46-1.91)0.6301.49 (1.35-1.63)0.604IHC4+C2.76 (2.40-3.18)0.7242.03 (1.87-2.21)0.671New Models CTSn2.64 (2.26-3.09)0.7212.16 (1.96-2.39)0.687IHC4n1.74 (1.52-2.01)0.6421.51 (1.36-1.68)0.603IHC4n+Cn2.91 (2.47-3.42)0.7382.28 (2.06-2.51)0.695(*Hazard Ratio for change in one Standard Deviation). CONCLUSION By separately remodellng the part of the IHC4+C score based on clinicopathological characteristics using the whole ATAC chemo-naïve cohort, and the part that uses IHC-derived information in chemo-naïve TransATAC patients, we increased the precision of the individual risk estimates produced by both CTSn and IHC4n compared to those given by the original algorithms. The new IHC4n+Cn shows a trend for improved prognostic ability compared to the original IHC4+C. Like its predecessor, it relies on information that is readily available to clinicians and integrates it in an evidence-based way to improve prognostication in ER+ early breast cancer. Citation Format: Dodson A, Sestak I, Bayani J, Dowsett M, Bartlett J, Cuzick J. A newly derived combined clinical treatment score and immunohistochemical-4 prognostic tool [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-07-02.

Abstract OT3-02-02: PATHWAY: Asian, multicenter, phase 3 trial of tamoxifen with or without palbociclib ± goserelin in women with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer

Abstract BACKGROUND: The incidence rates of breast cancer (BC) in Asian counties have been rising rapidly. The age-specific female BC incidence rates peak before menopause (around 40-50 years of age) in Asia, however treatment options for pre/perimenopausal patients are limited. Palbociclib (P) is an oral novel cyclin-dependent kinase 4/6 (CDK4/6) inhibitor. The addition of P to endocrine therapy (ET) such as aromatase inhibitor or fulvestrant has been demonstrated improved progression-free survival (PFS) in phase 3 studies PALOMA-2 and PALOMA-3. This study is designed to evaluate efficacy and safety of P plus tamoxifen (TAM) in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic BC regardless of menopausal status. This study is conducted as a Clinical Research Collaboration by National Cancer Center Hospital with research funding from Pfizer. TRIAL DESIGN: PATHWAY/NCCH1607 is a double-blind, placebo-controlled, randomized, phase 3 study. Patients will be randomized 1:1 to receive either P (125 mg once daily, days1-21 of a 28-day cycle) or placebo in combination with TAM (20 mg once daily, continuously). Pre/perimenopausal women should receive concurrent ovarian function suppression with goserelin. Randomization will be stratified by prior ET for advanced/metastatic BC (1st line ET vs. 2nd line ET) and menopausal status (pre/perimenopausal vs. postmenopausal). KEY ELIGIBILITY CRITERIA: Eligible patients include women of any menopausal status with HR-positive, HER2-negative advanced or metastatic BC; candidates to receive TAM as 1st line or 2nd line ET for advanced/metastatic disease; ≥18 years of age; measurable or non-measurable disease (RECIST v.1.1); ECOG performance status 0-1; adequate organ function; have not received treatment with TAM (except for patients who have had more than 12 months from completion of adjuvant therapy with TAM); and have not received any CDK4/6 or phosphoinositide 3-kinase (PI3K) - mammalian target of rapamycin (mTOR) inhibitors. SPECIFIC AIMS: The primary endpoint is PFS as assessed by the investigator. Secondary endpoints include overall survival (OS), 1, 2, and 3-year survival probabilities, objective response (OR), duration of response, clinical benefit rate (CBR), pharmacokinetics, safety, and patient-reported outcomes. STATISTICAL METHODS: The sample size was determined to detect a 38% reduction in the hazard of disease progression or death in P plus TAM arm with a 1-sided significance level of 2.5% and power of 80%. A stratified log rank test will be used to compare PFS between the 2 treatment arms. PRESENT ACCRUAL AND TARGET ACCRUAL: Target accrual of 180 patients will be enrolled within 23 sites among Japan, Korea, Taiwan, and Singapore. As of June 2018, 46 patients have been enrolled. CONTACT INFORMATION: This trial is registered at ClinicalTrials.gov NCT03423199 and UMIN000030816. For more information, email NCCH1607_office@ml.res.ncc.go.jp Citation Format: Noguchi E, Hata T, Nakamura K, Kuchiba A, Hayashi M, Hamada A, Yonemori K, Sohn J, Lu Y-S, Yap Y-S, Fujiwara Y, Tamura K. PATHWAY: Asian, multicenter, phase 3 trial of tamoxifen with or without palbociclib ± goserelin in women with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-02-02.

