Primary Endocrine Therapy Research Articles

Cytoplasmic cyclin E independently predicts recurrence in older patients with primary breast cancer.

3128 Background: Primary breast cancer in the older ( > 70 years) population has distinct biological characteristics associated with favourable outcome, such as higher rate of estrogen receptor (ER) positivity. Due to comorbidities, older patients with primary breast cancer are more likely to die of non-breast cancer-related causes compared to their younger counterparts. Biomarkers that may influence treatment strategy therefore require interpretation in the specific biological and clinical context of older women. Cyclin E regulates cell cycle transition from G1 to S phase, and its deregulation is implicated in breast cancer pathogenesis. Tumour-specific isoforms of cyclin E localise to the cytoplasm. Expression of cytoplasmic cyclin E (c-cyclin E) is linked with poor clinical outcome. We now present multivariate analysis of breast cancer-specific survival (BCSS) by c-cyclin E and clinical markers of disease biology from a cohort of older women. The primary outcome, BCSS, excludes deaths from competing causes and is used as a surrogate for tumour biology. Methods: Between 1973 and 2010, 813 older women underwent initial surgery for early breast cancer and were followed up in a dedicated clinic in Nottingham. Excised tumours from 517 of these patients were successfully incorporated into a tissue microarray (TMA). Expression of c-cyclin E was assessed by IHC using an assay developed at MDACC, along with a panel of 24 biomarkers. Of these, ER, progesterone receptor (PR), human epidermal growth factor 2 (HER2) and Ki67 are in current clinical use and are analysed alongside c-cyclin E. Grade was assessed from the primary tumour. Multivariate analysis of BCSS was performed by Cox proportional hazard test. Results: In multivariate analysis alongside markers of disease biology currently used in the clinic (ER, PR, HER2, Ki67 and grade), c-cyclin E is the only factor that independently predicts BCSS in this cohort of older women (HR 5.0, 95% CI 2.1 – 12.0; p< 0.001). Conclusions: In the older population with primary breast cancer, c-cyclin E expression is the only independent biological marker of BCSS. Patients with low c-cyclin E expression are unlikely to die of breast cancer. These data have potential to influence treatment strategy in older patients. For example, patients with ER+, c-cyclin E negative disease plus multiple co-morbidities may be suitable for primary endocrine therapy. This hypothesis warrants prospective clinical evaluation.

Family history in primary hormone therapy for prostate cancer from a community-based multi-institutional Japan-wide database.

e16549 Background: Although a positive family history is known to increase the risk of morbidity of prostate cancer, little is known about the prognoses with hormone therapy of individuals with familial prostate cancer. Thus, in this study we aimed to determine the associations between hormone therapy and outcomes of a cohort of men with familial prostate cancer from a large community-based multi-institutional Japan-wide registry. Methods: Data of patients with prostate cancer who had received hormone therapy were extracted from a nationwide community-based database established by the Japan Study Group for Prostate Cancer. Family history of prostate cancer was available for 15,873 of these patients, who thus comprised the study cohort. Prognostic variables, including progression-free survival, cancer-specific survival, and overall survival, were compared between men with familial and men with sporadic prostate cancer. Results: A positive family history was identified in 247 patients (1.6%). Patients with a positive family history were younger than those without; however, other clinicopathological characteristics and prognoses were comparable. In subgroup analysis, family history was identified as a significant favorable prognostic factor for progression-free survival among patients treated by castration, as was overall survival among patients with PSA level at diagnosis less than 100 ng/mL and those with low or intermediate J-CAPRA risk. Conclusions: Our findings indicate that familial prostate cancer has an early-onset feature or is diagnosed earlier than sporadic prostate cancer. However, with hormone therapy the prognoses of individuals with familial prostate cancer are comparable to those of individuals with sporadic prostate cancer.

