Endocrine Treatment Of Breast Cancer Research Articles

Pharmacogenetics of Toxicities Related to Endocrine Treatment in Breast Cancer: A Systematic Review and Meta-analysis.

Endocrine therapy is the standard treatment for hormone receptor-positive (HR+) breast cancer (BC). Yet, it is accompanied by treatment-related toxicities, leading to poor treatment adherence, high relapse, and low rates of survival. While pharmacogenomic variants have the potential to guide personalized treatment, their predictive value is inconsistent across published studies. To systematically assess the literature's current landscape of pharmacogenomics of endocrine therapy-related adverse drug effects, systematic searches in MEDLINE, Embase, Cochrane CENTRAL, Google Scholar and PharmGKB databases were conducted. We identified 87 articles. Substantial heterogeneity and variability in pharmacogenomic effects were evident across studies, with many using data from the same cohorts and predominantly focusing on the Caucasian population and postmenopausal women. Meta-analyses revealed Factor V Leiden mutation as a predictor of thromboembolic events in tamoxifen-treated women (p<0.0001). Meta-analyses also found that rs7984870 and rs2234693 were associated with musculoskeletal toxicities in postmenopausal women receiving aromatase inhibitors (p<0.0001 and p<0.0001, respectively). Overall, the current body of evidence regarding the potential role of pharmacogenomics in endocrine therapy-related toxicity in BC remains largely inconclusive. Key concerns include the heterogeneity in toxicity definitions, lack of consideration for genotype-treatment interactions, and the failure to account for multiple testing. The review underscores the necessity for larger and well-designed studies, particularly with the inclusion of premenopausal women and non-Caucasian populations.

Cognitive function in patients with HR+ advanced breast cancer treated with endocrine therapy with or without CDK4/6 inhibitors in the SONIA trial.

1016 Background: Given the important role of estrogen in normal neuronal function, endocrine treatment for breast cancer may adversely affect cognition, including memory, planning and attention. Previous studies showed mixed results but were often underpowered. It is unknown whether CDK4/6 inhibitors have cognitive side effects. SONIA-EfFECT is a side-study of the SONIA trial that investigates cognitive functioning in HR+ advanced breast cancer patients treated with endocrine therapy with or without CDK4/6 inhibitors. Methods: Patients randomized in the SONIA trial to receive first-line treatment with aromatase inhibitors with (Arm A) or without (Arm B) CDK4/6 inhibition were approached to participate in the SONIA-EfFECT side-study. Patients were asked to identify a female relative or friend without cancer to serve as a cancer-free control. Both patients and controls were asked to complete the Amsterdam Cognition Scan, an online neuropsychological test battery, at baseline and after 9 months. Patients who switched to second-line treatment within nine months were not retested. To prevent confounding effects of imbalance in age, education, and computer use between patient groups and controls, propensity score matching was performed. Baseline cognitive function was assessed by converting raw test scores to standardized Z-scores adjusted for computer use, based on baseline performance in the matched control group. To investigate the effect of endocrine therapy ±CDK4/6 inhibitors over time, standardized regression-based change scores were computed based on baseline and follow-up performance in the matched control group. One-way analyses of variance were conducted to compare baseline performance and cognitive change between the two arms and the matched control group. Results: 260 patients (130 Arm A/130 Arm B) and 196 controls completed baseline assessments. A matched sample of 130 controls was selected. 199 patients (108 Arm A/91 Arm B) and 119 matched controls had complete follow-up assessments. Patients in both study arms performed significantly worse than the controls on the domains of verbal memory, working memory, processing speed, executive function, and motor function. In both patient arms and the controls, standardized regression-based change scores showed limited decline in cognitive function over the 9-month interval. Moreover, minimal differences in cognitive change were observed between the patients treated with and without CDK4/6 inhibitors, and between patients and the controls. Conclusions: HR+ advanced breast cancer patients show worse cognitive function on all cognitive domains compared to a control group without cancer. Nine months of treatment with endocrine therapy with or without CDK4/6 inhibitors does not further worsen cognitive function in this study. Clinical trial information: NCT03425838 .

