Short-term Hormone Therapy Research Articles

Abstract PO1-02-04: The efficacy of endocrine therapy during the waiting period for surgery for hormone receptor-positive breast cancer

Abstract Background: Although neoadjuvant endocrine therapy has been used to improve breast conservation rate, its prognostic relevance is unknown. The search for a valid prognostic factor equivalent to pCR in neoadjuvant chemotherapy is a current challenge in neoadjuvant endocrine therapy. In this study, we investigated the efficacy of short term neoadjuvant endocrine therapy utilizing the waiting period for surgery and the prognostic factor including Preoperative Endocrine Prognostic Index (PEPI) score. Methods: A total of 480 patients with StageⅠ-Ⅲ hormone receptor-positive, HER2-negative breast cancer was treated with endocrine therapy during the waiting period for surgery between October 2012 and December 2021. Premenopausal and postmenopausal patients received tamoxifen (TAM) and non-steroidal aromatase inhibitor (AI), respectively. The primary endpoint was change in tumor size by ultrasound and Ki67 expression before and after short term endocrine therapy. The secondary endpoint was prognosis of patients divided by PEPI score which was calculated using tumor size, lymph node metastasis, Ki67 expression, and ER Allred score. This study was approved by the institutional review board of Teikyo University. Results: Median age and tumor size of the entire 480 patients was 55 years (range, 31 - 89), 1.65 cm (range, 0.4 – 7.5), respectively. The median duration of endocrine therapy was 39 days (range, 1-90). 19 (0.3 %) pts were clinically node-positive. Of the entire 480 patients, 211 and 269 patients had TAM and AI, respectively. After short term endocrine therapy, the tumor size was significantly reduced from 1.83cm to 1.62cm in AI group (p=0.02), although TAM did not decrease the tumor size (p=0.89). The Ki67 expression was significantly decreased from 16.4% to 11.3% in TAM group (p=0.002), and from 15.9% to 6.98% in AI group (p < 0.001). There were significant differences in the distribution of PEPI scores between TAM and AI group (p < 0.05) (Table). At the median follow-up of 1012 days, patients with PEPI score ≥ 4 showed worse disease-free survival compared with patients with PEPI score < 4 in TAM group (Figure1). Overall survival is not available because there were no deaths in TAM group. At the median observation period of 833 days, patients with PEPI score ≥ 4 showed worse disease-free survival compared with patients with PEPI score < 4 in AI group (Figure2). In terms of mortality, patients with PEPI score ≥ 4 had worse overall survival than patients with PEPI score 0 and 1-3 (p=0.07). Conclusions: These results suggested that neoadjuvant endocrine therapy during the waiting period for surgery might be effective in reducing Ki67 expression level and PEPI score might be useful in predicting the prognosis of hormone receptor positive breast cancer patients. Table. Distribution of PEPI score Figure 1. Disease-free survival in patients treated with tamoxifen Figure 2. Disease-free survival in patients treated with non-steroidal aromatase inhibitor Citation Format: Yuka Maeda, Saki Naruse, Yuka Isono, Ayana Sato, Akiko Matsumoto, Tatsuhiko Ikeda, Hiromitsu Jinno. The efficacy of endocrine therapy during the waiting period for surgery for hormone receptor-positive breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-02-04.

Effective Ki-67 Reduction by Pre-Surgery Short-Term Administration of Letrozole in (Hormone-Positive) Breast Cancer.

Antigen Ki-67 (histone-based nuclear protein) is a static marker of tumor cell proliferation and growth and is commonly measured to indicate the effect of treatment in breast cancer patients. This single-arm trial study aimed to evaluate the effect of short-term endocrine therapy (letrozole) on Ki-67 levels in menopausal women with early hormone-positive breast cancer who were referred to two university hospitals. Patients with a pre-treatment Ki67 of 5% or less were excluded from the study. Participants (n=25) received oral letrozole (2.5 mg daily) seven days before surgery. Ki-67% on both biopsies and the surgical specimens were measured and compared. The mean age of patients was 62±9.4 (48-83 years). Our result indicated that pre-surgery consumption of letrozole for hormone-positive breast cancer can significantly decrease the of Ki-67 labeling index (23.24±9.74 vs. 16.92±9.55, P=0.001 by paired t-test), with no drug-related adverse events.

Feasibility of Symptom Monitoring During the First Year of Endocrine Therapy for Early Breast Cancer Using Patient-Reported Outcomes Collected via Smartphone App.