27-year patterns in high-risk prostate cancer treatment in a racially diverse, equal-access health care setting.

e16583 Background: Despite the significant stage migration of prostate cancer (CaP), a large proportion of patients harbor high-risk disease. Few CaP series provide long term outcomes with the ability to assess disparities in diverse populations. We examined 27-year outcomes among men treated for high risk CaP in a large, racially diverse, equal access system. Methods: A retrospective cohort study was conducted of patients enrolled into the Center for Prostate Disease Research (CPDR) Multi-Center National Database from 1990-2017. There were 2,241 CaP patients who were NCCN-defined high risk, had a self-reported race of Caucasian (CA) or African American (AA), and had a primary treatment of hormonal therapy (HT), radical prostatectomy (RP), radiation therapy (RT) or no treatment (NoTX). Demographic and clinico-pathological variables were evaluated and stratified by race and treatment. Primary study outcomes included temporal patterns in race-specific treatment intensity and type(s). Secondary outcomes included biochemical recurrence (BCR)-free survival (BRFS) and distant metastasis-free survival (DMFS). Unadjusted Kaplan-Meier estimation curves and multivariable Cox proportional hazards analysis were used. Results: Mean patient age at CaP diagnosis and follow-up time were 68.1 years and 7.8 years, respectively. AAs made up 26.9% of the study cohort. Median prostate specific antigen level was 20.9 ng/mL (IQR: 7.8 - 35.0). 52% of patients had a biopsy Gleason score of 8 or greater. 714 (31.9%) underwent RP, 966 (43.1%) underwent RT, 288 (12.9%) received primary HT, and 273 (12.2%) had NoTX. A decreasing trend of HT, with stable rates of RP and RT, was observed. Median time to BCR after RP and RT was 1.3 and 3.1 years, respectively. After RP and RT, 51.2% and 39.3% experienced BCR while 10.9% and 12.7% experienced distant metastasis, respectively. There were no significant racial differences in treatment intensity, treatment type, BRFS or DMFS. Conclusions: In this longitudinal series, there was racial comparability for all study outcomes. Moreover, in this high-risk patient series with long-term follow up (median = 6.9 years), nearly 50% did not experience BCR, and only 1 in 10 men developed metastasis.

Oncological control in high-risk prostate cancer after radical prostatectomy and salvage radiotherapy compared to radiotherapy plus primary hormone therapy

IntroductionIn patients with high-risk localized prostate cancer (HRPCa), multimodal treatment plays a fundamental role. ObjectiveTo compare relapse-free survival (RFS) in patients with HRPCa, treated primarily with radiotherapy (RT)+hormone therapy (HT) versus radical prostatectomy (RP) and salvage RT (sRT)±HT when biochemical recurrence (BCR) appears. Material and methodsRetrospective analysis of 226 patients with HRPCa (1996–2008), treated primarily with RT+HT (n=137) or RP (n=89). The Kaplan–Meier method has been used to evaluate survival and the log-rank test has been used to evaluate the contrast between the different categories of the variables. Multivariate analysis has been performed using Cox regression to determine variables with an impact on RFS with statistical significance (p<0.05). ResultsThe median follow-up of the series was 111 (IQR 85–137.5) months. After RT+HT, 32 (23.4%) patients relapsed, and after RP 41 (46.1%) cases, (p=0.0001). When comparing the primary treatments, the RFS at 5 and 10 years was higher after RT+HT versus RP in monotherapy (p=0.001). The primary treatment with RT+HT reduced the risk of BCR when compared to the RP (HR=0.41, p=0.002). The estimation of the RFS at 5 and 10 years after RP+sRT±HT was 89.7 and 87.1%, while after primary RT+HT was 91.6 and 71.1%, respectively (p=0.01). The only factor that behaved as an independent predictor of RFS was the multimodal treatment with RP+sRT±HT when BCR showed up (HR=2.39, p=0.01). ConclusionIn HRPCa, multimodal treatment with RP+sRT±HT if BCR, significantly improves RFS with respect to treatment with RT+HT.

05. Bridging the Age Gap in Breast Cancer - analysis of the impact of Comorbidity, Dementia and Frailty on the rates of surgery in older women

Background: Up to 40% of UK women >70 years with primary operable breast cancer are treated with Primary Endocrine Therapy (PET) rather than surgery, often due to co-existing co-morbidity or frailty. Factors predicting non-surgical treatment were assessed in a large prospective UK cohort study.