Adverse event signal mining and serious adverse event influencing factor analysis of fulvestrant based on FAERS database

Fulvestrant, as the first selective estrogen receptor degrader, is widely used in the endocrine treatment of breast cancer. However, in the real world, there is a lack of relevant reports on adverse reaction data mining for fulvestrant. To perform data mining on adverse events (AEs) associated with fulvestrant and explore the risk factors contributing to severe AEs, providing a reference for the rational use of fulvestrant in clinical practice. Retrieved adverse event report information associated with fulvestrant from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database, covering the period from market introduction to September 30, 2023. Suspicious AEs were screened using the reporting odds ratio (ROR) and proportional reporting ratio methods based on disproportionality analysis. Univariate and multivariate logistic regression analyses were conducted on severe AEs to explore the risk factors associated with fulvestrant-induced severe AEs. A total of 6947 reports related to AEs associated with fulvestrant were obtained, including 5924 reports of severe AEs and 1023 reports of non-severe AEs. Using the disproportionality analysis method, a total of 210 valid AEs were identified for fulvestrant, with 45 AEs (21.43%) not listed in the product labeling, involving 11 systems and organs. The AEs associated with fulvestrant were sorted by frequency of occurrence, with neutropenia (325 cases) having the highest number of reports. By signal strength, injection site pruritus showed the strongest signal (ROR = 658.43). The results of the logistic regression analysis showed that concurrent use of medications with extremely high protein binding (≥ 98%) is an independent risk factor for severe AEs associated with fulvestrant. Age served as a protective factor for fulvestrant-related AEs. The co-administration of fulvestrant with CYP3A4 enzyme inhibitors did not show statistically significant correlation with the occurrence of severe AEs. Co-administration of drugs with extremely high protein binding (≥ 98%) may increase the risk of severe adverse reactions of fulvestrant. Meanwhile, age (60–74 years) may reduce the risk of severe AEs of fulvestrant. However, further clinical research is still needed to explore and verify whether there is interaction between fulvestrant and drugs with high protein binding through more clinical studies.

Abstract PO2-12-11: Ocular Toxicity of Tamoxifen in Patients with Breast Cancer

Abstract Background: The latest recommendations in breast cancer treatment protocols with tamoxifen indicate that it should be used from five to 10 years. It depends mainly on the cumulative dose of the drug in the body. Despite its multiplicity, the various studies conducted on this subject did not reach conclusive results. Objectives: This research aims to study retinopathy associated with hormonal treatment of breast cancer using tamoxifen. Methods: A cross-sectional study was conducted at Al-Mouwasat University Hospital on a sample of 130 eyes according to (G-Power) with a statistical power of 95%. The participants were briefed on the research and consented on the ethical considerations. Then, the patients who entered the study were interrogated, clinically examined, and were asked about their medical history, the time of breast cancer diagnosis along with the details about the treatment protocols they underwent or currently undergoing. The refractive errors were measured with an automatic refractive device, then they were examined on the slit lamp to investigate the refractory media, then the corrected and uncorrected visual acuity were taken. Finally, after ensuring that the inclusion criteria were met and excluding those who fulfil one or more of the exclusion criteria, optical coherence tomography was performed using SD-OCT technique to measure and review the retinal thickness map in circles of 1-3-6 mm, respectively, to notice possible changes on it. Results: We found that the use of tamoxifen irrespective to cumulative dose leads to increase in the macula thickness values in the upper and lower sectors within the 3 mm circle, and to significant decrease in the macula thickness values in the upper and lower sectors within the 6 mm circle, in addition to decrease in nasal sector thickness within the circles of 3 and 6 mm. Conclusion: We conclude that the difference between people treated with tamoxifen and those not treated with it is not limited to the occurrence of crystals deposition in the macular area or the presence of a cavity in the central macula (with or without typical cystic macular edema), but rather to existence of macula thickness differences unrelated to the cumulative dose of the drug, whether by increase or decrease in thickness of the upper, lower and nasal segments. Citation Format: Husain Alhouz, Arwa Azmeh, Maher Saifo. Ocular Toxicity of Tamoxifen in Patients with 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 PO2-12-11.

Combination of chemotherapy and endocrine treatment in breast cancer — is it still a taboo?

Combination of chemotherapy and endocrine treatment in breast cancer — is it still a taboo?

