Concurrent Tamoxifen Research Articles

Identification of new risk factors for hydroxychloroquine and chloroquine retinopathy in systemic lupus erythematosus patients

BackgroundLong-term hydroxychloroquine (HCQ) or chloroquine (CQ) intake causes retinal toxicity in 0.3–8 % of patients with rheumatic diseases. Numerous risk factors have been described, eg, daily dose by weight, treatment duration, chronic kidney disease, concurrent tamoxifen therapy and pre-existing retinal or macular disease. However, those factors cannot explain the entire risk of developing antimalarial retinopathy. ObjectiveThis study was undertaken to identify new risk factors associated with HCQ or CQ retinopathy (QRNP) in systemic lupus erythematosus (SLE) patients. MethodsThis case–control (1:2) study compared SLE patients with QRNP (cases) to those without (controls). Controls were matched for sex and known QRNP risk factors: HCQ and/or CQ treatment duration (±1 year) and age (±5 year) at SLE diagnosis. ResultsForty-eight cases were compared to 96 SLE controls. Multivariable logistic-regression analysis retained the following as independent determinants significantly associated with QRNP: concomitant selective serotonin-reuptake inhibitor (SSRI) or serotonin- and norepinephrine-reuptake inhibitor (SNRI) intake (OR [95 % confidence interval] 6.6 [1.2 to 40.9]; p < 0.01); antiphospholipid syndrome (OR=8.9 [2.2 to 41.4] p < 0.01); blood hydroxychloroquine/desethylchloroquine concentration ([HCQ]/[DCQ]) ratio <7.2 (OR 8.4 [2.7 to 30.8]; p < 0.01) or skin phototype ≥4 (OR 5.5 [1.4 to 26.5]; p = 0.02), but not daily HCQ dose, blood [HCQ] or body mass index. ConclusionThe results of this case–control study identified blood [HCQ]/[DCQ] ratio, concurrent SSRI/SNRI therapy, skin phototype ≥4 and antiphospholipid syndrome as new risk factors for QRNP.

Abstract P2-11-16: Computerized Measurements of Nuclear Morphology Features, Mitosis Rate, and Tubule Formation from H&amp;E Images Predicts Disease-Free Survival in Patients with HR+ &amp; LN+ Invasive Breast Cancer from SWOG S8814

Abstract Background: Lymph node (LN) involvement is a strong indicator of poor prognosis for breast cancer (BC), with adjuvant chemotherapy remaining fundamental to management of these patients. SWOG S8814 was a Phase III randomized trial of postmenopausal patients with pathologic LN-positive BC who were hormone receptor positive (HR+). The objectives of the clinical trial were to compare disease free survival (DFS) and overall survival (OS) of 1) these postoperative patients treated with a combination of cyclophosphamide, doxorubicin, fluorouracil (CAF) plus tamoxifen versus tamoxifen alone; and 2) patients treated with CAF followed by tamoxifen versus CAF plus concurrent tamoxifen. In this study we sought to evaluate the potential of applying computational image analysis on whole slide images (WSI) for predicting DFS and OS in SWOG S8814. Methods: A cohort of 135 patients (N=53 DFS event) diagnosed with HR+ &amp; LN+ BC from clinical trial ECOG 2197 was utilized as training set D1. Validation set D2 comprised 630 patients (N=260 DFS event, N=195 death) with HR+&amp; LN+ BC from SWOG S8814. Three deep learning models were employed to respectively detect nuclei, mitosis, and tubules in WSIs. Subsequently, a total of 1,810 features relating to nuclear morphology (e.g., spatial distribution, shape, texture, orientation), mitotic activity (e.g., mitosis hotspot, mitotic rates) and tubule formation (e.g., tubular nuclei distribution, ratio of tubule to non-tubule area) were extracted from each WSI. A lasso regularized Cox regression model (IbRiS) was trained on D1 to respectively identify four features from each of the feature categories (nuclei morphology, mitotic activity, and tubule formation) most strongly associated with DFS, a continuous risk score based on the selected features was then constructed. An optimal risk threshold was identified on D1 to dichotomize the risk scores into high vs. low risk of recurrence categories. Blinded validation of the machine learning model on SWOG S8814 using Cox regression was performed by SWOG to evaluate its performance in terms of DFS and OS. Results: In D2, patients identified as high risk of recurrence by IbRiS had a significantly worse prognosis in terms of DFS with hazard ratio=1.30 (p=0.039, 95% CI=1.01-1.66). IbRiS was also found to be significantly prognostic of OS with hazard ratio=1.38 (p=0.026, 95% CI=1.04-1.83). IbRiS was however, neither prognostic of DFS (HR = 1.20; 95% CI 0.93-1.54) nor OS (HR = 1.28; 95% CI 0.96-1.71) in multivariable analysis adjusting for treatment, tumor size, and number of positive nodes. IbRiS was also not a significant predictor of chemotherapy benefit (DFS p=0.45; OS p=0.25). Conclusion: We developed a prognostic model (IbRiS) based on the combined features of nuclear morphology, mitosis count, and tubule formation that can help further risk stratify HR+ &amp; LN+ BC patients by only using H&amp;E slides. Citation Format: Yuli Chen, William E. Barlow, Haojia Li, Cheng Lu, Andrew Janowczyk, German Corredor, Shridar Ganesan, Michael Feldman, Pingfu Fu, Hannah Gilmore, Kathy S. Albain, Lajos Pusztai, James Rae, Daniel Hayes, Andrew K. Godwin, Alastair M. Thompson, Anant Madabhushi. Computerized Measurements of Nuclear Morphology Features, Mitosis Rate, and Tubule Formation from H&amp;E Images Predicts Disease-Free Survival in Patients with HR+ &amp; LN+ Invasive Breast Cancer from SWOG S8814 [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 P2-11-16.