Two years of tamoxifen or no adjuvant systemic therapy for patients with high-risk breast cancer: long-term follow-up of the Copenhagen breast cancer trial

Background: The Copenhagen Breast Cancer Trial (CBCT) randomly assigned patients with early breast cancer to two years of tamoxifen or placebo and we evaluated the effect over the following four decades.Patient and methods: Between 1975 and 1978, 327 patients with primary breast cancer were randomly assigned to two years of daily placebo or tamoxifen. Survival statistics was collected from the Danish Civil Registration System.Results: The five-year invasive breast cancer recurrence (BCR) rate was 43.2% in the placebo arm and 31.9% in the tamoxifen arm. Compared with the placebo arm the hazard ratio for a BCR event was 0.73 in the tamoxifen arm (p = .07). With an estimated median follow-up on overall survival of 40.9 years, 154 and 145 patients had died in the placebo and tamoxifen arm, respectively. After adjustment for baseline characteristics a significant reduction in mortality was obtained from tamoxifen (HR 0.79; p = .04).Conclusion: Two years of adjuvant tamoxifen resulted in a sustained reduction in mortality in pre- and postmenopausal high-risk breast cancer patients with long-term follow-up data.

Participant-Reported Symptoms and Their Effect on Long-Term Adherence in the International Breast Cancer Intervention Study I (IBIS I).

PurposeTo assess the role of participant-reported symptoms on long-term adherence to preventive therapy in the United Kingdom sample of the International Breast Cancer Intervention Study (IBIS-I). IBIS-I was a randomized controlled trial that investigated the effectiveness of tamoxifen in reducing the risk of breast cancer among women at increased risk of the disease.Participants and MethodsWomen were randomly assigned to tamoxifen versus placebo (20 mg/day; n = 4,279). After 456 exclusions, 3,823 women were included in this analysis. Adherence (< 4.5 years or ≥ 4.5 years) was calculated using data from six monthly clinical visits. Analyses were adjusted for age, Tyrer-Cuzick risk, smoking, use of hormone replacement therapy, menopausal status, baseline menopausal symptoms, and treatment.ResultsOverall, 69.7% of women were adherent for at least 4.5 years (tamoxifen: 65.2% v placebo: 74.0%; P < .001). Differences in adherence between treatment arms were observed from 12 months onward (all P < .01) and were largest at 54 months. Dropout rates were highest in the first 12 to 18 months and decreased thereafter. Women reporting nausea/vomiting were less likely to be adherent in both the tamoxifen (odds ratio [OR], 0.57; 95% CI, 0.37 to 0.86; P = .007) and placebo (OR, 0.58; 95% CI, 0.37 to 0.93; P = .023) arms. Headaches were associated with adherence only in the placebo arm (OR, 0.62; 95% CI, 0.42 to 0.91; P = .016), whereas gynecologic symptoms were significant only in the tamoxifen arm (OR, 0.77; 95% CI, 0.62 to 0.97; P = .024). Effect sizes for each symptom on adherence were not significantly different between the treatment groups (P > .05). In both treatment arms, we observed significant trends for lower adherence with increasing severity for all symptoms (P < .01) except headaches (P = .054).ConclusionIn the IBIS-I trial, experiencing predefined symptoms in the first 6 months reduced long-term adherence. Effects were similar between treatment arms, suggesting that women were attributing age-related symptoms to preventive therapy. Interventions were required to support symptom management.

Immunohistochemical Phenotype of Breast Cancer during 25-Year Follow-up of the Royal Marsden Tamoxifen Prevention Trial.