Association of serum cortisol and cortisone levels and risk of recurrence after endocrine treatment in breast cancer

Metabolic reprogramming in breast cancer involves changes in steroid hormone synthesis and metabolism. Alterations in estrogen levels in both breast tissue and blood may influence carcinogenesis, breast cancer growth, and response to therapy. Our aim was to examine whether serum steroid hormone concentrations could predict the risk of recurrence and treatment-related fatigue in patients with breast cancer. This study included 66 postmenopausal patients with estrogen receptor-positive breast cancer who underwent surgery, radiotherapy, and adjuvant endocrine treatment. Serum samples were collected at six different time points [before the start of radiotherapy (as baseline), immediately after radiotherapy, and then 3, 6, 12 months, and 7–12 years after radiotherapy]. Serum concentrations of eight steroid hormones (cortisol, cortisone, 17α-hydroxyprogesterone, 17β-estradiol, estrone, androstenedione, testosterone, and progesterone) were measured using a liquid chromatography–tandem mass spectrometry-based method. Breast cancer recurrence was defined as clinically proven relapse/metastatic breast cancer or breast cancer-related death. Fatigue was assessed with the QLQ-C30 questionnaire. Serum steroid hormone concentrations measured before and immediately after radiotherapy differed between relapse and relapse-free patients [(accuracy 68.1%, p = 0.02, and 63.2%, p = 0.03, respectively, partial least squares discriminant analysis (PLS-DA)]. Baseline cortisol levels were lower in patients who relapsed than in those who did not (p < 0.05). The Kaplan–Meier analysis showed that patients with high baseline concentrations of cortisol (≥ median) had a significantly lower risk of breast cancer recurrence than patients with low cortisol levels (<median) (p = 0.02). During follow-up, there was a decrease in cortisol and cortisone concentrations in relapse-free patients, whereas these steroid hormones increased in patients who relapsed. In addition, steroid hormone concentrations immediately after radiotherapy were associated with treatment-related fatigue (accuracy of 62.7%, p = 0.03, PLS-DA). However, baseline steroid hormone levels did not predict fatigue at 1 year or at 7–12 years. In conclusion, breast cancer patients with low baseline cortisol levels were more likely to experience recurrence. During follow-up, cortisol and cortisone levels decreased in relapse-free patients but increased in patients with recurrence. Thus, cortisol and cortisone may act as potential biomarkers indicating individual risk of recurrence.

(106) Hormonally-Mediated Vestibulodynia: A Chart Review

Abstract Introduction The borders of the vestibule are Hart’s line laterally, hymen medially, frenulum of the clitoris anteriorly, and fourchette posteriorly. Provoked vestibulodynia (PVD) is characterized by severe burning pain in response to pressure localized to the vestibule. Numerous factors may negatively affect the vestibule causing PVD such as hormonal changes, infections, trauma, exaggerated immunologic or inflammatory responses, dermatologic conditions, high-tone pelvic floor dysfunction, pudendal neuropathy, and sacral radiculopathy. PVD specifically associated with hormonal changes in pre-menopausal women has been termed hormonally mediated vestibulodynia (HMV). Dense labeling of androgen receptors has been noted in the germinal layer of the vestibular epithelium and mucinous minor vestibular glands, implying a critical role of testosterone in vestibular health. Low calculated free testosterone caused by elevated sex hormone binding globulin (SHBG) in pre-menopausal women using combined hormonal contraception may thus be harmful to the vestibular epithelium and minor vestibular glands, resulting in HMV. In HMV, vulvoscopy shows diffuse vestibular tenderness of the entire vestibule, the ostia of the minor vestibular glands are frequently erythematous (Fig 1) and blood testing is consistent with a low calculated free testosterone. Objective We describe the variation in etiologies for HMV and emphasize the importance of measuring total testosterone and SHBG to monitor calculated free testosterone levels in patients with HMV. Methods This is a retrospective chart review of premenopausal patients presenting to a clinic with entrance dyspareunia who were diagnosed with HMV, and whose symptoms were alleviated by treatment. Inclusion criteria were as follows: premenopausal females with initial testosterone and SHBG blood values below the reference range, initial vulvoscopy findings significant for vestibulodynia, follow-up testosterone and SHBG approaching the reference range, and follow-up vulvoscopies demonstrating a relief from symptoms. Results A total of 9 patients met the inclusion criteria. The mean age was 32 years old, with a range of 22 years old to 39 years old. Presenting complaints in addition to dyspareunia (n=9) included recurrent irritative bladder voiding symptoms without positive urine culture (n=3) and pelvic pain (n=4). Vulvoscopic examination including cotton-tipped swab testing of the vestibule revealed signs of vestibular hypersensitivity with pain ranging from 1 to 9 in all 7 regions of the vestibule tested. Patients had histories of having taken combined hormonal contraceptives (n=6), isotretinoin (n=1), spironolactone (n=1) and/or hormonal treatment for breast cancer (n=1), all of which can decrease calculated free testosterone. All patients were treated with systemic testosterone and compounded estradiol/testosterone cream to be applied daily to the vestibule. On follow-up blood testing, all patients had calculated free testosterone values approaching 0.6-0.8 ng/dl, established by Guay et al. as the optimum range. All patients reported significantly decreased dyspareunia and significant relief of other bothersome symptoms, especially bladder symptoms. Conclusions This chart review illustrates a variety of etiologies associated with low calculated free testosterone and the diagnosis of HMV. This data emphasizes the importance of calculating free testosterone and performing vulvoscopy to establish a diagnosis in pre-menopausal patients with entrance dyspareunia. Additionally, this chart review demonstrates the efficacy of systemic testosterone and local vestibular androgen/estradiol therapies in ameliorating vestibular pain and associated symptoms in patients with HMV. Disclosure No