Abstract P2-11-11: Computer analysis of nuclear morphology with Multiple Instance Learning Predicts Overall Survival for Node Positive Breast Cancer Patients from SWOG S8814: A Blinded Validation Study

Abstract Background: Adjuvant chemotherapy is a common treatment for breast cancer patients with aggressive tumors, but imposes severe side effects. Although lymph node involvement is associated with higher likelihood of mortality, a subset of LN+ patients can survive without relapse, even without adjuvant chemotherapy. SWOG-8814 (S8814) was a randomized clinical trial of hormone receptor positive, LN+ post-menopausal women (pathologic stage T1-3N1-2) to compare patient outcome between endocrine therapy alone (tamoxifen), chemotherapy (cyclophosphamide, doxorubicin, and 5-fluorouracil) followed by 5 years of tamoxifen, and chemotherapy with concurrent tamoxifen. In this work, we evaluated the ability of a machine learning approach called multiple instance learning (MIL) to predict long-term overall (OS) and disease-free survival (DFS) in patients from the S8814 clinical trial via analysis of digitized H&amp;E tissue slides. Methods: The training set (St, n=121) consisted of digitized H&amp;E Whole Slide Images (WSIs) of ER+ LN+ patients from ECOG-2197 - a clinical trial to compare patient outcome under chemotherapy with doxorubicin/docetaxel vs. doxorubicin/cyclophosphamide. For each WSI, the nuclei of ten tumor patches (2000 × 2000 pixels) were automatically segmented by a pretrained machine learning algorithm called Convolutional Neural Networks (CNN). The results of the CNN’s segmentations were used to obtain ten corresponding feature vectors of 3963 features relating to nuclear morphology and spatial arrangement. Five top discriminative features (Haralick texture, Delaunay triangulation, orientation entropy, perimeter kurtosis, architecture) were identified by reliefF-MI feature filtering and forward selection on St. A Normalized Set Kernel Support Vector Machine classifier was trained on St to construct a MIL binary classifier (M+), which generates a continuous survival score to predict which patients would have &amp;gt;10-years of DFS and OS. The score cutoff thatmaximized F1 score on St was used to generate binary predictions of patient outcome. Blinded validation of the risk scores on S8814 was performed by SWOG. Results: M+ was significantly prognostic of OS in univariate analysis (HR=0.72, p=0.020, 95% CI= 0.55 – 0.95) on S8814. M+ stratifications remained statistically significant after multivariable analysis controlling for treatment, number of positive lymph nodes, and tumor size (HR = 0.71, p=0.017, 95% CI=0.54-0.94). M+ predictions did not achieve statistical significance for DFS in univariate analysis (HR=0.81, p=0.081, 95% CI 0.64-1.03) nor multivariable analysis (HR=0.81, p=0.080, 95% CI 0.63-1.03). M+ was not predictive of chemotherapy benefit for OS (p=0.88) and DFS (p=0.65). There was no correlation of the generated continuous score with Recurrence Score (r=-0.05), previously shown to be a predictive factor for chemotherapy benefit. Conclusion: Our findings demonstrate that nuclear morphology provides insight into overall survival in ER+ LN+ breast cancer patients. Future work will involve combining the MIL based morphologic predictor with other clinicopathologic factors to improve DFS risk stratification. Funding: Funding NIH/NCI grants U10CA180888, U10CA180819, U24CA196175; and in part by Genomic Health, INC. (now Exact Sciences Corp.) Citation Format: Daniel Shao, William E. Barlow, Haojia Li, Cheng Lu, Kathy S. Albain, James Rae, Daniel F. Hayes, Andrew K. Godwin, Alastair M. Thompson, Anant Madabhushi, Lajos Pusztai. Computer analysis of nuclear morphology with Multiple Instance Learning Predicts Overall Survival for Node Positive Breast Cancer Patients from SWOG S8814: A Blinded Validation Study [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 P2-11-11.