Treatment-associated symptoms drive early discontinuation of adjuvant endocrine therapy (ET) for breast cancer. We hypothesized that symptom monitoring with electronic patient-reported outcomes (ePROs) during adjuvant ET will enhance symptom detection, symptom management, and persistence. Eligible patients were initiating ET for stage 0-III breast cancer. Participants completed ePRO surveys via smartphone at baseline and 1, 3, 6, and 12 months. Measures included Patient-Reported Outcomes Measurement Information System Anxiety, Depression, Fatigue, and Vaginal Discomfort; plus Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events items assessing joint pain, hot flashes, vaginal dryness, concentration problems, and memory problems. Scores surpassing prespecified thresholds triggered alerts, and recommended symptom management pathways were provided to clinicians. The primary objective was to evaluate feasibility, assessed by survey completion rates, with targets of >65% for the baseline survey and ≥1 follow-up survey during the first 6 months. Secondary objectives included 12-month ET discontinuation rate (target: ≤15%), describing symptoms and evaluating pathway implementation. Among 250 participants, 73.2% completed the baseline survey and 69.6% completed ≥1 follow-up survey during the first 6 months. Thirty-one percent of participants had ≥1 symptom alert at baseline and 74% had ≥1 symptom alert during follow-up. The proportions of participants for whom pathway-concordant symptom management was documented at each time point ranged from 12.8% to 36.6%. Twenty-eight participants (11.2%) discontinued ET by 12 months. Symptom monitoring with ePROs during adjuvant ET is feasible. Despite infrequent documentation of pathway-concordant symptom management after symptom alerts, ePROs were associated with favorable short-term ET persistence.

Impact of Long-term Adjuvant Hormonal Therapy in High-dose IMRT for Unfavorable Locally Advanced Prostate Cancer.

The aim of this study was to evaluate the benefit of adding long-term adjuvant hormonal therapy to high-dose intensity-modulated radiation therapy for locally advanced prostate cancer patients with multiple unfavorable risks. All cT3-4N0M0 prostate cancer patients with Gleason score 8-10 and prostate-specific antigen ≥30 ng/ml who received intensity-modulated radiation therapy to the prostate and seminal vesicle alone (78 Gy in 39 fractions) between September 2000 and June 2017 at our institution were analyzed retrospectively. All patients received short-term neoadjuvant hormonal therapy. Before May 2011, salvage hormonal therapy was initiated when prostate-specific antigen levels exceeded 4.0 ng/ml (early salvage hormonal therapy cohort). In June 2011, 2-year adjuvant hormonal therapy was added (adjuvant hormonal therapy cohort). Clinical outcomes were retrospectively compared using the log-rank test. In total, 88 patients (44 in both cohorts) were analyzed. Median follow-up periods were 10.9 and 6.1 years in early salvage hormonal therapy and adjuvant hormonal therapy cohorts, respectively. No significant difference in overall survival rates was observed (p=0.58). Disease controls were significantly better in the adjuvant hormonal therapy cohort: 95.5 versus 73.6% for castration-resistant prostate cancer-free rate (p=0.04), and 73.6 versus 34.1% for biochemical failure-free rate (p<0.001), both at 8 years, respectively. Among locally advanced prostate cancer patients with multiple unfavorable risks, adding long-term adjuvant hormonal therapy to high-dose intensity-modulated radiation therapy resulted in significantly better disease control than short-term hormonal therapy, even when salvaged early after biochemical failure.

Abstract P2-03-19: The efficacy of neoadjuvant endocrine therapy during the waiting period for surgery in postmenopausal hormone receptor positive breast cancer

Abstract Background: Although neoadjuvant endocrine therapy has been used to improve breast conservation rate, its prognostic relevance is unknown. The search for a valid prognostic factor equivalent to pCR in neoadjuvant chemotherapy is a current challenge in neoadjuvant endocrine therapy. In this study, we investigated the efficacy of short term neoadjuvant endocrine therapy utilizing the waiting period for surgery and the prognostic factor including Preoperative Endocrine Prognostic Index (PEPI) score. Patients and Methods: A total of 269 postmenopausal women with hormone receptor-positive, HER2-negative breast cancer was treated with endocrine therapy with non-steroidal aromatase inhibitor during the waiting period for surgery between October 2012 and November 2021. Of the entire 269 patients, 92 and 177 patients had anastrozole and letrozole, respectively. The primary endpoint was change in tumor size by ultrasound and Ki67 before and after short-term endocrine therapy. The secondary endpoint was prognosis of patients divided by PEPI score which was calculated using tumor size, lymph node metastasis, Ki67, and ER Allred score. This study was approved by the institutional review board of Teikyo University. Results: Median age was 68 years old (range, 41-89). ER and PgR was positive in 266 (98%) and 232 (86%) of the entire 269 patients, respectively. Median tumor size was 1.65 cm (range, 0.4-7.5). Seventeen (6.3%) pts were clinically node-positive. Patients with histological grade I tumor were 190 (70.6%). The median duration of endocrine therapy was 39 days (range, 2-88). Average pretreatment Ki67 expression was 10% (range, 0-90). Tumor diameter was significantly decreased to 1.43cm (range,0.45-5.83) after short-term endocrine therapy (p=0.01). The Ki67 expression was significantly decreased to 3.0% (range, 0-85) after endocrine therapy (p&amp;lt; 0.01) and only five patients (1.9%) showed marked increase in Ki-67 expression. PEPI score 0, 1-3 and ≥ 4 was found in 83 (30.9%),147 (54.7%) and 39 patients (14.5%), respectively. After the median observation period of 928 days, patients with PEPI score ≥ 4 showed worse disease-free survival (Figure) compared with patients with PEPI score 0 and 1-3 (p=0.06). In terms of mortality, patients with PEPI score ≥ 4 had worse overall survival than patients with PEPI score 0 and 1-3 (p=0.07). Conclusions: These results suggested that neoadjuvant endocrine therapy during the waiting period for surgery might be effective in reducing the size and Ki67 expression level and PEPI score might be useful in predicting the prognosis of postmenopausal hormone receptor positive breast cancer patients. Citation Format: Yuka Maeda, Saki Naruse, Yuka Isono, Ayana Sato, Miki Yamada, Akiko Matsumoto, Tatsuhiko Ikeda, Hiromitsu Jinno. The efficacy of neoadjuvant endocrine therapy during the waiting period for surgery in postmenopausal 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 P2-03-19.