The randomized, double-blinded Royal Marsden Tamoxifen Breast Cancer Prevention Trial in healthy high-risk women started in 1986 and is still blinded. Eligible participants (n = 2,471) were randomly assigned to tamoxifen (20 mg/d) or placebo for 8 years. Analysis in 2006 showed a 30% risk reduction of estrogen receptor (ER)-positive invasive breast cancer mostly in the posttreatment period. Biomarker analysis in this population may identify any subgroup-specific preventive effects tamoxifen. After a median follow-up of 18.4 years, 242 patients had developed invasive cancer, 134 on placebo and 108 on tamoxifen. From these, 180 tissue blocks were available and ER, progesterone receptor (PgR), Ki67, HER2, and EGFR were immunohistochemically analyzed. A 32% reduction in ER+ and PgR+ invasive cancers resulted after 8 years of treatment. Quantitative levels of ER and PgR were lower in the tamoxifen-treated group, significantly so for ER (P = 0.001). These lower ER levels were restricted to the posttreatment period (P = 0.018). Among the ER+ group, there was a similar proportional decrease in PgR+ and PgR- tumors by tamoxifen. The median levels of Ki67 were similar in both arms. The numbers of HER2-positive and EGFR-positive cancers were higher in the tamoxifen arm but not significantly so. In conclusion, the preventive effects of tamoxifen result in reduced ER-positive but not ER-negative tumors and reduced ER expression in the ER-positive cases largely confined to the posttreatment period. Overall reductions in PgR expression are explained by lower frequency of ER-positive cases. Impact on Ki67, HER2, and EGFR was modest. Cancer Prev Res; 10(3); 171-6. ©2017 AACR.

Abstract S5-03: Menopausal symptoms as predictors of long-term adherence in the International breast cancer intervention study (IBIS-1)

Abstract Tamoxifen reduces the risk of breast cancer among women at increased risk of the disease. The effectiveness of the drug is dependent on its appropriate use for the duration of therapy. Adherence for the full course of preventive therapy ranges from 60-80%. Early discontinuation is largely attributed to side-effects, but no studies have validated this using 5-year follow-up data. We assessed the role of menopausal side-effects on long-term adherence in the UK arm of the International Breast Cancer Intervention Study (IBIS-1). In the IBIS-1 trial, 4279 women in the UK were randomised to placebo vs. tamoxifen (20mg/day). A total of 292 were excluded (breast cancer, death, or other cancer), leaving 3987 to be included in the analysis (2000 placebo arm, 1987 tamoxifen arm). Adherence was calculated using data from six monthly clinical visits during the trial. Adherence (&amp;lt;4.5 years, ≥4.5 years) was calculated using the Kaplan-Meier estimator. Our main objective was to investigate the effect of menopausal side effects experienced during the first six months on adherence overall and by treatment arm. All analyses were adjusted for age, Tyrer-Cuzick risk, smoking, hormone replacement therapy use, menopausal status, baseline symptoms, and treatment. Overall, 66.8% of women were adherent for at least 4.5 years (placebo: 71.5% vs. tamoxifen: 62.1%, p&amp;lt;0.001). Highest drop-out rates were found within the first 12 months of follow-up, and a significant difference in adherence between treatment arms was observed thereafter (p&amp;lt;0.05). A low number of women experienced nausea/vomiting (5.0%) and headaches (7.0%), while higher proportions reported gynaecological symptoms (irregular bleeding/vaginal dryness/vaginal discharge, 13.8%) and hot flushes (31.5%). Women reporting nausea/vomiting (OR=1.82 [95% CI, 1.35-2.47], p&amp;lt;0.001) and headaches (OR=1.41 [1.08-1.84], p=0.01) were significantly more likely to be non-adherent at 4.5 years. Long-term adherence was not significantly affected for those who reported hot flushes (OR=1.10 [0.94-1.30], p=0.2) or gynaecological symptoms (OR=1.18 [0.99-1.41], p=0.07) compared with their counterparts. Nausea/vomiting was significantly associated with non-adherence in both the placebo (OR=1.82 [1.16-2.87], p=0.009) and tamoxifen (OR=1.84 [1.22-2.76], p=0.004) arms. Headaches were associated with non-adherence in the placebo arm (OR=1.70 [1.16-2.50], p=0.006), while gynaecological symptoms were only significant in the tamoxifen arm (OR=1.30 [1.05-1.63], p=0.02). The majority of side effects were of mild or moderate severity and we observed significant trends for lower adherence with increasing severity for all symptoms (p&amp;lt;0.05 to &amp;lt;0.001). In the IBIS-I trial, we observed a significant effect of common menopausal symptoms on long-term adherence. These effects were largely similar between tamoxifen and placebo arms, suggesting women are attributing age-related menopausal symptoms to preventive therapy. To ensure women experience the full benefit of preventive therapy, interventions are required to support the management of menopausal symptoms and to promote adherence. The higher rate of drop-out in the early months of the trial suggests early intervention may be an effective way to promote long-term adherence. Citation Format: Smith SG, Sestak I, Forbes J, Howell A, Cuzick JJ. Menopausal symptoms as predictors of long-term adherence in the International breast cancer intervention study (IBIS-1) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S5-03.