P011 Audit and Outcomes of Hydroxychloroquine Screening for Retinopathy in a Cohort of Patients with Rheumatological Conditions

Abstract Background/Aims Hydroxychloroquine (HCQ) is used to treat rheumatoid arthritis (RA) and other inflammatory arthritides. In 2018, the Royal College of Ophthalmologists (RCOphth) published new guidelines to monitor the risk of HCQ associated retinopathy. Risk factors for retinopathy were: dosage &amp;gt;5mg/kg/day, impaired renal function (eGFR &amp;lt;60ml/min/1.73m²) and concurrent tamoxifen use. This report aims to audit 1) HCQ dosing based on RCOphth 2018 guidelines 2) whether patients were appropriately referred for screening 3) outcome of screening. Methods All patients (n = 207) who newly started HCQ between April 2013 and November 2014 were identified from hospital outpatient pharmacy records and followed until they reached 5 years’ of follow-up or 30 Nov 2019, whichever came first (censor date). Patients who were still on HCQ by the censor date were reviewed to extract data on demographics, rheumatological diagnosis, starting HCQ dose and risk factors, and were subsequently referred for retinopathy screening via a referral proforma. Exclusions were those who stopped HCQ, prescribed HCQ for non-rheumatological conditions, transferred to a different trust, duplicate or deceased patients. Screening took place between 1 Nov 2018 until 30 June 2019, after which referrals were paused due to lack of capacity and finally stopped due to COVID-19. Results 86 patients were identified and eligible for screening (study cohort) (Table). The median age of the cohort was 57 years, with 67% of the cohort being female. 23% of patients were prescribed a dose of &amp;gt; 5mg/kg/day. 10% of patients had an eGFR of &amp;lt; 60 ml/min/1.73m2. No patients were on tamoxifen. Conclusion After 5 years of follow-up, the drug survival for HCQ is just under half the number (43%) who started the drug. This will help plan screening service capacity issues. The department is investigating the “lost referrals” which seem disproportionately high, which could be due to IT issues or occurred when the screening service was paused. Of the 29 patients who attended for screening, none had evidence of HCQ retinopathy which is reassuring, these included 15 patients with risk factors for retinopathy. Disclosure G. Tehseen: None. S. Wills: None. A. Chadwick: None. A. Low: None.

Prevalence of hydroxychloroquine retinopathy using 2018 Royal College of Ophthalmologists diagnostic criteria

IntroductionTo measure the prevalence of hydroxychloroquine retinopathy in patients attending a hydroxychloroquine monitoring service using 2018 Royal College of Ophthalmologists diagnostic criteria.MethodsA service evaluation audit of a hydroxychloroquine retinopathy monitoring service was undertaken. Results of Humphrey 10–2 field tests, spectral-domain optical coherence tomography and fundus autofluorescence were collected with data on dose, weight, duration of treatment, estimated glomerular filtration rate, and concurrent tamoxifen therapy. Visual field tests were assessed as reliable or unreliable, and classified as normal, hydroxychloroquine-like, poor test or related to other pathology. Cases of definite and possible retinopathy were identified using the 2018 RCOphth criteria.ResultsThere were 1976 attendances over two years of 1597 patients. Seven hundred and twenty-eight patients had taken hydroxychloroquine for less than 5 years and 869 had taken hydroxychloroquine for 5 years or more. Fourteen patients were identified with definite hydroxychloroquine retinopathy (1.6%), and 41 patients with possible retinopathy (4.7%). Sixty-seven per cent of 861 visual fields were performed reliably, with 66.9% classified as normal, 24.9% as poor test, 5.2% hydroxychloroquine-like and 3.0% abnormal due to other pathology.ConclusionsThe 1.6% prevalence of hydroxychloroquine retinopathy is lower than the previously reported prevalence of 7.5% as reported by Melles and Marmor JAMA Ophthalmol 132: 1453–60 (2014). This is because of a difference in the diagnostic criteria. Both definite and possible retinopathy would meet the diagnostic criteria of the Melles and Marmor study; 6.3% in our data, compared with 7.5%, a much smaller difference and likely to be explained by differences in the risk characteristics of the two groups.

Association Between 21-Gene Assay Recurrence Score and Locoregional Recurrence Rates in Patients With Node-Positive Breast Cancer