Evaluation of the role of human chorionic gonadotropin therapy in the management of retractile testes in children

Background and objective: Retractile testis is relatively common in pediatric population. This study followed up boys with retractile testis to investigate the natural course and the need for hormonal therapy and surgical treatments. Methods: A total of 110 boys aged 1.5-10.1 years (mean: 3.2 years) diagnosed as retractile testes, 67 (60.9%) unilateral and 43 (39.09%) bilateral. The mean follow-up period was 4.9±1.3 years. The diagnosis is confirmed on history and examination and ultrasound was made for measuring the size of the testis. Results: A total of 47 (42.72%) cases received human chorionic gonadotropin (17 bilateral and 30 unilateral). Response occurred in 32 boys (68.1%),12 bilateral and 20 unilateral. Failure of response occurred in 15 boys (31.9%). Fourteen of 110 boys (12.72 %) were referred for orchiopexy, including 1 of 12 (8.3%) of bilateral cases and 2 of 20 (10%) of unilateral cases who responded to human chorionic gonadotropin injection, 2 of 5 bilateral cases (40%) and 1 in 10 unilateral cases (10%) in those did not respond to treatment. In those who did not receive treatment, orchiopexy was performed in 6 of 26 bilateral cases (23.1) and in 2 of 37 unilateral cases (5.4%). Conclusion: Although testicular descent was achieved by short-term hormone therapy, the study revealed that there is no significant statistical difference for the need for orchiopexy between those received and those did not receive human chorionic gonadotropin.

Obesity and metabolic syndrome are associated with short-term endocrine therapy resistance in early ER + breast cancer.

Increased body mass index (BMI) and metabolic syndrome (MS) are associated with increased breast cancer recurrence risk. Whether this is due to intrinsic tumor biology or modifiable factors of the obese state remains incompletely understood. Oncotype DX Recurrence Scores of 751 patients were stratified by BMI to assess association with tumor-intrinsic recurrence risk. Cellular proliferation by Ki67 after 10-21days of presurgical letrozole treatment was used to stratify endocrine therapy response (sensitive-ln(Ki67) < 1; intermediate-ln(Ki67)1-2; resistant-ln(Ki67) > = 2). BMI at the time of surgery and MS variables were collected retrospectively for 143 patients to analyze association between therapy response and BMI/MS. Additionally, PI3K pathway signaling was evaluated by immunohistochemistry of phosphorylated Akt and S6. There was no significant association between BMI and recurrence score (p = 0.99), and risk score distribution was similar across BMI groups. However, BMI was associated with short-term endocrine therapy resistance, with a significant enrichment of intermediate and resistant tumors in patients with obesity (55%, p = 0.0392). Similarly, the relative risk of an endocrine therapy-resistant tumor was 1.4-fold greater for patients with MS (p = 0.0197). In evaluating PI3K pathway mediators, we found patients with 3 or more MS criteria had more tumors with pAkt scores above the median (p = 0.0436). There were no significant differences in S6 activation. Our findings suggest the association between obesity/metabolic syndrome and breast cancer recurrence is better reflected by response to treatment than tumor-intrinsic properties, suggesting interventions to reverse obesity and/or MS may improve outcomes for breast cancer recurrence.

De‐escalation of five‐year adjuvant endocrine therapy in patients with estrogen receptor‐low positive (immunohistochemistry staining 1%‐10%) breast cancer: Propensity‐matched analysis from a prospectively maintained cohort