Unchartered waters: Significance of fall in Ki67 index after short-term preoperative endocrine therapy in early breast cancers.

Endocrine treatment for breast cancer acts largely by inhibiting tumor cell proliferation. The biomarker Ki67 is linked to the proliferative index of the tumour. To identify the factors affecting the fall in Ki67 value in early-stage hormone receptor (HR) positive breast cancer patients receiving short-term preoperative endocrine therapy in an Indian cohort. Women with hormone receptor positive, invasive, nonmetastatic, and early breast cancer (<T2, <N1) were assigned to short-term preoperative tamoxifen 20 mg daily (pre-menopausal women) or Letrozole 2.5 mg daily (post-menopausal women) for a minimum of 7 days after noting the baseline Ki67 value from the diagnostic core biopsy specimen. The postoperative Ki67 value was estimated from the surgical specimen, and the factors determining the extent of fall were evaluated. The short-term preoperative endocrine therapy resulted in a reduction in the median Ki67 index, which was significantly greater among postmenopausal women who received Letrozole (63.25 (31.94-80.5)) than among premenopausal women who received Tamoxifen (0 (-28.99-62.25)) (p-value 0.001). The fall in Ki67 value was particularly marked for patients with low-grade tumors with high Estrogen and progesterone receptor expression (p-value < 0.05). The duration of treatment (<2 week or 2-4 week or >4 week) did not affect the fall in Ki67. Preoperative therapy with Letrozole resulted in a more significant fall in Ki67, as compared to therapy with Tamoxifen. Determining the fall in Ki67 value in response to preoperative endocrine therapy could provide an insight into the response to endocrine therapy in luminal breast cancer.

Fall in Ki67 Index After Short-Term Preoperative Letrozole: a Gateway to Assess the Response in Hormone-Positive Early Breast Cancers.

Endocrine treatment for breast cancer acts largely by inhibiting tumor cell proliferation. The study aimed to explore the fall in proliferative marker Ki67 in patients receiving preoperative endocrine therapy and the factors associated with it. A prospective series of hormone receptor-positive postmenopausal women with early N0/N1 breast cancer were enrolled. Patients were requested to take letrozole OD while they await surgery. The fall in Ki67 after the endocrine therapy was defined as the percentage of the difference between the pre-and postoperative Ki67 value with the preoperative Ki67. Sixty cases matched the criteria of which 41 (68.3%) of women showed a good response to preoperative letrozole (fall in Ki67 > 50%; p-value < 0.001). The average mean fall in Ki67 was 57.083 ± 37.97. Postoperative Ki67 after the therapy was less than 10% in 39 (65%) patients. Ten patients (16.6%) had a low Ki67 index at baseline, which continued to remain low after preoperative endocrine therapy. The duration of the therapy did not affect the percentage of Ki67 fall in our study. Short-term changes in the Ki67 index in the neoadjuvant settings may predict outcomes during adjuvant use of the same treatment. Proliferation index on residual tumor holds prognostic importance, and our results reflect that greater attention should be given to the percentage of reduction of Ki67, rather than focusing purely on a fixed value. This could help predict patients who respond well to endocrine therapy, while those who respond poorly may require further adjuvant treatment.