The 21-gene assay recurrence score is increasingly used to personalize treatment recommendations for systemic therapy in postmenopausal women with estrogen receptor (ER)- or progesterone receptor (PR)-positive, node-positive breast cancer; however, the relevance of the 21-gene assay to radiotherapy decisions remains uncertain. To examine the association between recurrence score and locoregional recurrence (LRR) in a postmenopausal patient population treated with adjuvant chemotherapy followed by tamoxifen or tamoxifen alone. This cohort study was a retrospective analysis of the Southwest Oncology Group S8814, a phase 3 randomized clinical trial of postmenopausal women with ER/PR-positive, node-positive breast cancer treated with tamoxifen alone, chemotherapy followed by tamoxifen, or concurrent tamoxifen and chemotherapy. Patients at North American clinical centers were enrolled from June 1989 to July 1995. Medical records from patients with recurrence score information were reviewed for LRR and radiotherapy use. Primary analysis included 316 patients and excluded 37 who received both mastectomy and radiotherapy, 9 who received breast-conserving surgery without documented radiotherapy, and 5 with unknown surgical type. All analyses were performed from January 22, 2016, to August 9, 2019. The LRR was defined as a recurrence in the breast; chest wall; or axillary, infraclavicular, supraclavicular, or internal mammary lymph nodes. Time to LRR was tested with log-rank tests and Cox proportional hazards regression for multivariate models. The final cohort of this study comprised 316 women with a mean (range) age of 60.4 (44-81) years. Median (interquartile range) follow-up for those without LRR was 8.7 (7.0-10.2) years. Seven LRR events (5.8%) among 121 patients with low recurrence score and 27 LRR events (13.8%) among 195 patients with intermediate or high recurrence score occurred. The estimated 10-year cumulative incidence rates were 9.7% for those with a low recurrence score and 16.5% for the group with intermediate or high recurrence score (P = .02). Among patients who had a mastectomy without radiotherapy (n = 252), the differences in the 10-year actuarial LRR rates remained significant: 7.7 % for the low recurrence score group vs 16.8% for the intermediate or high recurrence score group (P = .03). A multivariable model controlling for randomized treatment, number of positive nodes, and surgical type showed that a higher recurrence score was prognostic for LRR (hazard ratio [HR], 2.36; 95% CI, 1.02-5.45; P = .04). In a subset analysis of patients with a mastectomy and 1 to 3 involved nodes who did not receive radiation therapy, the group with a low recurrence score had a 1.5% rate of LRR, whereas the group with an intermediate or high recurrence score had a 11.1% LRR (P = .051). This study found that higher recurrence scores were associated with increased LRR after adjustment for treatment, type of surgical procedure, and number of positive nodes. This finding suggests that the recurrence score may be used, along with accepted clinical variables, to assess the risk of LRR during radiotherapy decision-making.

Abstract 2940: 4-Hydroxytamoxifen enhances sensitivity of estrogen receptor α-positive breast cancer to docetaxel in an estrogen and ZNF423 SNP-dependent fashion

Abstract Background: In early stage, ERα-positive breast cancer, the concurrent use of endocrine therapy and chemotherapy has not been shown to be superior to sequential use. We hypothesized that genetic biomarkers can aid in selecting patients who would benefit from chemo-endocrine therapy. Our previous genome-wide association study (GWAS) and functional studies revealed that a single nucleotide polymorphism (SNP) in ZNF423, rs9940645, determines tamoxifen response. Specifically, 4-hydroxytamoxifen (4-OH-TAM) increases the gene expression of ZNF423, a transcription factor for BRCA1, in cells that are carry the rs9940645 variant, but not the wildtype, genotype. In this study, we set out to identify additional genes regulated by ZNF423, which, upon identifying a relationship between ZNF423 and cell cycle genes, led us to investigate taxane response in a SNP- and tamoxifen-dependent fashion. Method: Gene correlation analysis using The Cancer Genome Atlas (TCGA) breast cancer dataset was used to identify genes with expression correlated with that of ZNF423. Quantitative reverse transcription PCR, chromatin immunoprecipitation, and luciferase reporter assays were used to validate the gene associations. To test ZNF423 rs9940645-specific phenotypes, we used ZR75-1 cells, which are homozygous for the variant SNP, and ZR75-1 cells that were generated to be homozygous wild type (WT) using CRISPR-Cas9 technology, in addition to Hs578T breast cells with ERα overexpression (WT) and HCC1500 cells (variant). Cell cycle was assessed by propidium iodide staining. Cytotoxicity was assessed using a colorimetric assay. Results: Mitosis-related genes VRK1 and PBK, which encode histone H3 kinases, were experimentally validated to be regulated by ZNF423. Specifically, ZNF423 knockdown resulted in decreased VRK1 and PBK expression and activity. Additionally, ZNF423 knockdown resulted in enhanced docetaxel-induced G2/M arrest and cytotoxicity which could be rescued by VRK1 or PBK overexpression. Lastly, breast cancer cells carrying the rs9940645 variant SNP genotype had increased G2-M arrest and decreased cell viability when treated with docetaxel in combination with estradiol and 4-OH-TAM. Conclusion: We identified ZNF423regulated genes involved in the G2/M phase of the cell cycle. We found that 4-OH-TAM sensitized ERα-positive breast cancer cells to docetaxel treatment in a ZNF423 SNP-dependent manner. Our findings suggest that patients with rs9940645 variant genotype may benefit from concurrent tamoxifen endocrine therapy and docetaxel chemotherapy. This would impact a substantial proportion of patients given the minor allele frequency of 0.47 for this SNP. Citation Format: Gen Wang, Sisi QIN, Jacqueline Zayas, James N. Ingle, Mohan Liu, Richard Weinshilboum, Kunwei Shen, Liewei Wang. 4-Hydroxytamoxifen enhances sensitivity of estrogen receptor α-positive breast cancer to docetaxel in an estrogen and ZNF423 SNP-dependent fashion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2940.

4-Hydroxytamoxifen enhances sensitivity of estrogen receptor α-positive breast cancer to docetaxel in an estrogen and ZNF423 SNP-dependent fashion.