P314 - Comparison of treatment outcomes between surgery and primary endocrine therapy for elderly patients with breast cancer

P314 - Comparison of treatment outcomes between surgery and primary endocrine therapy for elderly patients with breast cancer

Primary hormonal therapy for breast cancer in patients aged over 80 years: single unit outcomes

Background. Patients with oestrogen receptor (ER)-positive breast cancer who wish to avoid surgery or those who are considered unsuitable for surgery may be treated with primary hormonal therapy. Elderly patients are more likely to present with more advanced cancers but are less likely to undergo an operation, 39% vs. 90% of those under 50. Recent studies advocate surgery for all patients with operable tumours except those with significant medical co-morbidities. We retrospectively assessed the number of patients treated with this method to determine their outcomes.

Polymer Nanoplatforms at Work in Prostate Cancer Therapy

AbstractProstate cancer (PCa) is the most common male urogenital malignancy worldwide. Surgery, endocrine therapy, radiotherapy, and chemotherapy are the main clinical management options for PCa. However, these three therapies each have limitations. For example, surgery is not suitable for the advanced PCa patients with extensive metastases, and radiotherapy causes serious side effects. Primary endocrine therapy promotes the progression of hormone‐sensitive PCa into the castration‐resistant prostate cancer. Therefore, considering these drawbacks, chemotherapy has become an effective and extensive treatment for PCa. Among the modern therapeutic strategies against advanced PCa, polymer‐nanocarrier‐incorporated formulations have gradually emerged due to their well‐controlled release profiles and improved tumor targeting abilities. The drug delivery systems based on polymer nanoplatforms passively target tumors via the enhanced permeability and retention effect. Simultaneously, stimuli‐responsive polymer nanoplatforms unload cargoes in response to certain stimuli in the tumor area. Furthermore, the active targeting ligand‐conjugated polymer nanoformulations against PCa‐specific markers have also achieved great success in PCa therapies. Herein, the advanced polymer nanoplatforms for PCa therapy are reviewed, while the future development of polymer nanoplatforms for PCa therapy is also predicted.

Efficient development and usability testing of decision support interventions for older women with breast cancer.

BackgroundAround one-third of breast cancers diagnosed every year in the UK are in women aged ≥70 years. However, there are currently no decision support interventions (DESIs) for older women who have a choice between primary endocrine therapy and surgery followed by adjuvant endocrine therapy (surgery+endocrine therapy), or who can choose whether or not to have chemotherapy following surgery. There is also little evidence-based guidance specifically on the management of these older patients. A large UK cohort study is currently underway to address this lack of evidence and to develop two DESIs to facilitate shared decision-making with older women about breast cancer treatments. Here, we present the development and initial testing of these two DESIs.MethodsAn initial prototype DESI was developed for the choice of primary endocrine therapy or surgery+endocrine therapy. Semi-structured interviews with healthy volunteers and patients explored DESI acceptability, usability, and utility. A framework approach was used for analysis. A second DESI for the choice of having chemotherapy or not was subsequently developed based on more focused development and testing.ResultsParticipants (n=22, aged 75–94 years, 64% healthy volunteers, 36% patients) found the primary endocrine therapy /surgery+endocrine therapy DESI acceptable, and contributed to improved wording and illustrations to address misunderstandings. The chemotherapy DESI (tested with 14 participants, aged 70–87 years, 57% healthy volunteers, 43% patients) was mostly understandable, however, suggestions for rewording sections were made. Most participants considered the DESIs helpful, but highlighted the importance of complementary discussions with clinicians.ConclusionIt was possible to use a template DESI to efficiently create a second prototype for a different treatment option (chemotherapy). Both DESIs were acceptable and considered helpful to support/augment consultations. Development of acceptable additional DESIs for similar target populations using simplified methods may be an efficient way to develop future DESIs. Further research is needed to test the effectiveness of the DESIs.

Treatment of elderly breast cancer patients in a breast center in India.