BackgroundThe standard 5 years of endocrine therapy has demonstrated additional benefits compared with short‐term (2‐3 years) treatment in patients with estrogen receptor (ER)‐positive breast cancer; however, data specific to ER‐low positive breast cancer (1%‐10% by immunohistochemistry) are limited, and it is unclear whether long‐term treatment is still necessary for this subgroup.MethodsThe authors used the prospectively maintained Breast Surgery Database of Fudan University Shanghai Cancer Center for this propensity‐matched analysis. The primary end point was disease‐free survival. Multivariate Cox regression analysis and propensity score‐matching methods were used to minimize bias. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. All statistics were 2‐sided.ResultsFrom 2012 to 2017, 22,768 consecutive women had pathologically confirmed, early stage breast cancer, and 1013 (4.45%) were identified with ER‐low positive disease. Among these, 634 patients met the inclusion criteria and were divided into 3 groups: those who received no endocrine therapy (n = 89), those who received 2 to 3 years of endocrine therapy (n = 185), and those who received approximately 5 years of endocrine therapy (n = 360). At a median follow‐up of 65 months, there was no significant difference in disease‐free survival between patients who received 2 to 3 years and 5 years of endocrine therapy (HR, 0.82; 95% CI, 0.51‐1.33; P = .43). The findings were consistent after multivariate Cox analysis of the propensity score‐matched samples (5 vs 2‐3 years of treatment: HR, 0.74; 95% CI, 0.41‐1.31; P = .30).ConclusionsShort‐term endocrine therapy for 2 to 3 years might be an alternative for patients who have ER‐low positive breast cancer instead of the standard 5 years of treatment.

Body Composition of Transgender Women After Long-Term Hormone Therapy - a Cross-Sectional Study

Introduction: Few studies of transgender women (TW) body composition (BC) in long-term gender-affirming hormone therapy (GAHT) have been reported. Objective: To evaluate BC parameters of TW in long-term GAHT. Methods: A cross-sectional study was carried out with 8 TW (average age of 34.0 yo ±4.8), 8 cisgender men (CM) and 8 cisgender women (CW) matched to age and body mass index (BMI). All TW were non-gonadectomized subjects and were in estrogen [(E); transdermal estradiol (n=2), oral estradiol (n=3) and conjugated estrogen (n=3)], plus cyproterone acetate (CA) (n=8) therapy in an average time of 15.6 ±8.7 years of treatment. Total testosterone (ng/dL) levels of TW, CW and CM were 83,5 (range 12,0-637,0), 20,5 (range 12,0-41,0) and 480,5 (range 264,0-843,0) at the time of the study, respectively. BC was assessed by InBody 720. Percentage of fat mass (%FM), skeletal muscle mass (SMM) were evaluated. Baumgartner Index was calculated. Results: Regards %FM, that of TW was lower than CW (29,59 ±7,56 vs 32,9 ±3,99; p=0,5394) and higher than CM (23,58 ± 6,44; p=0.1512). SMM of TW was 33.6% higher than that of CW (p<0.001) and 14,7% lower than that of CM (p=0,014). Baumgartner Index of CM group was 17.7% higher than TW group (p=0,001), which presented rates 20.3% higher than the CW (0,002). Discussion: BC changes in the first two years of GAHT in TW were consistent with loss of lean mass and gained fat mass associated with an increase of body weight. This profile was identified in adults and youth transgender after short-term hormone therapy. Conclusion: Our data shown a similar profile of short-term treatment, with a body composition intermediate between BMI-matched cisgender males and females. However, unlike young TW undergoing short-term GAHT, the parameters of BC in the TW using estrogens plus cyproterone acetate in the long term did not present %FM statistically different from CW and CM, in contrast to the lean mass that maintained significant differences in the long term.

Phase III randomized trial of PSMA PET prior to definitive radiation therapy for unfavorable intermediate-risk or high-risk prostate cancer [PSMA dRT]: Study protocol NCT04457245.

TPS172 Background: Definitive radiation therapy (dRT) is an effective initial treatment of intermediate-risk (IR) and high-risk (HR) prostate cancer (PCa). Positron emission tomography (PET) using small molecule probes targeting prostate-specific membrane antigen (PSMA PET) is superior to standard of care imaging (CT, MRI, bone scan) for detecting regional and distant metastatic PCa. PSMA PET thus has the potential to guide primary radiotherapy planning in patients and improve outcomes. The purpose of the present randomized trial is to evaluate the success rate of dRT for IR or HR PCa with and without planning based on PSMA PET. Methods: We will randomize 312 patients to proceed with standard dRT (control Arm 1, n=150), or undergo a PSMA PET scan prior to dRT planning (intervention arm 2, n = 162). In the control arm, dRT will be performed as routinely planned in accordance with initial stratification. In the intervention arm, the treating radiation oncologist can incorporate PSMA PET findings into the RT planning. We assume that approximately 8% of subjects randomized to arm 2 will be found to have M1 disease and thus will be more appropriate candidates for long-term systemic or multimodal therapy, rather than curative intent dRT. PET M1 patients will thus not be included in the analysis of the primary endpoint. The primary endpoint is the success rate of dRT measured as PFS after initiation of dRT. Progression is defined as (whichever occurs first): biochemical recurrence defined as a rise by 2 ng/mL or more above the nadir PSA (defined as the lowest PSA achieved) after radiotherapy with or without short-term hormonal therapy; appearance of metastasis or loco-regional recurrence (diagnosed by any imaging or biopsy); initiation of any new salvage therapy, or death from any cause. Discussion: This is the first randomized phase 3 prospective trial designed to determine whether PSMA PET molecular imaging can improve outcomes in patients with PCa who receive dRT. In this trial the incorporation of PSMA PET may improve the success rate of curative intent radiotherapy in two ways: to optimize patient selection and to personalizes the radiotherapy plan. Clinical trial registration: IND#147591, UCLA IRB #20-000378, ClinicalTrials.gov Identifier NCT04457245. Clinical trial information: NCT04457245.