182P Trends and variations of endocrine treatment in "in situ” breast cancer in Europe

Quality indicators (QI) are a specific tool to measure the quality of provided care. QI must be reliable, relevant, interpretable, actionable, and measurable. Contrarily to invasive breast cancer (IBC), the management of in situ breast cancer (BCIS) with adjuvant endocrine treatment (ET) remains controversial. The study aims to investigate the use of adjuvant ET in breast cancer in European (EU) countries, employing the European Society of Breast Cancer Specialists (EUSOMA) database that contains data collected by EU breast centers, that in the relevant time period were part of the EUSOMA Network.

CO102 Effectiveness of Short Term Neoadjuvant Endocrine Therapy on KI67 in Luminal Breast Cancers

Endocrine treatment for breast cancer acts largely by inhibiting tumor cell proliferation. This study aimed to determine the efficacy of short-term neoadjuvant endocrine therapy by response on Ki67-index in early-stage breast cancer.

Abstract PD15-06: Estrogen receptor expression thresholds by IHC and mRNA for Ki67 response to aromatase inhibition: A POETIC study

Abstract Background. Estrogen receptor (ER) expression is the key determinant for endocrine treatment of breast cancer (BC). In clinical practise ER analysis is currently almost entirely by immunohistochemistry (IHC). ASCO/CAP recommends cut-offs of &amp;lt;1% (negative) and 1-10% (low) to minimise the risk of false negatives. There is uncertainty in the level of responsiveness of those with low ER. mRNA assessment could be acceptable or preferable if a similar or better threshold was shown to identify response to endocrine therapies. Change of Ki67 after 2 weeks’ presurgical treatment with aromatase inhibitors (AIs) relates to reduction in risk of recurrence. We aimed to define IHC and mRNA cut-points for predicting change in Ki67 in response to AI. Method. POETIC is a phase III trial in postmenopausal patients with ER+ (by local assessment) BC randomized to receive 2-weeks’ pre-surgical AI vs no presurgical treatment. Cases were selected from the AI treatment group. All HER2+ cases were analysed. To enrich the HER2- study set for lower ER values, we selected all of the 15% poorest Ki67 suppression (ie PR, &amp;lt;40% suppression) and 30% of the remainder categorised as intermediate (IR, 40-79%) and good-responders (GR, &amp;gt;79%). 770 baseline FFPE samples were analysed (582 HER2-, 188 HER2+). IHC used the NCL-L-ER6F11 (Novocastra, Leica) antibody with the DAKO Flex kit and were scored centrally. mRNA was assessed by rtPCR. Values were expressed according to an arbitrary scale (“A units”). Results. ER IHC was available from 517 HER2- and 188 HER2+ tumors and ER mRNA from 376 HER2- and 173 HER2+ tumors. The correlation between ER levels by IHC and rtPCR was moderately high (Rho=0.616, p&amp;lt;0.00001). In IHC &amp;lt;1%, 1-10% and &amp;gt;10% tumors median (range) mRNA levels were 1.290 (0.188-11.346), 2.368 (0.575-13.863) and 111.150 (0.826-1001.423), respectively. The tables show the %age of PR, IR and GR for each category of ER by IHC or mRNA. The number of cases was adjusted to cater for the analysis of only 30% of the HER2- IR and GR , by multiplying the HER2- IR and GR number of cases by 3.3, resulting in this not being an integer for some categories. IHC: 87% of cases had &amp;gt;60% of cells +ve and only 11-12% of these were PRs. For cases with &amp;lt;10% cells +ve (4.9% of the population) over 90% of cases were PRs and there were no GRs. Cases between 1 and 10% +ve were not less responsive than those &amp;lt;1% +ve. For cases with &amp;gt;10% &amp;lt;20% cells +ve there was a substantial number of GRs and IRs (14.6% and 19.0%, respectively). mRNA: 82% of cases had ≥ 40 A units and only 10-14% of these showed PR. For cases with 5 A units (4.2% of the population) there were 9.5% % IR and no GR. In the next category, ≥5 &amp;lt;10 A units, 34.4% of cases were IR or GR. The levels of ER that distinguished PRs from IR/GRs was no different between HER2+ and HER2- cases. Conclusions. Ki67 responsiveness increases with increasing levels of ER by both IHC and mRNA. There was little responsiveness at IHC&amp;lt;10% and no distinction in responsiveness between &amp;lt;1% and 1-10% cells positive. Above 10% positive cells substantial numbers of patients showed IR or GR. Similar separation of PRs from IR/GRs was achieved by IHC and mRNA. IHC (%)0 &amp;lt; 1≥1 &amp;lt; 10≥10 &amp;lt; 20≥20 &amp;lt; 40≥40 &amp;lt; 60≥60 &amp;lt; 80≥80No. of cases42.32922.625.671.7239.81010.6PR87.596.566.462.541.811.710.8IR12.53.419.020.741.640.933.1GR0.00.014.616.816.647.456.1 mRNA (A units)&amp;lt;5≥5 &amp;lt; 10≥10 &amp;lt; 20≥20 &amp;lt; 40≥40 &amp;lt; 80≥80 &amp;lt; 120≥120No. of cases45.318.336.589.2168.1177.6550.4PR90.565.638.426.913.710.710.7IR9.416.458.947.946.835.226.8GR0.018.02.725.239.554.162.5 Citation Format: Elena Lopez Knowles, Simone Detre, Margaret Hills, Gene F Schuster, Maggie CU Cheang, Holly Tovey, Lucy Kilburn, Judith Bliss, John Robertson, Ian Smith, Mitch Dowsett, POETIC investigators. Estrogen receptor expression thresholds by IHC and mRNA for Ki67 response to aromatase inhibition: A POETIC study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD15-06.