The management of breast cancer in older patients is challenging due to factors such as comorbidities, limited mobility, functional dependence, cognitive functions, and socioeconomic aspects. Data about the outcomes in elderly patients with breast cancer in our country are sparse. The aim of this study was to evaluate and compare the clinical and pathological variables, treatment, and survival outcomes of elderly women (those of 70 years and above) with women under 50 years and those between the ages of 50 and 69 years treated at our center. Prospectively collected clinical and pathological data from January 2007 to December 2014 were recorded and entered into OncoCollect™ software. Statistical analysis was done using Microsoft R Open software. Survival analysis was estimated using Kaplan-Meier curves. A total of 1226 Stage I-III breast cancer patients were treated between January 2007 and December 2014. Of these, 11.3% (139) were aged 70 years and above. Invasive ductal carcinoma was predominant and majority had Stage II disease and grade 1 tumors. Receptor positivity was observed in 79% of elderly patients and 9% had triple-negative disease. Primary hormone therapy was given to 7% of the patients and chemotherapy was administered to 12%. The 5-year overall survival for patients 70 years and older is 85%. Elderly patients are more likely to have an indolent course with low grade and estrogen receptor-positive tumors. For healthy older women, treatment according to standard guidelines including surgery, chemotherapy, and radiation should be followed. However, for those who are unfit and cannot tolerate surgery, primary endocrine therapy is a suitable option.

Anti-androgen monotherapy versus gonadotropin-releasing hormone agonists in men with advanced, non-metastatic prostate cancer: a register-based, observational study

Background: In randomised controlled trials, men with advanced, non-metastatic prostate cancer (PCa) treated with anti-androgen monotherapy (AA) had similar all-cause mortality as men treated with gonadotropin-releasing hormone (GnRH) agonists. Using real-world evidence (i.e., observational data), we aimed to further assess the difference in mortality between these two drug categories.Material and Methods: We emulated a trial using data from Prostate Cancer data Base Sweden 3.0. We specifically focused on men diagnosed in 2006–2012 with high-risk PCa who had no distant metastasis. They either received primary hormonal therapy with AA (n = 2078) or GnRH agonists (n = 4878) who were followed for a median time of 5 years. Risk of death from PCa and other causes was assessed using competing risk analyses and Cox proportional hazards regression analyses, including propensity score matching.Results: The cumulative 5-year PCa mortality was lower for men treated with AA (16% [95% confidence interval, CI, 15–18%]) than men treated with GnRH agonists (22% [95% CI 21–24%]). The 5-year other cause mortality was also lower for men on AA (17% [95% CI 15–19%] compared to men on GnRH agonists (27% [95% CI 25–28%]). In regression analyses, the risk of PCa death was similar, GnRH agonists versus AA (reference), hazard ratio (HR) 1.08 (95% CI 0.95–1.23), but the risk of death from all causes was higher for men on GnRH agonists, HR 1.23 (95% CI 1.13–1.34). Consistent results were seen in the propensity score-matched cohort.Conclusion: Our results indicate that the use of AA as primary hormonal therapy in men with high-risk non-metastatic PCa does not increase PCa-specific mortality compared to GnRH. Using AA instead of GnRH agonists may result in shorter time on/exposure to GnRH-treatment, which may reduce the risk of adverse events associated with this treatment.

In silico screening for ERα down modulators identifies thioridazine as an anti-proliferative agent in primary, 4OH-tamoxifen-resistant and Y537S ERα-expressing breast cancer cells

Most breast cancers (BCs) express estrogen receptor α (ERα) and are treated with the endocrine therapy (ET) drugs 4OH-tamoxifen (Tam) and fulvestrant (ICI 182,780; ICI). Unfortunately, a high fraction of ET treated women relapses and becomes resistant to ET. Therefore, additional anti-BC drugs are needed. Recently, we proposed that the identification of novel anti-BC drugs can be achieved using modulation of the intracellular ERα content in BC cells as a pharmacological target. Here, we searched for Food and Drug Administration (FDA)-approved drugs that potentially modify the ERα content in BC cells. We screened in silico more than 60,000 compounds to identify FDA-approved drugs with a gene signature similar to that of ICI. We identified mitoxantrone and thioridazine and tested them in primary, Tam-resistant and genome-edited Y537S ERα-expressing BC cells. We found that mitoxantrone and thioridazine induced ERα downmodulation and prevented MCF-7BC cell proliferation. Interestingly, while mitoxantrone was found to be toxic for normal breast epithelial cells, thioridazine showed a preferential activity towards BC cells. Thioridazine also reduced the ERα content and prevented cell proliferation in primary, Tam-resistant and genome-edited Y537S ERα expressing BC cells. We suggest that modulation of the intracellular ERα concentration in BC cells can be exploited in in silico screens to identify anti-BC drugs and uncover a re-purposing opportunity for thioridazine in the treatment of primary and metastatic ET resistant BCs.

