Years Of Tamoxifen Research Articles

Extended adjuvant endocrine therapy in hormone-receptor-positive early breast cancer.

The risk of relapse associated with oestrogen receptor-positive early breast cancer persists for at least 15 years after diagnosis. Several large clinical trials have examined extended adjuvant endocrine therapy. The MA.17 trial demonstrated improved disease-free survival (DFS) with use of letrozole for 5 years after some years of tamoxifen and an overall survival advantage for this approach in women with node-positive oestrogen receptor-positive cancer at diagnosis. The subsequent adjuvant tamoxifen - to offer more? and adjuvant tamoxifen: longer against shorter trials demonstrated a DFS advantage for 10 years of tamoxifen over 5 years. The recently reported MA.17R trial randomized women who had already completed 5 years of aromatase inhibitor therapy with or without previous tamoxifen to further 5 years of letrozole or placebo. DFS was significantly improved in the extended letrozole group, quality of life was similar but bone fracture rates were higher. The absolute benefit in terms of reduced distant recurrences in these studies is modest, and tolerability and compliance challenges remain. Physicians and patients now have multiple evidence-based treatment options for women who complete 5 years of adjuvant endocrine therapy. Extended therapy with either tamoxifen or letrozole should be considered for all and decision based on menopausal status, individual risk, tolerance and magnitude of potential benefit.

Breast Cancer - Specifics of Gynecological Care and Counseling

This paper summarizes current knowledge about clinically important aspects of gynecological care in female breast cancer patients. Despite the overall positive acceptance of oral contraceptives and hormone replacement drugs, hormone therapy may raise fears of developing breast cancer. Specifics of gynecological care of fertile patients are discussed as these patients face ovarian failure when undergoing oncological treatment of breast cancer. Tamoxifen is used in adjuvant therapy of breast cancer, in metastatic breast cancer or as prophylaxis of breast cancer in high-risk patients. We aim to study the influence of hormonal treatment on breast cancer development in women with and without congenital predisposition. The main risk factors for developing breast cancer are family history, increased density of breast tissue, atypical hyperplasia of the breast and previous radiotherapy to the chest area. All these factors increase the relative risk of cancer more than four times. Contraceptives and hormone replacement therapy show generally less than two-fold or no increase at all (RR 0.96-1.6). We concentrate with safety of hormonal therapy in breast cancer patients after they finish breast cancer treatment in pre- and postmenopausal period. We discuss fertility-sparing methods for preservation of ovarian function due to oncological treatment. Those methods are cryopreservation of embryos, oocytes in metaphase II and ovarian tissue. Simultaneous administration of GnRH agonists may protect ovarian function before gonadotoxic chemotherapy. We describe in detail the effects of tamoxifen on gynecological organs in both pre- and postmenopausal women in relation to the potential risk of developing secondary malignancy. In premenopausal women, tamoxifen has no increased risk of cancer of the uterine body. In postmenopausal patients, the risk after five years of tamoxifen is increased 2-3 times. Transvaginal sonography is not the screening tool for detection of the pathology in the uterine cavity during tamoxifen therapy, and so we only recommend looking for symptoms. Hysteroscopy is the golden standard for the examination of the uterine cavity in symptomatic postmenopausal patients using tamoxifen. This paper summarizes the current knowledge in areas where oncological and gynecological cares for breast cancer patients mingle. It should lead to greater understanding and deepening cooperation between clinical oncologists and oncogynecologists for the benefit of our patients.Key words: adjuvant hormonal therapy - fertility preservation - GnRH analogs - contraceptives - endometrial hyperplasia - hormone replacement therapy - breast neoplasm - tamoxifenThis work was supported by the Czech Ministry of Health - RVO (FNBr, 65269705).The authors declare they have no potential confl icts of interest concerning drugs, products, or services used in the study.The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 6. 6. 2016Accepted: 22. 7. 2016.