In early stage, ERα-positive breast cancer, concurrent use of endocrine therapy and chemotherapy has not been shown to be superior to sequential use. We hypothesized that genetic biomarkers can aid in selecting patients who would benefit from chemo-endocrine therapy. Our previous studies revealed that ZNF423 is a transcription factor for BRCA1 and an intronic single nucleotide polymorphism (SNP) in ZNF423, rs9940645, determines tamoxifen response. Here, we identified mitosis-related genes that are regulated by ZNF423 which led us to investigate taxane response in a rs9940645 SNP- and tamoxifen-dependent fashion. The Cancer Genome Atlas (TCGA) breast cancer dataset was used to identify genes correlated with ZNF423. Quantitative reverse transcription PCR, chromatin immunoprecipitation, and luciferase reporter assays were used to validate the gene regulation. We used CRISPR/Cas9 to engineer paired ZR-75-1 cells which differ only in ZNF423 rs9940645 SNP genotype to test SNP-dependent phenotypes including cell cycle and cell viability. We validated our findings in an additional two breast cancer cell lines, Hs578T-ERα and HCC1500. Mitosis-related genes VRK1 and PBK, which encode histone H3 kinases, were experimentally validated to be regulated by ZNF423. ZNF423 knockdown decreased VRK1 and PBK expression and activity. Additionally, ZNF423 knockdown enhanced docetaxel-induced G2/M arrest and cytotoxicity through VRK1 or PBK regulation. Lastly, cells carrying the rs9940645 variant genotype had increased G2/M arrest and decreased cell viability when treated with docetaxel in combination with estradiol and 4-OH-TAM. We identified ZNF423 regulated genes involved in the G2/M phase of the cell cycle. 4-OH-TAM sensitized ERα-positive breast cancer cells to docetaxel in a ZNF423 SNP-dependent manner. Our findings suggest that patients with rs9940645 variant genotype may benefit from concurrent tamoxifen and docetaxel. This would impact a substantial proportion of patients because this SNP has a minor allele frequency of 0.47.

Concurrent tamoxifen and CYP2D6 inhibitor SSRIs not risky

Concurrent tamoxifen and CYP2D6 inhibitor SSRIs not risky

Assessing the Risks Associated with Antidepressant Use in Plastic Surgery: A Systematic Review.

Antidepressant use has increased dramatically over the past decade. Although there is no question about the benefits of these medications, uncertainty exists with regard to the implications of antidepressant treatment surrounding plastic surgery. This systematic review collates all of the available literature that evaluates the risks of patient antidepressant treatment, in relation to plastic surgery. A comprehensive literature review of the PubMed and Cochrane databases was conducted. Articles were assessed by two independent reviewers using predefined data fields and selected using specific inclusion criteria. The two authors independently reviewed the literature and extracted data from included reviews, and discrepancies were resolved by consensus. Twenty-six articles were included in the analysis and were categorized into five groups for comparison: risk of bleeding, risk of breast cancer, risk of breast cancer recurrence, breast enlargement, and miscellaneous (unique complications). Extracted information included study type, statistical analyses, conclusion, and limitations. This review does not support the cessation of antidepressants in patients before plastic surgery, as the numbers needed to harm are low and the implications of withdrawal may prove to be detrimental to postoperative management. However, the use of antidepressants for mental disorders may also implicate key patient risk factors for surgical complications, and sufficient exploration into the patient's indications for the prescription is crucial. Evidence so far does not suggest that antidepressants increase the risk of breast cancer or recurrence in general, but caution should be exercised for those specifically on concurrent tamoxifen and paroxetine treatment.

Comparison of survival outcome of concurrent GnRH agonist plus tamoxifen to that of sequential adriamycin and cyclophosphamide chemotherapy plus tamoxifen in premenopausal, lymph node-negative, hormone-responsive, HER2-negative, T1-2 breast cancer patients.

137 Background: The purpose of this study was to compare treatment outcomes between gonadotropin-releasing hormone (GnRH) agonist plus tamoxifen and adriamycin and cyclophosphamide (AC)-containing chemotherapy plus tamoxifen in hormone-responsive, premenopausal, node-negative, breast cancer patients. Methods: Among 7278 breast cancer patients who were diagnosed as breast cancer at Asan medical center, Seoul, Korea, 994 premenopausal women with node-negative, hormone receptor-positive, HER2-negative, T1-2 breast cancers were included in this retrospective cohort study: A median follow-up was 7.4 years (range, 0.5-11.4 years). 608 patients (61.2%) were treated with GnRH agonist together with tamoxifen, and 386 patients (38.8%) were treated with AC-containing chemotherapy with tamoxifen. The propensity score matching and inverse probability weighting was applied to original cohort based on patients’ age, operation method, nuclear and histologic grade, estrogen receptor and progesterone receptor positivity, T stage, Her2 positivity, and p53 positivity. In final analysis, 260 patients for each treatment arm were included. Results: In propensity matched cohorts (n = 520), a total of 34 patients had recurrence. There were 5 cancer-specific deaths and 12 overall deaths among total 520 patients. There were no survival differences for recurrence-free survival (p= 0.306), cancer-specific survival (p= 0.212), and overall survival (p= 0.102) between the two treatment groups. After applying inverse probability weighting, there were no survival differences for recurrence-free survival (p = 0.522), cancer-specific survival (p= 0.154). However, GnRH agonist with tamoxifen arm showed better overall survival than AC chemotherapy with tamoxifen arm (p= 0.021). Conclusions: Adding GnRH agonist to tamoxifen is a reasonable alternative to adding AC chemotherapy to tamoxifen in premenopausal, hormone-responsive, HER2-negative, lymph node-negative, T1-2, breast cancer patients.