Treatment outcomes in triple negative breast cancer patients undergoing neoadjuvant chemotherapy.

Background: Ki-67 immunohistochemical determination is a widely used biomarker of cell proliferation in pts undergoing endocrine treatment for breast cancer. The role of Ki-67 in triple negative breast cancer (TNBC) pts undergoing NAC for early disease remains controversial. Pathological Complete Response following NAC has been proposed as a prognostic indicator of long-term outcome. The aim of this retrospective project is to evaluate the treatment outcomes including pathological complete response (pCR), time to progression and overall survival in patients (pts) treated with taxane, and/or anthracycline/alkylating agents based neoadjuvant chemotherapy (NAC).

Can maternal exposure to tamoxifen compromise sperm and behavioural parameters of male rat offspring?

Tamoxifen, a selective non-steroidal estrogen receptor modulator, is the standard adjuvant endocrine treatment for breast cancer. Since information on the risk of using tamoxifen during pregnancy is still scarce, this study evaluated whether the in utero and lactational treatment with this drug could compromise reproductive and behavioural parameters in male offspring. Pregnant Wistar rats were exposed to three doses of tamoxifen (0.12; 0.6; 3 μg/kg), by gavage, from gestational day 15 to lactational day 20. Tamoxifen exposure did not alter the anogenital distance in the male offspring; however, there was a significant increase in the body weight in the 0.12 μg/kg dose and a decrease in the 0.6 μg/kg dose. The male offspring treated with the highest dose exhibited a delay in the onset of puberty, evidenced by an increase in the age of preputial separation. Regarding sperm parameters, there was an increase in the sperm count in the cauda epididymis in the intermediate and highest dose groups, in addition to an increase in the number of static sperm and a decrease in the progressive sperm in the same groups. Moreover, an increase in the number of hyperplasia of the epithelial clear cells was observed in the epididymis. In conclusion, the present study demonstrated that maternal exposure to tamoxifen compromised the installation of puberty of the male offspring and the maturation of the epididymis, affecting sperm storage and motility in the adult life.

Sequential usage of imidazole followed by tamoxifen to enhance the anticancer effect of tamoxifen in estrogen receptor-positive breast cancer cell lines.