Abstract P5-13-04: Gene expression profiling of breast cancers between high and low Ki-67 after short-term preoperative hormone therapy among hormone receptor-positive / human epidermal growth factor receptor 2-negative breast cancers with high Ki-67

Abstract Background In hormone receptor (HR)-positive / human epidermal growth factor receptor 2 (HER2)-negative breast cancers, high Ki-67 predicts poor prognosis. Recently, it has been reported that among breast cancers with high Ki-67, low Ki-67 after short-term preoperative hormone therapy (post Ki-67) might predict favorable prognosis compared to high post Ki-67 (SABCS 2017). However, the differences in gene expression profiling of breast cancers between high and low post Ki-67 among high Ki-67 before treatment are unclear. Therefore, this study aimed to clarify genetic differences in two groups and to explore novel therapeutic targets for the poor prognostic group after the treatment. Methods Seventy-seven patients with primary HR-positive / HER2-negative breast cancer who received an aromatase inhibitor for 2 weeks [NCBI Gene Expression Omnibus repository GSE80077:19 cases, GSE20181:58 cases] were enrolled in this study. Forty-five patients with high pre Ki-67 among them were stratified into two groups, high (H→H) and low (H→L) post Ki-67 after short-term preoperative hormone therapy. We compared gene expression profiling in two groups about the followings. 1) 3 genes (ESR1, PGR and ERBB2) related to classical clinical treatment strategy of breast cancer, immune- and inflammatory-related genes 2) 178 pathways (gene set analysis) 3) 41 genes that are targeted by FDA-approved drugs or have been investigated with clinical trials as molecular target agents for various malignant tumors including breast cancer Results 1) TNF that is inflammatory-related gene were significantly overexpressed in H→L group (P=0.021). However, 3 genes related to clinical treatment of breast cancer and immune-related genes expression had no significant difference between two groups. 2) 5 gene sets (Tryptophan metabolism, Propanoate metabolism, beta-Alanine metabolism, SNARE interactions in vesicular transport and Nucleotide excision repair) were significantly upregulated in H→L group. (P ≤ 0.005) 3) 5 targeted genes (PARP, BRCA2, FLT4, CDK6 and PDCD1LG2) were significantly overexpressed in H→H group (P ≤ 0.05). Conclusions There were different gene expression and biological processes in two groups stratified by post-Ki67. In the future, it is necessary to seek new therapeutic strategies for poor prognostic group with high post-Ki67 in considerations of these differences. Citation Format: Yukiko Kajiwara, Takayuki Iwamoto, Yusuke Otani, Miwa Fujihara, Yoko Suzuki, Minami Hatono, Takahiro Tsukioki, Kengo Kawada, Mariko Kochi, Hirokuni Ikeda, Tadahiko Shien, Naruto Taira, Hiroyoshi Doihara. Gene expression profiling of breast cancers between high and low Ki-67 after short-term preoperative hormone therapy among hormone receptor-positive / human epidermal growth factor receptor 2-negative breast cancers with high Ki-67 [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 P5-13-04.

Abstract P2-11-17: Expression levels of some genes associated with tumor shrinkage by neoadjuvant endocrine therapy were paradoxically related with poor prognosis in patients with ER-positive/HER2-negative operable breast cancer

Abstract Purpose: We previously published that the expression levels of 5 genes (ADCK2, CUL2, FAM13A, KRAS, LILRA2) related to tumor shrinkage by neoadjuvant endocrine therapy (NAET) were identified though the gene expression profiles (Goto-Yamaguchi L et al, Breast Cancer Res Treat. 72:353-362,2018). In this study, we examined whether expression levels of these 5 genes were associated with prognosis in patients with ER-positive/HER2-negative operable breast cancer. Methods: Formalin-fixed paraffin embedded tumor tissues before systemic treatment were provided by 273 patients with ER-positive/HER2-negative operable breast cancer receiving standard of care at our institute from June 2000 to January 2011. We examined gene expression levels of these 5 genes determined by real time-quantitative PCR using RNA extracted from the tumor samples. We analyzed the prognostic impact of these 5 genes in terms of relapse-free survival (RFS) and breast cancer-specific survival (BCSS). We also study the relationship between 5 genes expression and clinic-pathological factors. Results: Median follow-up time was 106 months. Among 5 genes, high expression levels of ADCK2 and CUL2 were significantly related with poor PFS (log-rank test, ADCK2: p=0.022, CUL2: p0.045) but not BCSS. On the other hand, high levels of FAM13A expression were significantly poor BCSS (log-rank test, p=0.042) but not RFS. Expression of KRAS and LILRA2 were not any correlation with prognosis. Multivariate analysis in terms of RFS revealed that ADCK2 was an independent prognostic factor (HR 2.26, 95%CI 1.04 to 5.07, p = 0.038). In addition, multivariate analysis in terms of BCSS revealed that FAM13A (HR 15.6, 95%CI 2.36 to 316.0, p = 0.0029), nodal status (HR 8.22, 95%CI 1.57 to 62.9, p=0.012) and PgR (HR 0.14, 95%CI 0.0068 to 0.93, p=0.042) were independent prognostic factors. Expression of ADCK2 and CUL2 were not associated with any clinic-pathological factors such as menopausal status, tumor size, nodal status, expression levels of ER and PgR, nuclear grade and ki67 labeling index. FAM13A expression was positively correlated with ki67 labeling index (chi-square test, p=0.0007). Conclusion: Despite the genes associated with tumor shrinkage by NAET, ADCK2, CUL2 and FAM13A among the genes were positively correlated with poor prognosis. This paradoxical phenomenon showed that endpoint of short-term endocrine therapy such as tumor shrinkage may not be reflect that of long-term endocrine therapy such as PFS and BCSS. Citation Format: Lisa Goto-Yamaguchi, Mutsuko Ibusuki-Yamamoto, Masako Takeno, Yositaka Fujiki, Mai Tomiguchi, Aiko Sueta, Yutaka Yamamoto. Expression levels of some genes associated with tumor shrinkage by neoadjuvant endocrine therapy were paradoxically related with poor prognosis in patients with ER-positive/HER2-negative operable breast cancer [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 P2-11-17.