The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy.

Hydroxychloroquine sulfate is widely used for the long-term treatment of autoimmune conditions but can cause irreversible toxic retinopathy. Prior estimations of risk were low but were based largely on short-term users or severe retinal toxicity (bull's eye maculopathy). The risk may be much higher because retinopathy can be detected earlier when using more sensitive screening techniques. To reassess the prevalence of and risk factors for hydroxychloroquine retinal toxicity and to determine dosage levels that facilitate safe use of the drug. Retrospective case-control study in an integrated health organization of approximately 3.4 million members among 2361 patients who had used hydroxychloroquine continuously for at least 5 years according to pharmacy records and who were evaluated with visual field testing or spectral-domain optical coherence tomography. Hydroxychloroquine use for at least 5 years. Retinal toxicity as determined by characteristic visual field loss or retinal thinning and photoreceptor damage, as well as statistical measures of risk factors and prevalence. Real body weight predicted risk better than ideal body weight and was used for all calculations. The overall prevalence of hydroxychloroquine retinopathy was 7.5% but varied with daily consumption (odds ratio, 5.67; 95% CI, 4.14-7.79 for >5.0 mg/kg) and with duration of use (odds ratio, 3.22; 95% CI, 2.20-4.70 for >10 years). For daily consumption of 4.0 to 5.0 mg/kg, the prevalence of retinal toxicity remained less than 2% within the first 10 years of use but rose to almost 20% after 20 years of use. Other major risk factors include kidney disease (odds ratio, 2.08; 95% CI, 1.44-3.01) and concurrent tamoxifen citrate therapy (odds ratio, 4.59; 95% CI, 2.05-10.27). These data suggest that hydroxychloroquine retinopathy is more common than previously recognized, especially at high dosages and long duration of use. While no completely safe dosage is identified from this study, daily consumption of 5.0 mg/kg of real body weight or less is associated with a low risk for up to 10 years. Knowledge of these data and risk factors should help physicians prescribe hydroxychloroquine in a manner that will minimize the likelihood of vision loss.

Successful Use of Agomelatine in the Treatment of Major Depression in a Woman Taking Tamoxifen

The selective estrogen receptor modulator, tamoxifen, is extensively used for the endocrine treatment of all stages of hormone receptor-positive breast cancer. Tamoxifen is a mainly inactive prodrug, necessitating metabolism by the cytochrome P450 (CYP450) pathway, predominantly the Cytochrome P450 2D6 (CYP2D6), into the active metabolites 4-hydroxytamoxifen and, in particular, endoxifen to achieve its therapeutic effect. As several women treated with tamoxifen may experience depressive symptoms or may have a previous or actual major depressive episode with ongoing antidepressant treatment or need for a new-onset therapy, the coprescription of an antidepressant drug may be particularly problematic as several antidepressants are potent CYP2D6-inhibiting drugs. We herein report a case of a patient with major depression and concurrent tamoxifen therapy successfully treated with agomelatine monotherapy.

Trial of concurrent versus sequential tamoxifen with radiotherapy in breast cancer patients with study of the combination of pentoxifylline and tocopherol for prevention of radiation-induced lung fibrosis.

e11599 Background: Although the efficacy of both radiation and tamoxifen (TAM) in early-stage breast cancer is well established, data are lacking about the impact of this sequence on outcomes, including local recurrence and complications of therapy. These are questions of practical importance in the treatment of breast cancer patients, many of whom require both radiation (RT) and adjuvant TAM. Methods: 160 eligible patients were prospectively randomized 1:1 into two groups: The control group (80 patients) , containing one arm (C) received sequential TAM and RT and the intervention group which was further subdivided into arm (A) (40 patients), received concurrent TAM 20 mg/day with RT, arm( B) (40 patients), received concurrent TAM + Pentoxifylline (PTX) ( 800 mg/day )+ Alpha-Tocopherol (AT) (1000 U/day) and RT. The primary endpoint was to compare the radiation induced pulmonary fibrosis using serial high resolution computed tomography (HRCT) and the role of the PTX and AT combination in reduction of pulmonary fibrosis, the secondary endpoint was to evaluate loco-regional control in the three arms usingChi-Square test, Fisher’s exact test, Log rank test andAnova test. Results: Analysis of the incidence of clinical pneumonitis was 25% in arm A ( TAM) , 12.5% in arm B (TAM+PTX+AT) and 18.8% in arm C (control) with p=.110. The incidence of lung fibrosis was 26.5% in arm A( TAM) , 12.9% in arm B (TAM+VIT.E) and 23.4% in arm C (Control) with p=.608. As regard loco-regional relapse, the preliminary result, revealed no significant difference in the 3 arms (1.3% in control arm, 5 % in TAM, 2.5% in TAM+VIT) (p=.827). Conclusions: It seems that the interaction between tamoxifen and radiotherapy could affect the tissue remodeling rather than the damage induction step of the radiation pathogenesis. In this case, temporal separation of the two modalities (Concurrent Versus Sequential) may not make much difference in the incidence of radiation induced lung fibrosis.