TBS and BMD at the end of AI-therapy: A prospective study of the B-ABLE cohort

IntroductionPatients with breast cancer under aromatase inhibitor (AI) treatment often develop osteoporosis and their average bone loss rate is twice that of natural reduction during menopause, increasing fracture risk. As the current diagnostic technique based on bone mineral density (BMD) provides no information on bone quality, the Trabecular Bone Score (TBS) has been proposed to reflect bone microarchitecture status. The present study was designed to assess prospective changes in TBS and lumbar spine (LS) BMD in postmenopausal women with breast cancer at completion of AI treatment. MethodsB-ABLE is a prospective cohort of 735 women with breast cancer treated with AIs according to American Society of Clinical Oncology recommendations: 5years of AI starting within 6weeks post-surgery or 1month after the last cycle of chemotherapy (5y-AI group), or switching to an AI to complete 5-year therapy after 2–3years of tamoxifen (pTMX-AI group). Patients with osteoporosis were treated with oral bisphosphonates (BP). TBS and LS-BMD changes at completion of AI therapy were evaluated by Student t-test for paired samples. Pearson correlation coefficients were computed for correlations between LS-BMD and TBS. ResultsAI treatment was completed by 277 women. Of these, 70 (25.3%) were allocated to BP therapy. The non-BP-treated patients (74.7%) showed significant decreases in TBS (−2.94% in pTMX-AI and −2.93% in 5y-AI groups) and in LS-BMD (−4.14% in pTMX-AI and −2.28% in 5y-AI groups) at the end of AI treatment. In BP-treated patients, TBS remained stable at the end of AI treatment, whereas LS-BMD showed significant increases (+2.30% in pTMX-AI and +5.33% in 5y-AI groups). Moderate associations between TBS and LS-BMD values at baseline and at the end of AI treatment (r=0.4; P<0.001) were observed. At the end of treatment, changes in spine BMD and TBS were weakly correlated (r=0.1, P<0.01). ConclusionsAI therapy induces significant decreases in TBS, comparable to BMD loss. BP-treated patients maintained TBS values, whereas BMD increased. AI treatment leads to deterioration of bone microarchitecture, which seems to be attenuated by BP therapy.

Factors associated with late recurrence after completion of 5-year adjuvant tamoxifen in estrogen receptor positive breast cancer.

BackgroundRecent large trials have shown the survival benefits of 10-year use of tamoxifen by reducing late recurrence compared with 5-year therapy in estrogen receptor(ER)-positive breast cancer. We tried to identify clinical factors associated with the late recurrence.MethodsWe reviewed our database of ER-positive patients who had received operations between 1996 and 2006 in two institutions. We selected 444 who had completed 5-year tamoxifen and were disease-free up to 10 years after the operation. Patients who had received aromatase inhibitors with any regimens were excluded. As a late recurrence group, 139 patients were identified who had completed 5-year tamoxifen, but had recurrence afterwards. Among them, 61 had local/contralateral breast recurrence and 78 had distant metastasis. The median follow-up was 9.7 years. Clinicopathological factors at the time of initial operation, such as age, menopausal status, progesterone receptor expression, HER2 status, tumor grade and Ki-67, were compared between the disease-free group and the late recurrence group.ResultsIn a univariate analysis, tumor size (>2 cm), lymph node metastasis and high histologic grade were significantly associated with late recurrences (p < 0.05). In a multivariate analysis, only axillary lymph node metastasis was significant (p < 0.001). Late distant metastasis was significantly associated with tumor size and axillary lymph node metastasis (p = 0.038, p < 0.001,respectively). Late local/contralateral breast recurrence was associated with axillary lymph node metastasis (p = 0.042).ConclusionsOur data showed axillary lymph node metastasis at initial operation was the only risk factor of late recurrence after completion of tamoxifen for 5 years. Our results can be helpful in making decisions to use extended tamoxifen beyond 5 years.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2423-x) contains supplementary material, which is available to authorized users.

A randomized trial (MA.17R) of extending adjuvant letrozole for 5 years after completing an initial 5 years of aromatase inhibitor therapy alone or preceded by tamoxifen in postmenopausal women with early-stage breast cancer.