Assessing the Role and Optimal Duration of Hormonal Treatment in Association with Salvage Radiation Therapy After Radical Prostatectomy: Results from a Multi-Institutional Study

BackgroundThe optimal duration of hormonal therapy (HT) when associated with postprostatectomy radiation therapy (RT) remains controversial. ObjectiveTo test the impact of HT duration among patients treated with postprostatectomy RT, stratified by clinical and pathologic characteristics. Design, setting, and participantsThe study included 1264 patients who received salvage RT (SRT) to the prostatic and seminal vesicle bed at eight referral centers after radical prostatectomy (RP). Patients received SRT for either rising prostate-specific antigen (PSA) or PSA persistence after RP, defined as PSA ≥0.1ng/ml at 1mo after surgery. Administration of concomitant HT was at the discretion of the treating physician. Outcome measurements and statistical analysisThe outcome of interest was clinical recurrence (CR) after SRT, as identified by imaging. Multivariable Cox regression analysis was used to test the association between CR and HT duration. We applied an interaction test between HT duration and baseline risk factors to assess the hypothesis that CR-free survival differed by HT duration according to patient profile. Three risk factors were prespecified for evaluation: pT stage ≥pT3b, pathologic Gleason ≥8, and PSA level at SRT >0.5 ng/ml. The relationship between HT duration and CR-free survival rate at 8yr was graphically explored according to the number of risk factors (0 vs 1 vs ≥2). Results and limitationsOverall, 1125 men (89%) received SRT for rising PSA and 139 (11%) were treated for PSA persistence. Concomitant HT was administered to 363 patients (29%), with a median HT duration of 9mo. At median follow-up of 93mo after surgery, 182 patients developed CR. The 8-yr CR-free survival was 92%. On multivariable analysis, HT duration was inversely associated with the risk of CR (hazard ratio 0.95; p=0.022). A total of 531 (42%) patients had none of the prespecified risk factors, while 507 (40%) had one and 226 (18%) had two or more risk factors. The association between HT duration and CR was significantly different by risk factors (0 vs 1, p=0.001; 0 vs ≥2, p<0.0001). We observed a significant effect of HT duration for patients with two or more risk factors, for whom HT administration was beneficial when given for up to 36mo. This effect was attenuated among patients with one risk factor, with concomitant HT slightly beneficial when administered for a shorter time (<12mo). Conversely, for patients with no risk factors, the risk of CR remained low and constant regardless of HT duration. ConclusionsThe oncologic benefit of HT duration among men receiving SRT for increasing PSA after RP depends on their clinical and pathologic characteristics. Our data suggested a significant effect of long-term HT for patients with two or more adverse features. Conversely, short-term HT was sufficient for patients with a single risk factor, whereas patients without any risk factors did not show a significant benefit from concomitant HT. Patient summaryWe tested the impact of hormonal therapy (HT) duration during radiation therapy after radical prostatectomy. We identified three risk factors and observed a different impact of HT duration by clinical and pathologic characteristics. Patients with more adverse features benefit from long-term concomitant HT. On the contrary, for patients with a single risk factor, short-term HT may be reasonable. Patients without any risk factors did not show a significant benefit from concomitant HT.

Adjuvant hormone therapy after radical prostatectomy in high-risk localized and locally advanced prostate cancer: First multicenter, observational study in China.