Influence of Concurrent Anastrozole on Acute and Late Side Effects of Whole Breast Radiotherapy

To retrospectively compare radiation toxicity in patients treated with concurrent anastrozole and whole breast irradiation versus women treated sequentially with whole breast irradiation followed by hormonal suppression. The records of 249 consecutive estrogen or progesterone receptor positive breast cancer patients treated with breast-conserving surgery and postoperative whole breast irradiation were reviewed. Of total, 57 patients (the concurrent anastrozole group) received concurrent anastrozole prior to and during radiotherapy. In 126 patients (the sequential group), adjuvant hormone suppression therapy (anastrozole, other aromatase inhibitors, or tamoxifen) was administered after the completion of breast irradiation. In 66, women either concurrent tamoxifen was given with radiation or the sequence of hormonal therapy was not known. These women were excluded from the analysis. The frequency of acute grade 2 radiation dermatitis (24.6% in the concurrent anastrozole group vs. 20.6% in the sequential group; P = 0.55), grade 3 radiation dermatitis (8.8% vs. 7.1%; P = 0.77) and treatment interruptions due to skin reactions (14.0% vs. 11.2%; P = 0.69) did not differ between groups. The rates of clinically detectable breast fibrosis were not different (24.2% vs. 24.7%; P = 0.97). With a median follow-up of 28 months and 30.8 months, respectively, 1 local failure occurred in the concurrent anastrozole group and 5 in the sequential group. Anastrozole, administered concurrently with whole breast irradiation, did not increase acute or late morbidity when compared with sequential administration of radiation and hormonal suppression therapy.

Letrozole plus GnRH analogue as preoperative and adjuvant therapy in premenopausal women with ER positive locally advanced breast cancer

Patients with large ER positive tumors candidate to preoperative chemotherapy may also benefit from a concurrent endocrine intervention, but this issue has been scarcely investigated due to concerns arising from unfavorable results emerged from an adjuvant trial of concurrent tamoxifen and chemotherapy. We retrospectively investigated the activity of letrozole plus GnRH analogue (GnRH-a) administered concurrently with preoperative chemotherapy and as adjuvant treatment in premenopausal women with locally advanced ER positive breast cancer consecutively admitted at the European Institute of Oncology. Results were compared with those of a non-randomized unmatched control group of premenopausal women with locally advanced ER positive breast cancer receiving preoperative chemotherapy, followed by tamoxifen and GnRH-a after surgery. Primary endpoints were pathological complete response (pCR) rate, decrease of Ki67 and disease free survival (DFS). One-hundred and nineteen women constituted the study group, while 95 patients served as controls. The pCR rate was 5.0 vs 1.1% in the study and control group, respectively. A statistically significant greater suppression of Ki67 was observed in patients receiving chemoendocrine therapy as compared with controls (P = 0.003). At a median follow up of 59 months, 26 events occurred in the chemoendocrine group and 48 in the control group. Five-year DFS was 78 vs 41% in the study and in the control group, respectively [adjusted HR 0.46, 95% CI 0.27-0.79, P = 0.0047]. The concurrent administration of letrozole and GnRH-a with preoperative chemotherapy was highly effective in premenopausal women with large ER positive breast cancer in terms of decreased proliferation and of improved DFS. Randomized studies are warranted to establish the role of the addition of endocrine therapy to chemotherapy as standard preoperative approach for ER positive locally advanced breast cancer as well as of letrozole in combination with GnRH-a for the treatment of premenopauasal women with early breast cancer.

Combining and Sequencing Adjuvant Chemotherapy and Tamoxifen in Postmenopausal Women with Node-Positive Breast Cancer

Evaluation of: Albain KS, Barlow WE, Ravdin PM et al.; Breast Cancer Intergroup of North America: Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a Phase 3, open-label, randomised controlled trial. Lancet 374(9707), 2055–2063 (2009). This Phase III trial randomized 1477 postmenopausal women with hormone receptor-positive, node-positive operable breast cancer to receive 5 years of adjuvant tamoxifen alone, or tamoxifen given concurrently or after cyclophosphamide, doxorubicin and fluorouracil (CAF) chemotherapy. After 13 years of follow-up, the 10-year disease-free survival was significantly improved in the group receiving the combination of CAF chemotherapy and tamoxifen, compared with the tamoxifen-alone group (57 vs 48%, respectively; p = 0.002); overall survival was also marginally improved in the combination group (65 vs 60%; p = 0.0057). Sequential tamoxifen given after CAF chemotherapy marginally improved disease-free survival compared with concurrent tamoxifen and chemotherapy (60 vs 53%, respectively; p = 0.057). Chemotherapy with CAF together with sequential tamoxifen is a more effective adjuvant therapy for postmenopausal women with hormone receptor-positive, node-positive breast cancer compared with tamoxifen alone.