LBA1 Background: Five years of aromatase inhibitor (AI) therapy either as up-front treatment or after 2-5 years of tamoxifen has become the standard of care for postmenopausal women with hormone receptor positive early breast cancer. Extending treatment with an AI to 10 years may further reduce the risk of breast cancer recurrence. Methods: We conducted a double-blind, placebo-controlled trial (Canadian Cancer Trials Group MA.17R) to test the efficacy of extending AI treatment for an additional five years using letrozole. The primary endpoint was disease-free survival. Results: A total of 1,918 women with early stage breast cancer were enrolled (median follow-up 75 months, 6.3 years). A total of 165 disease-free survival (DFS) events (67 on letrozole and 98 on placebo) occurred, of which 42 versus 53 were distant recurrences on letrozole and placebo, respectively. There were 200 deaths (100 in each treatment group). The 5 year DFS was respectively 95% for patients receiving letrozole versus 91% for those on placebo (HR 0.66; P = 0.01) from a two-sided log-rank test stratified by nodal status, prior adjuvant chemotherapy, interval between last dose of AI therapy and randomization, and duration of prior tamoxifen at randomization. The 5 year overall survival was respectively 93% for subjects on letrozole and 94% on placebo with a HR of 0.97 (P = 0.83). The annual incidence rate of contralateral breast cancer was 0.21% for subjects on letrozole versus 0.49% on placebo (P = 0.007). Conclusions: Compared to 5 years of AI treatment as initial therapy or preceded by 2-5 years of tamoxifen, extending AI treatment to 10 years significantly improves disease-free survival. Further analyses will provide a comprehensive picture of toxicities and QOL. Clinical trial information: NCT00754845.

Prognostic Impact of the Combination of Recurrence Score and Quantitative Estrogen Receptor Expression (ESR1) on Predicting Late Distant Recurrence Risk in Estrogen Receptor-Positive Breast Cancer After 5 Years of Tamoxifen: Results From NRG Oncology/National Surgical Adjuvant Breast and Bowel Project B-28 and B-14.

We determined the utility of the 21-Gene Recurrence Score (RS) in predicting late (> 5 years) distant recurrence (LDR) in stage I and II breast cancer within high and low-ESR1-expressing groups. RS was assessed in chemotherapy/tamoxifen-treated, estrogen receptor (ER) -positive, node-positive National Surgical Adjuvant Breast and Bowel Project B-28 patients and tamoxifen-treated, ER-positive, node-negative B-14 patients. The association of the RS with risk of distant recurrence (DR) 0 to 5 years and those at risk > 5 years was assessed. An ESR1 expression cut point was optimized in B-28 and tested in B-14. Median follow-up was 11.2 years for B-28 and 13.9 years for B-14. Of 1,065 B-28 patients, 36% had low (< 18), 34% intermediate (18 to 30), and 30% high (≥ 31) RS. Of 668 B-14 patients, 51% had low, 22% intermediate, and 27% high RS. Median ESR1 expression by reverse transcriptase polymerase chain reaction was: B-28, 9.7 normalized expression cycle threshold units (CT) and B-14, 10.7 CT. In B-28, RS was associated with DR 0 to 5 years (log-rank P < .001) and > 5 to 10 years (log-rank P = .02) regardless of ESR1 expression. An ESR1 expression cut point of 9.1 CT was identified in B-28. It was validated in B-14 patients for whom the RS was associated with DR in years 5 to 15: 6.8% (95% CI, 4.4% to 10.6%) versus 11.2% (95% CI, 6.2% to 19.9%) versus 16.4% (95% CI, 10.2% to 25.7%) for RS < 18, RS 18 to 30, and RS ≥ 31, respectively (log-rank P = .01). For LDR, RS is strongly prognostic in patients with higher quantitative ESR1. Risk of LDR is relatively low for patients with low RS. These results suggest the value of extended tamoxifen therapy merits evaluation in patients with intermediate and high RS with higher ESR1 expression at initial diagnosis.