ObjectivePotential of combined androgen blockade (CAB) has not been explored extensively in Chinese males with prostate cancer (PCa). Therefore, this study evaluated the 2-year prostate-specific antigen (PSA) recurrence rate and quality of life (QoL) in patients with high-risk localized and locally advanced PCa receiving adjuvant hormone therapy (HT) after radical prostatectomy (RP).MethodsThis prospective, multicenter, observational study conducted in 18 centers across China enrolled patients with high-risk factor (preoperative PSA>20 ng/mL or Gleason score >7) or locally advanced PCa. Different adjuvant HT were administered after RP according to investigator’s decision in routine clinical practice. Relationship of baseline and postoperative characteristics was assessed with recurrence rate. PSA recurrence rate and Functional Assessment of Cancer Therapy-Prostate (FACT-P) QoL scores were recorded at 12 months and 24 months. Kaplan-Meier analysis was used to construct the PSA recurrence rate during follow-up.ResultsA total of 189 patients (mean age: 66.9±6.5 years) were recruited, among which 112 (59.3%) patients showed serum PSA>20 ng/mL preoperatively. The highest postoperative pathological advancement noticed was from clinical T2 (cT2) to pathological T3 (pT3) (43.9%) stage. The majority of the patients (66.1%) received CAB as adjuvant HT, for a median duration of 20.0 months. The least recurrence (15.2%) was noticed in patients treated with CAB, followed by those treated with luteinizing hormone-releasing hormone agonist (LHRHa) (16.1%), and antiandrogen (19.0%), with non-significant difference noted among the groups. None of the baseline or postoperative characteristics was related with PSA recurrence in our study. The 24-month FACT-P QoL score of 119 patients treated for >12 months showed significant improvement above baseline compared with those treated for ≤12 months.ConclusionsAdjuvant CAB therapy after RP showed reduction trend in 2-year PSA recurrence rate in high-risk Chinese patients with localized and locally advanced PCa, compared with adjuvant anti-androgens (AA) or LHRHa therapy. Further long-term therapy (>12 months) significantly improved QoL compared to short-term HT therapy, suggesting the beneficial effect of long-term CAB therapy in improving QoL.

Salvage radiotherapy with or without hormone therapy: for whom and when?

We thank Dr. Williams for their comments (1) on the recent published results of the GETUG 16 trial (2) and the potential impact that could have these results on daily practice. First, as it was underlined in the publication, it is truth that 5 years is a too short time for determining an impact on overall survival but the disease-free survival was the primary end point of the trial and by increasing the biological relapse free survival (BRFS) we avoid secondary treatments such as chemotherapy or second line of hormone therapy for one third of patients compare to salvage radiotherapy alone arm. I agree also with Williams: in a next future, a probably dramatic improvement to identified subclinical metastases would avoid for some patients an inappropriate radiotherapy treatment, but that means also that selected patients with pure pelvic or prostate bed relapse would have a higher benefit of salvage radiotherapy combined with short term hormone therapy.

The effect of hormone therapy on quality of life and breast cancer risk after risk-reducing salpingo-oophorectomy: a systematic review

BackgroundIt is unclear if the use of hormone therapy (HT) in carriers of BRCA mutations improves the quality of life (QOL) without increasing the risk of breast cancer following a risk-reducing salpingo-oophorectomy (RRSO). Our objective was to assess the effect of HT on QOL and breast cancer risk, after RRSO.MethodsWe searched MEDLINE, EMBASE, CINHAL, and others, from inception to July 22, 2016, to identify relevant studies. Two reviewers independently screened identified records for controlled trials and observational studies that addressed the effect of HT on QOL and breast cancer risk in women with BRCA mutations, post RRSO. Two reviewers independently extracted data on populations, interventions, comparators, outcomes, and methodological quality. Studies addressing the same outcome were synthesized using written evidence summaries or tables.ResultsOf the 1,059 records identified, 13 met our inclusion criteria. All studies were observational. Six studies assessed the effect on QOL. Of these, 3 showed improvement in QOL with HT use. The risk of breast cancer was evaluated in 4 studies. The mean duration of follow-up was 2.6 years (range 0.1-19.1). The risk of breast cancer did not change with HT use in all 4 studies.ConclusionsCumulative evidence from our review suggests that short-term HT use following RRSO improves QOL. The effect on breast cancer risk is still unclear. There are too few long-term studies to draw any strong conclusions. The need for future well-designed RCTs for more established evidence is imperative.

Immunohistochemical Ki67 after short-term hormone therapy identifies low-risk breast cancers as reliably as genomic markers.

BackgroundThe purpose of this study was to test whether immunohistochemical (IHC) Ki67 levels after short-term preoperative hormone therapy (post-Ki67) predict similar numbers of patients with favorable prognoses as genomic markers.ResultsThirty paired cases (60 samples) were enrolled in this study. Post-Ki67 levels were significantly lower than pre-treatment Ki67 levels (P < 0.001). Post-Ki67 predicted more low-risk cases (83.3%, 25/30) than pre-genomic surrogate signature(GSS) (66.7%: 20/30), but the difference in predictive power was not significant (P = 0.233). Proliferation (MKI67, STK15, Survivin, CCNB1, and MYBL2) and estrogen (ER, PGR, BCL2, and SCUBE2) related signatures were significantly downregulated after therapy (P < 0.001 and 0.041, respectively).Materials and MethodsCore needle biopsy specimens of primary breast cancer were collected at Okayama University Hospital from hormone receptor-positive and human epidermal growth factor 2-negative patients that subsequently received two weeks of neoadjuvant hormone therapy. Paired post-treatment specimens from surgical samples were also collected. IHC Ki67 levels and GSS were compared between pre- and post-hormone treatment samples. Changes of gene expression pattern in short-term hormone therapy were also assessed.ConclusionsIHC based post-Ki67 levels may have distinct predictive power compared with the naïve IHC Ki67. Future studies with larger cohorts and longer follow-up periods may be needed to validate our results.