Patients electing to have PET rather than surgery for operable breast cancer are a high risk of treatment failure.

Primary endocrine therapy (PET) is a treatment option for elderly patients with ER-positive breast cancer enabling frail patients to avoid surgery. As a long-term treatment option, it has been shown to be inferior to surgery in controlling local disease. Decision-making in these patients is crucial in avoiding treatment failure. We examined the influence of decision-making on outcomes of PET failure as a secondary analysis as part of a large observational study. Consecutive patients treated with PET between 2005 and 2015 for operable breast cancers were included in a retrospective observational study in 3 breast centres in the North-East. Treatment decision processes were examined by case note review and outcomes of treatment success or failure recorded. 488 patients were included with mean follow-up of 31months. Overall 63 (12%) experienced treatment failure. 227 (46.6%) were given a choice between surgery and PET at diagnosis. Logistic regression identified older age [OR 0.94 (0.91-0.96) p < 0.001] and reduced mobility [OR 0.6 (0.37-0.97) p 0.036] to be less likely offered surgery. Those offered surgery were more likely to experience treatment failure with PET [SHR 1.78 (1.05-3.02) p 0.033]. Despite a low failure rate in our series (literature failure rates vary between 12 and 85%), these results suggest that those actively offered a choice between surgery and PET are at greater risk of failure when choosing PET.

Hormonal Therapy Resistant Estrogen-receptor Positive Metastatic Breast Cancer Cohort (HORSE-BC) Study : Current Status of Treatment Selection in Japan.

The Hormonal therapy resistant estrogen-receptor positive metastatic breast cancer cohort (HORSE-BC) study is a multicenter observational study evaluating the efficacy and safety of secondary endocrine therapy (ET) for postmenopausal cases of metastatic breast cancer (MBC) with poor response to primary ET. In this initial report we analyze the HORSE-BC baseline data to clarify the current status of treatment selection for MBC in Japan. Baseline data for the 50 patients enrolled in HORSE-BC were analyzed, including patient characteristics, types of secondary ET, and reasons for selecting secondary ET. Postoperative recurrence was detected in 84% of patients (42/50) and de novo stage IV breast cancer in 16% (8/50). Forty-one patients (41/50; 82%) received fulvestrant, 5 patients (10%) received selective estrogen receptor modulators (SERMs), 3 patients (6%) received ET plus a mammalian target of rapamycin (mTOR) inhibitor, and 1 patient received an aromatase inhibitor (AI) as the secondary ET. Forty-five patients selected their secondary ET based on its therapeutic effect, while 14 patients selected it based on side effects. Most patients with progression after primary ET selected fulvestrant as the secondary ET based on its therapeutic and side effects. We await the final results from the HORSE-BC study.

Patient-reported factors influencing the treatment decision-making process of older women with non-metastatic breast cancer: a systematic review of qualitative evidence.