Adjuvant Tamoxifen Plus Ovarian Function Suppression Versus Tamoxifen Alone in Premenopausal Women With Early Breast Cancer: Patient-Reported Outcomes in the Suppression of Ovarian Function Trial.

The Suppression of Ovarian Function trial showed improved disease control for tamoxifen plus ovarian function suppression (OFS) compared with tamoxifen alone for the cohort of premenopausal patients who received prior chemotherapy. We present the patient-reported outcomes. The quality-of-life (QoL) analysis includes 1,722 of 2,045 premenopausal patients with hormone receptor-positive breast cancer randomly assigned to receive adjuvant treatment with 5 years of tamoxifen plus OFS or tamoxifen alone. Chemotherapy use before enrollment was optional. Patients completed a QoL form consisting of global and symptom indicators at baseline, every 6 months for 24 months, and annually during years 3 to 6. Differences in the change of QoL from baseline between the two treatments were tested at 6, 24, and 60 months with mixed models for repeated measures with and without chemotherapy and overall. Patients on tamoxifen plus OFS were more affected than patients on tamoxifen alone by hot flushes at 6 and 24 months, by loss of sexual interest and sleep disturbance at 6 months, and by vaginal dryness up to 60 months. Without prior chemotherapy, patients on tamoxifen alone reported more vaginal discharge over the 5 years than patients on tamoxifen plus OFS. Symptom-specific treatment differences at 6 months were less pronounced in patients with prior chemotherapy. Changes in global QoL indicators from baseline were small and similar between treatments over the whole treatment period. Overall, OFS added to tamoxifen resulted in worse endocrine symptoms and sexual functioning during the first 2 years of treatment, with variable magnitudes of treatment differences. Short-term differences in symptom-specific QoL, treatment burden, and coping effort between treatment groups were less pronounced for patients with prior chemotherapy, the cohort that benefited most from OFS in terms of disease control.

Prognostic and predictive effects of diabetes, hypertension, and coronary artery disease among women on extended adjuvant letrozole: NCIC CTG MA.17

BackgroundWomen with breast cancer and diabetes mellitus (DM) have poorer survival. Mechanisms include insulin dysregulation and/or DM related co-morbidities (CM). In MA.17 adjuvant letrozole (LET) after 5 years of tamoxifen (TAM) reduced the risk of recurrence and improved survival. We evaluated DM, hypertension (HTN), and coronary artery disease (CAD) as prognostic and predictive factors in MA.17. Patients and methodsDisease free survival, distant disease free survival (DDFS) and overall survival (OS) were compared using Cox regression model adjusting for other prognostic factors: in women treated by placebo (PLAC) based on the presence or absence of baseline DM (n = 462), HTN (n = 1627), CAD (n = 604) or any one of these CM (n = 2049), and between LET and PLAC groups in each CM. Analyses based on nodal status were performed. ResultsDM was neither prognostic nor predictive for women on extended LET. Women with one CM had similar outcomes on LET compared to women free of CM. For node positive women, the difference between LET and PLAC in DDFS was greater among women with one CM (hazard ratio [HR] = 0.30 [0.15–0.60], p = 0.001) compared to those without CM (HR = 0.72 [0.45–1.16], p = 0.17, p interaction = 0.04). Women on PLAC with HTN trended towards lower DDFS (HR = 1.50 [0.98–2.3], p = 0.06) and OS (HR = 1.61 [0.95–2.72], p = 0.08) than non-HTN women. HTN women had better DDFS on LET than non-HTN women. Women with one CM on PLAC had lower OS (HR = 2.10 [1.26–3.51], p = 0.004) than those free of CM. ConclusionsDM was not prognostic or predictive of outcomes. Women with CM who remain disease free after 5 years of TAM should be offered LET. HTN trended towards a negative prognosticator and outcomes among this group were improved on LET. More studies are needed to assess impact of adrenergic stimulation as a possible link to poorer breast cancer outcomes.