Abstract OT2-01-11: Phase II of POSEIDON: A phase Ib / randomized phase II trial of tamoxifen plus taselisib or placebo in hormone receptor positive, HER2 negative, metastatic breast cancer patients with prior exposure to endocrine treatment

Abstract Background: The combination of PI3K-AKT-mTOR pathway inhibitors with endocrine therapy can improve clinical outcomes of hormone receptor positive (HR+) metastatic breast cancer (MBC) patients. Taselisib is a potent and selective PI3K inhibitor, with greater selectivity against mutant (MUT) PI3Kα isoforms than wild-type (WT) via a unique mechanism. Phase Ib data of POSEIDON with Taselisib + tamoxifen (TAM) demonstrated encouraging activity in patients with heavily pre-treated MBC, with an acceptable toxicity profile (Baird et al, ASCO 2016). The recommended phase II dose (RP2D) was Taselisib 4mg plus TAM 20mg, both administered on a daily continuous schedule. ctDNA monitoring may have value in drug development by (1) assessing predictive biomarkers to therapy, (2) providing an early indication of treatment response, and (3) shedding light on potential mechanisms of acquired drug resistance. In some patients included in phase Ib of POSEIDON, tumor response was preceded by a corresponding early change in plasma PIK3CA ctDNA levels. Methods: The phase II portion of the POSEIDON trial is a two-arm, randomized, double blind study of Taselisib plus TAM versus placebo (PLA) plus TAM in pre- and postmenopausal women with HR+/HER2- MBC. In the first part of the Phase II, 180 patients will be randomized (1:1) to receive continuous TAM with either Taselisib at the RP2D or PLA until disease progression, unacceptable toxicity or patient / physician decision. Crossover is allowed upon progressive disease in those patients receiving PLA plus TAM, after collection of tumor and blood samples for exploratory biomarker analysis. Stratification is based on menopausal status, histology [lobular breast cancer (LBC) vs. ductal/others], PIK3CA mutation (WT vs. exon 9 vs. exon 20), prior everolimus, timing of recurrence/progression after prior endocrine therapy, number of prior chemotherapy (CT) lines, and treatment center. After recruiting the initial 180 patients, trial will focus in LBC, until a total number of 110 patients with LBC are enrolled. Other key eligibility criteria include presence of measurable or evaluable disease (RECIST 1.1), prior progression to endocrine treatment, maximum of 5 prior CT lines in the metastatic setting, absence of diabetes under medical treatment, and absence of chronic inflammatory bowel disease. Primary endpoint is investigator-assessed PFS. Key secondary endpoints are PFS in LBC, objective response rate, clinical benefit rate, safety, and exploratory biomarker analysis (including ctDNA). The study has a 90% power at a two-sided log-rank test significance level of 0.2 to detect an HR of 0.64, which corresponds to an increase in median PFS from 4.5 months in the PLA plus TAM arm to 7 months in the Taselisib plus TAM arm. Enrollment to POSEIDON Phase II started in June 2016 (Clinicaltrials.gov NCT02285179). Citation Format: Oliveira M, Baird RD, van Rossum AGJ, Beelen K, Garcia-Corbacho J, Mandjes IAM, Vallier AL, van Werkhoven E, Garrigós L, Kumar S, van Tinteren H, Muñoz S, Linossi C, Rosing H, Miquel JM, Schrier M, de Vries Schultink A, Saura C, Gallagher WM, Bernards R, Tabernero J, Cortés J, Caldas C, Linn SC. Phase II of POSEIDON: A phase Ib / randomized phase II trial of tamoxifen plus taselisib or placebo in hormone receptor positive, HER2 negative, metastatic breast cancer patients with prior exposure to endocrine treatment [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-01-11.