e15057 Background: In women, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death worldwide. Tamoxifen is the most commonly used drug for the endocrine treatment of breast cancer. It reduces the risk of recurrence and death from breast cancer when given to estrogen-receptor-positive breast cancer patients. It has recently been shown that imidazoles, an antifungal drug, possess anticancer potentials, and it can be a novel therapeutic in cancer treatment. However, the effects of combined treatment with imidazole and tamoxifen are unknown in estrogen receptor-positive breast cancer cell lines. Our study aimed to investigate the effects of imidazole and tamoxifen combination in estrogen receptor-positive breast cancer cell lines. Methods: MCF7 cell line, an estrogen receptor-positive breast cancer cell line, was used in this study. Following 24 hours 50 mM imidazole (molecular grade) treatment, 15µM tamoxifen was treated to MCF-7 cells by 72 hours. As control groups, following for 24-hour imidazole alone treated, only medium treated cells for 72 hours were used. MTT assay was performed for the determination of cell viability. Apoptosis was shown using acridine orange/ethidium bromide staining. The cellular morphological alterations were observed on bright-field microscopy using Giemsa staining. Cell migration status was determined using by in vitro scratch assay. Results: MTT assay results showed that tamoxifen alone treatment for 72 hours decreased cell viability by 18 percent (p &lt; 0.001). On the other hand, cell viability is not affected by imidazole alone treatment for 24 hours compared with the control group (p &gt; 0.05). However, it was calculated that 24 hours of imidazole followed by tamoxifen for 72 hours decreased cell viability up to 42 percent (p &lt; 0.001). Tamoxifen alone group, compared with combined treatment with tamoxifen and imidazole, observed an increase of apoptotic cell numbers in combined treatment with tamoxifen and imidazole group, statistically significantly (p &lt; 0.01). It was observed that cellular morphology was affected by combined treatment with tamoxifen and imidazole. Giemsa staining results showed that MCF 7 cells changed their cellular morphology, lost cell-cell contact, differentiated from parental morphology and cellular morphology, and appeared unhealthy. Parallel to these findings, a decrease in cell migration was observed in the combined-treated group compared to the tamoxifen alone group (p &lt; 0.01). Conclusions: Our results showed that sequential usage of imidazole followed by tamoxifen has an enhanced anticancer effect of tamoxifen in estrogen receptor-positive breast cancer cell lines. These results allow us to establish a new hormonal treatment for patients with breast cancer.

Patient interactive digital support for women with adjuvant endocrine therapy in order to increase compliance and quality of life

PurposeThe primary aim of the study was to develop and investigate a patient interactive digital support (an app) for patients on adjuvant endocrine breast cancer treatment. Patient’s interactive digital applications are a fast-growing area for research and development. In general, patients want more information and support with regard to their diagnosis, treatment and self-care. At the same time, the health care system has limited resources for follow-up. Our primary endpoints were usability of the app and if it added any value to the patients.MethodsWe designed and constructed a prototype, in dialogue with patients, containing four main modules for registration of drug compliance, performed physical exercise, self-care activities, and questions on health and quality of life. The app was then tested by patients and improved further before we completed a pilot study in which 15 patients used the app for 3 months.ResultsPatients perceived the app easy to use with a very high median system usability score of 88.8, range 30–100. The 15 women registered in total 4251 times, range 118 to 372. The majority of registrations concerned compliance (adherence to treatment) and physical exercise.ConclusionThe app was perceived easy to use and of support in every-day life of breast cancer survivors. How to best integrate electronically collected patient reported outcome measures in clinical routine needs to be further studied, and future research will show if it will be cost-effective in terms of better health outcome and less resource use.

Optimizing Expectations About Endocrine Treatment for Breast Cancer: Results of the Randomized Controlled PSY-BREAST Trial.

Medication side effects are strongly determined by non-pharmacological, nocebo mechanisms, particularly patients' expectations. Optimizing expectations could minimize side effect burden. This study evaluated whether brief psychological expectation management training (EXPECT) optimizes medication-related expectations in women starting adjuvant endocrine therapy (AET) for breast cancer. In a multisite randomized controlled design, 197 women were randomized to EXPECT, supportive therapy (SUPPORT), or treatment as usual (TAU). The three-session cognitive-behavioral EXPECT employs psychoeducation, guided imagery, and side effect management training. Outcomes were necessity-concern beliefs about AET, expected side effects, expected coping ability, treatment control expectations, and adherence intention. Both interventions were well accepted and feasible. Patients' necessity-concern beliefs were optimized in EXPECT compared to both TAU and SUPPORT, d = .41, p < .001; d = .40, p < .001. Expected coping ability and treatment control expectations were optimized compared to TAU, d = .35, p = .02; d = .42, p < 001, but not to SUPPORT. Adherence intention was optimized compared to SUPPORT, d = .29, p = .02, but not to TAU. Expected side effects did not change significantly. Expectation management effectively and partly specifically (compared to SUPPORT) modified medication-related expectations in women starting AET. Given the influence of expectations on long-term treatment outcome, psychological interventions like EXPECT might provide potential pathways to reduce side effect burden and improve quality of life during medication intake.