Abstract P3-07-35: Tumour immune subtyping as a predictive biomarker for adjuvant endocrine therapy in early breast cancer

Abstract Adjuvant endocrine therapy is one of the mainstays in the treatment of breast cancer. Approximately 75% of all patients is treated with either tamoxifen or an aromatase inhibitor (AI), without any predictive biomarkers besides the estrogen receptor. It is known, that the immune system plays a pivotal role in the treatment of breast cancer. Earlier, subtyping the local immune response has been shown to predict therapy efficacy for chemotherapy. The current study was performed to discover predictive relations between the local immune response and survival in two different cohorts treated with adjuvant endocrine therapy. Tumour tissue was collected from a cohort of 236 Dutch post-menopausal patients from the Intergroup Exemestane Study (IES-trial) who were randomized between 5 years of tamoxifen and 2.5 years of tamoxifen followed by 2.5 years of an AI (switch-scheme). The tumour tissue was stained for infiltration of CD8+ cytotoxic T-cells, FoxP3+ regulatory T-cells and CD68+ macrophages and the expression of different HLA-markers (classical HLA-I, HLA-E, HLA-G). These results were combined into three immune profiles (strong, intermediate, weak), and correlated to survival. Similar analyses were performed on a cohort of 2596 patients participating in the international TEAM trial, who were randomized between 2.5 years of tamoxifen followed by 2.5 years of an AI (switch scheme) and 5 years of an AI. In the IES-cohort, patients with a strong local immune response had a significant better recurrence free survival when treated with 5 years of tamoxifen (5-year RFS 89.5%) compared to the switch scheme (5-year RFS 76.5%) (p=0.003). In patients with a weak local immune response, RFS was improved for patients treated with the switch scheme (5-year RFS 100%) compared to tamoxifen monotherapy (5-year RFS 75.6%) (P=0.003). Similar trends were observed for overall survival, although not statistically significant (p-values of 0.051 and 0.109 respectively). In the TEAM-cohort, no statistical significant differences were observed between both treatments in either immunological subtype (strong immune subtype: 5-year RFS 87.2% for 5-years AI versus 82.8% for the switch scheme (p=0.495), weak immune subtype: 85.9% for 5-year of AI vs 82.2% for the switch scheme (p=0.343)). This study is the first to show combined immunological markers as a predictive marker for endocrine therapy. A strong immune response predicts a benefit for tamoxifen monotherapy, whereas a weak response predicts a benefit for AI-containing therapy. Although the exact mechanism of this effect is not known, we hypothesize that it might be contributed to immunomodulatory capacities of AIs. If the effect observed in the IES- cohort is indeed contributed to the effect of AIs, it would be expected that there is no difference in the TEAM-cohort between both arms since they both contain AIs, which was indeed observed. Future studies will be directed towards validation of these findings in an independent cohort. Citation Format: Blok EJ, Engels CC, Jongste E, Dekker-Ensink G, Kroep JR, Kuppen PJK, van de Velde CJH. Tumour immune subtyping as a predictive biomarker for adjuvant endocrine therapy in early breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-35.

Abstract P5-12-01: Adjuvant endocrine therapy and risk of contralateral breast cancer among a cohort of U.S. women with breast cancer