In the interest of full disclosure

We read the recent article by Albain and colleagues1 with interest. In this translational study, the 21-gene recurrence assay (Genomic Health, Redwood City, CA, USA) was successfully performed on 601 samples from Southwest Oncology Group-8814, INT-0100. We were surprised that results were not reported for the 234 tissue samples from patients who received cyclophosphamide, doxorubicin, and fluorouracil with concurrent tamoxifen (CAFT). This subset was excluded after the results were obtained despite comprising more than a third of the successful 21-gene assays in the study.

Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a phase 3, open-label, randomised controlled trial

Tamoxifen is standard adjuvant treatment for postmenopausal women with hormone-receptor-positive breast cancer. We assessed the benefit of adding chemotherapy to adjuvant tamoxifen and whether tamoxifen should be given concurrently or after chemotherapy. We undertook a phase 3, parallel, randomised trial (SWOG-8814, INT-0100) in postmenopausal women with hormone-receptor-positive, node-positive breast cancer to test two major objectives: whether the primary outcome, disease-free survival, was longer with cyclophosphamide, doxorubicin, and fluorouracil (CAF) given every 4 weeks for six cycles plus 5 years of daily tamoxifen than with tamoxifen alone; and whether disease-free survival was longer with CAF followed by tamoxifen (CAF-T) than with CAF plus concurrent tamoxifen (CAFT). Overall survival and toxicity were predefined, important secondary outcomes for each objective. Patients in this open-label trial were randomly assigned by a computer algorithm in a 2:3:3 ratio (tamoxifen:CAF-T:CAFT) and analysis was by intention to treat of eligible patients. Groups were compared by stratified log-rank tests, followed by Cox regression analyses adjusted for significant prognostic factors. This trial is registered with ClinicalTrials.gov, number NCT00929591. Of 1558 randomised women, 1477 (95%) were eligible for inclusion in the analysis. After a maximum of 13 years of follow-up (median 8.94 years), 637 women had a disease-free survival event (tamoxifen, 179 events in 361 patients; CAF-T, 216 events in 566 patients; CAFT, 242 events in 550 patients). For the first objective, therapy with the CAF plus tamoxifen groups combined (CAFT or CAF-T) was superior to tamoxifen alone for the primary endpoint of disease-free survival (adjusted Cox regression hazard ratio [HR] 0.76, 95% CI 0.64-0.91; p=0.002) but only marginally for the secondary endpoint of overall survival (HR 0.83, 0.68-1.01; p=0.057). For the second objective, the adjusted HRs favoured CAF-T over CAFT but did not reach significance for disease-free survival (HR 0.84, 0.70-1.01; p=0.061) or overall survival (HR 0.90, 0.73-1.10; p=0.30). Neutropenia, stomatitis, thromboembolism, congestive heart failure, and leukaemia were more frequent in the combined CAF plus tamoxifen groups than in the tamoxifen-alone group. Chemotherapy with CAF plus tamoxifen given sequentially is more effective adjuvant therapy for postmenopausal patients with endocrine-responsive, node-positive breast cancer than is tamoxifen alone. However, it might be possible to identify some subgroups that do not benefit from anthracycline-based chemotherapy despite positive nodes. National Cancer Institute (US National Institutes of Health).

Concurrent hormone and radiation therapy in patients with breast cancer: what is the rationale?

Endocrine therapy is often given together with postoperative radiotherapy in patients with breast cancer and positive hormone-receptor status. However, few experimental or clinical studies address the combined effects of hormone and radiation therapy. Preclinical models have shown changes in tumour cell kinetics with the addition of tamoxifen, and some show reduced tumour cell death with concurrent anti-oestrogen treatment and radiotherapy. Although data from in-vitro studies support the notion of antagonistic effects of concurrent tamoxifen and radiotherapy on tumour cells, in-vivo research suggests a synergistic effect that could be attributable to micro-environmental changes in tumour responsiveness to ionising radiation and hormone therapy. Retrospective studies suggest that in practical application, concurrent administration of tamoxifen with radiotherapy does not compromise local control but might increase toxicity. Preliminary results from simultaneous treatment with aromatase inhibitors and radiation indicate that this combination of endocrine and radiation therapy could enhance cytotoxicity and improve tumour response. Further studies are needed to clarify the physiological mechanisms activated by oestrogens, which will allow a more thorough understanding of the complex interactions between 17beta-oestradiol and P53/P21(WAF1/CIP1)/Rb pathways and of the interaction between endocrine therapy and radiotherapy.