Invited commentary on GETUG-AFU 16

I am grateful to accept the invitation to provide this commentary on the recently published article entitled “Salvage radiotherapy with or without short-term hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomized, multicenter, open-label phase 3 trial” (1). This important trial adds to the salvage radiotherapy literature which historically has been largely populated with retrospective analyses. The GETUG-AFU 16 trial observed improved progression-free survival when 6 months of goserelin was added to radiotherapy. In this short note I will provide a critical appraisal of the GETUG study, briefly describe another trial of salvage radiotherapy and androgen suppression (RTOG/NRG Oncology 96-01) and at the end describe how I incorporate the findings of each of these studies into my practice.

Effect of Long-Term Hormonal Therapy (vs Short-Term Hormonal Therapy): A Secondary Analysis of Intermediate-Risk Prostate Cancer Patients Treated on NRG Oncology RTOG 9202

NRG Oncology RTOG 9202 was a randomized trial testing long-term adjuvant androgen deprivation (LTAD) versus initial androgen deprivation only (STAD) with external beam radiation therapy (RT) in mostly high-risk and some intermediate-risk prostate cancer patients. RTOG 9408 found an overall survival (OS) advantage in patients with cT1b-T2b disease and prostate-specific antigen (PSA) <20ng/mL, with benefit observed mostly among intermediate-risk patients. It was still unknown whether intermediate-risk patients would experience an additional survival benefit with LTAD; thus, we performed a secondary analysis to explore whether LTAD had any incremental benefit beyond STAD among the intermediate-risk subset of RTOG 9202. The study endpoints were OS, disease-specific survival (DSS), and PSA failure (PSAF). An analysis was performed for all patients enrolled in RTOG 9202 defined as intermediate-risk (cT2 disease, PSA<10ng/mL, and Gleason score=7 or cT2 disease, PSA 10-20ng/mL, and Gleason score <7). This review yielded 133 patients: 74 (STAD) and 59 (LTAD). The Kaplan-Meier method was used to estimate OS; the cumulative incidence approach was used to estimate DSS and PSAF. A 2-sided test was used, with significance level defined to be .05. With over 11years of median follow-up, 39 STAD patients were alive and 33 LTAD patients were alive. There was no difference in OS (10-year estimates, 61% STAD vs 65% LTAD; P=.53), DSS (10-year DSS, 96% vs 97%; P=.72), or PSAF (10-year PSAF, 53% vs 55%; P=.99) between groups. LTAD did not confer a benefit in terms of OS, DSS, or PSAF rates in the intermediate-risk subset in this study. Whereas the subset was relatively small, treatment assignment was randomly applied, and a trend in favor of LTAD would have been of interest. Given the small number of disease-specific deaths observed and lack of benefit with respect to our endpoints, this secondary analysis does not suggest that exploration of longer hormonal therapy is worth testing in the intermediate-risk prostate cancer subset.

Postmenopausal Hormone Therapy and Risk of Stroke: Impact of the Route of Estrogen Administration and Type of Progestogen.

The benefit/risk analysis of hormone therapy in postmenopausal women is not straightforward and depends on cardiovascular disease. Evidence supports the safety of transdermal estrogens and the importance of progestogens for thrombotic risk. However, the differential association of oral and transdermal estrogens with stroke remains poorly investigated. Furthermore, there are no data regarding the impact of progestogens. We set up a nested case-control study of ischemic stroke (IS) within all French women aged 51 to 62 years between 2009 and 2011 without personal history of cardiovascular disease or contraindication to hormone therapy. Participants were identified using the French National Health Insurance database, which includes complete drug claims for the past 3 years and French National hospital data. We identified 3144 hospitalized IS cases who were matched for age and zip code to 12 158 controls. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI). Compared with nonusers, the adjusted ORs of IS were1.58 (95% CI, 1.01-2.49) in oral estrogen users and 0.83 (0.56-1.24) in transdermal estrogens users (P<0.01). There was no association of IS with use of progesterone (OR, 0.78; 95% CI, 0.49-1.26), pregnanes (OR, 1.00; 95% CI, 0.60-1.67), and nortestosterones (OR, 1.26; 95% CI, 0.62-2.58), whereas norpregnanes increased IS risk (OR, 2.25; 95% CI, 1.05-4.81). Both route of estrogen administration and progestogens were important determinants of IS. Our findings suggest that transdermal estrogens might be the safest option for short-term hormone therapy use.