Abstract P2-16-20: Treatment outcomes in triple negative breast cancer patients undergoing neoadjuvant chemotherapy. The importance of Ki-67

Abstract Aim of study: The aim of this retrospective project is to evaluate the treatment outcomes including pathological complete response (pCR), time to progression and overall survival in patients (pts) treated with taxane, and/or anthracycline/alkylating agents based neoadjuvant chemotherapy (NAC). Background: Ki-67 immunohistochemical determination is a widely used biomarker of cell proliferation in pts undergoing endocrine treatment for breast cancer. The role of Ki-67 in triple negative breast cancer (TNBC) pts undergoing NAC for early disease remains controversial. Pathological Complete Response following NAC has been proposed as a prognostic indicator of long-term outcome. Methods: We analyzed retrospectively data on 86 pts with TNBC. Pathological complete response (pCR) was defined as the complete disappearance of the invasive cancer in the breast and absence of tumor in the axillary lymph nodes examined by axillary clearance. The purpose of this analysis was to investigate factors associated with combined pCR. Results: There were 35 pCR’s (40.7%). At 2 years 82% of pts who attained a pCR were disease free compared to 67% of pts who did not attain a pCR (log rank test p &amp;lt; 0.0117). On univariate analysis factors associated with higher combined pCR included primary tumor size (T1=84% vs T2 and T3 =50% of pts, chi2= 6.81, p&amp;lt;0.03317), Ki67 (&amp;gt;30=68% vs. eq or &amp;lt; 30%= 18% of pts, p&amp;lt;0.00020), age (&amp;lt; than 50 =71% vs. equal or &amp;gt;50 =44% of pts), tumor grade (1=88% vs. 2=60% vs. 3=44% of pts, chi2 = 6.2560 p&amp;lt;0.04381) and stage (I= 89% vs. IIA=60% vs. IIB=46% vs. III=40% of pts, p&amp;lt;0.01350). Factors not associated with a higher pCR included menopausal status, extranodal spread and lympho-vascular invasion. In a logistic regression model Ki-67 as a continuous variable (p&amp;lt;0.012577) and age &amp;lt; than 50 (p&amp;lt;0.03318) retained its significance; while tumor size, stage of disease, tumor grade loss significance. Conclusion: Ki67 and age are independent prognostic factors of pCR in pts with early TNBC undergoing NAC. Citation Format: Bernardo Leon Rapoport, Jacqui Barnard-Tidy, Ronwyn van Eeden, Teresa Smit, Simon Nayler, Carol Benn. Treatment outcomes in triple negative breast cancer patients undergoing neoadjuvant chemotherapy. The importance of 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 P2-16-20.

GPER-1 expression is associated with a decreased response rate to primary tamoxifen therapy of breast cancer patients.

Endocrine therapies using tamoxifen and/or aromatase inhibitors are important therapeutic options for the targeted treatment of hormone-responsive breast cancer. In addition to nuclear estrogen receptors ERα and β, G-protein-coupled estrogen receptor GPER-1 is a third receptor-mediating estrogen effects in breast cancer cells. The aim of this study was to examine to what extent GPER-1 expression might affect the efficacy of primary endocrine treatment of breast cancer. GPER-1 expression was determined in tissue samples from patients with early breast cancer by means of immunohistochemistry and a GPER-1 score of ≥ 3 was considered to be positive. In a total of 165 patients, the response to a primary therapy with tamoxifen (TAM) or aromatase inhibitors (AI) was assessed by ultrasound imaging for up to 6months. The primary endpoint of this study was the response to treatment evaluated by RECIST 1.1 criteria. GPER-1 expression was observed in 127 (77.0%) out of 165 cases. Based on GPER-1 expression and the type of endocrine treatment, the patients were divided into 4 groups: GPER-1 negative/TAM (12.1%), GPER-1 negative/AI (10.9%), GPER-1 positive/TAM (44.8%), and GPER-1 positive/AI (32.1%). The groups were well balanced regarding different clinical and pathological factors. After 4 and 6months of treatment, a high level of stable disease or progressive disease was observed in the GPER-1 positive/TAM group only (p < 0.0001), whereas in the other three groups of patients, the most common objective response was classified as partial response. We observed a continuous reduction of mean tumor size in patients treated with aromatase inhibitors irrespective of the GPER-1 status and in GPER-1 negative patients treated with TAM. In contrast, in GPER-1 positive patients treated with TAM, a reduction of mean tumor size was observed only in the first 2months after beginning of treatment. Four and six months after start of treatment, no reduction, but even a slight increase of tumor size was observed in this patients group. GPER-1 expression is significantly associated with a reduced effect of primary treatment with tamoxifen in breast cancer patients.

Primary endocrine treatment for breast cancer in the elderly.

Primary endocrine treatment for breast cancer in the elderly.