Older women (≥ 70years old) with breast cancer undergo different treatments than young women. Studies have examined factors that influence this disparity, but synthesized patient-reported data are lacking in the literature. This study aims toidentify, appraise, and synthesize the existing qualitative evidence on patient-reported factors influencing older women's decision to accept or decline breast cancer treatment. A systematic review was performed in accordance with Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA) principles. Medline, Embase, CINAHL, and PsycINFO were searched for qualitative studies describing patient-reported factors influencing the decision-making process of older women (≥ 70years old) withnon-metastatic invasive breast cancer. Quality was assessed using the Standards for Reporting Qualitative Research (SRQR) criteria. Common ideas were coded, thematically organized, and synthesized within a theoretical framework. Of 5998 studies identified, 10 met eligibility criteria. The median SRQR total score was 13.04 (IQR 12.84-13.81). The studies represented a range of cancer treatments; most of the studies focused on surgery and primary endocrine therapy. Our data show that the most common patient-reported factors in the decision-making process included treatment characteristics, personal goals/beliefs, patient characteristics, physician's recommendation, and personal/family experience. These factors led the patient to either accept or decline treatment, and were not consistent across all studies included. Studies used different interview guides, which may have affected these results. This systematic review highlights the complexity of factors that influence an older woman's treatment decision-making process. Acknowledging and addressing these factors may improve discussions about treatment choices between older women and their health care providers, and encourage maximization of a patient-centered approach.

Demonstration of an effective nurse-led clinic for patients with oestrogen receptor-positive breast cancer treated with primary endocrine therapy (PET)

Introduction: PET is an effective treatment for oestrogen receptor-positive breast cancer for patients unfit for surgical intervention. This institution has run a nurse-led follow-up clinic for PET patients since January 2013, to monitor tumour response, encourage medication compliance and detect disease progression. An audit was performed exploring its effectiveness and the progress of a cohort of patients over a 55-month period.

Impact of decision-making on outcomes of primary endocrine therapy for operable breast cancer in the elderly

Impact of decision-making on outcomes of primary endocrine therapy for operable breast cancer in the elderly

Omission of surgery in older women with early breast cancer has an adverse impact on breast cancer-specific survival

Primary endocrine therapy is used as an alternative to surgery in up to 40 per cent of women with early breast cancer aged over 70 years in the UK. This study investigated the impact of surgery versus primary endocrine therapy on breast cancer-specific survival (BCSS) in older women. Cancer registration data for 2002-2010 were obtained from two English regions. A retrospective analysis was performed for women with oestrogen receptor (ER)-positive disease, using statistical modelling to show the effect of treatment (surgery or primary endocrine therapy) and age and health status on BCSS. Missing data were handled using multiple imputation. Cancer registration data on 23 961 women were retrieved. After data preprocessing, 18 730 of 23 849 women (78·5 per cent) were identified as having ER-positive disease; of these, 10 087 (53·9 per cent) had surgery and 8643 (46·1 per cent) had primary endocrine therapy. BCSS was worse in the primary endocrine therapy group than in the surgical group (5-year BCSS rate 69·4 and 89·9 per cent respectively). This was true for all strata considered, although the difference was less in the cohort with the greatest degree of co-morbidity. For older, frailer patients the hazard of breast cancer death had less relative impact on overall survival. BCSS in older women with ER-positive disease is worse if surgery is omitted. This treatment choice may contribute to inferior cancer outcomes. Selection for surgery on the basis of predicted life expectancy may permit choice of women for whom surgery confers little benefit.

Methylomes variation to predict exemestane resistance in advanced breast cancer.

e24029Background: In estrogen receptor-positive breast cancer patients (pts), more than 30% have primary hormone therapy (HT) resistance while the precise mechanism underlies remain unclear. Our st...

Individualizing Local-Regional Therapy of Breast Cancer in the Elderly

The treatment of breast cancer in the elderly population requires a tailored approach. We summarize the current best evidence for personalized local-regional therapy in breast cancer patients older than 70. Breast cancer treatment in older adults incorporates the use of geriatric assessment tools to best evaluate functional status and treatment tolerability while accounting for the biologic profile of the disease. Surgical resection of the primary tumor with lymph node evaluation remains the cornerstone of local-regional control. Recent clinical trials demonstrate that surgery and radiation therapy may, however, be safely omitted in selected patients who are eligible for primary endocrine therapy. In patients with high-risk node-positive disease, DFS can be improved by systemic chemotherapy, but potential toxicity should be carefully considered in this population. Patient-specific evaluation of the risks of both under- and over-treatment of breast cancer in the older adult is essential for delivering optimal care in this population.