Abstract Background: The increasing incidence of estrogen receptor (ER)-positive breast cancer in the U.S. in concert with the aging population and improved survival have resulted in an increased number of women at risk of developing a second contralateral primary breast cancer. Results from randomized clinical trials have suggested a reduced risk of contralateral breast cancer among women taking tamoxifen or aromatase inhibitors. However, little is known about the duration of beneficial effects of endocrine therapy within the context of real life treatment scenarios, where gaps in treatment and varying durations of use may influence risk. Methods: We assessed contralateral breast cancer risk associated with adjuvant tamoxifen treatment among a cohort of 7,541 women, ages 24-85 years, who were members of Kaiser Permanente (KP) Northwest or Colorado, and were diagnosed with invasive breast cancer between 1990 and 2008 and remained at risk of contralateral breast cancer for at least one year. We also assessed risk in relation to aromatase inhibitor use, though statistical power was somewhat limited due to the relatively recent introduction of aromatase inhibitors in this older cohort. Use of tamoxifen, aromatase inhibitors and other treatments was ascertained from KP prescription and medical records. Relative risks (RR) and 95% confidence intervals (CI) were estimated using multivariable Poisson regression adjusting for study site, age at and year of diagnosis, stage at diagnosis, ER status, chemotherapy, and radiotherapy. Results: Over a median (range) of 6.3 (1.0-20.9) years of follow-up, 248 women developed contralateral breast cancer. Among patients surviving at least five years (n=4,668), 58% were prescribed tamoxifen with a median (range) duration of use of 4.2 (0.25-16.2) years. In models evaluating joint effects of tamoxifen duration and time since last use, we observed a statistically significant reduced risk of contralateral breast cancer among current tamoxifen users (RR=0.47, 95% CI: 0.30, 0.74) and among former users with 4+ years of tamoxifen (RR=0.39, 95% CI: 0.24, 0.63) as compared with women not treated with tamoxifen. Former users with 1-4 years of tamoxifen demonstrated a suggestive reduction in risk (RR=0.71, 95% CI: 0.45, 1.10), but there was no evidence of risk reduction for former users with &amp;lt;1 year of tamoxifen (RR=0.96, 95% CI: 0.56, 1.64). The reduced risks associated with 4+ years of tamoxifen persisted among patients surviving at least 7 years but were attenuated among those with more than 10 years since their first primary diagnosis. Aromatase inhibitor use was also associated with reduced contralateral breast cancer risk (RR=0.46, 95% CI: 0.22, 0.97). In subgroup analyses restricted to women whose first primary cancer was ER-positive (n=5,951), findings were consistent with those observed in the overall cohort. Conclusions: Adjuvant tamoxifen and aromatase inhibitor therapy considerably reduce the risk of contralateral breast cancer. Furthermore, our data suggest that tamoxifen protects against contralateral breast cancer while women are being treated and that the protective effect appears to continue after cessation with longer durations of use. Citation Format: Gierach GL, Curtis RE, Pfeiffer RM, Mullooly M, Hoover RN, Nyante SJ, Feigelson HS, Glass AG, Berrington de Gonzalez A. Adjuvant endocrine therapy and risk of contralateral breast cancer among a cohort of U.S. women with breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-12-01.

Abstract P5-12-08: Time course of changes in serum FSH, serum estradiol, and menstruation in premenopausal patients with breast cancer taking tamoxifen after completing chemotherapy: A report from the ASTRRA study

Abstract BACKGROUND Ovarian suppression with tamoxifen after chemotherapy is a promising therapeutic approach, particularly in young, high-risk breast cancer patients. Assessment of restoration of ovarian function is important with respect to the initiation of ovarian suppression. METHODS In total, 1289 women who remained or resumed premenopausal status after chemotherapy were randomized to receive 5 years of tamoxifen or 5 years of tamoxifen plus 2 years of ovarian suppression. Prospectively collected hormone data were available for 24 months after completing chemotherapy for 267 breast cancer patients without ovarian suppression. RESULTS At 6 months, a premenopausal status was identified in 56.6%, 36%, and 16.2% of patients using serum FSH, E2, and with menstruation bleeding, respectively, and about 30% more women achieved ovarian restoration using all three parameters during the 24-month follow-up. Ovarian function restoration differed significantly according to age group (log-rank, P&amp;lt;0.001 for all definitions). At 6 months, the distribution of patients according to hormone levels was as follows: group 1 (FSH &amp;lt;30 mIU/ml, E2 &amp;gt;20 pg/ml), 28.0%; group 2 (FSH &amp;lt;30 mIU/ml, E2 ≤20 pg/ml), 28.4%; group 3 (FSH ≥30 mIU/ml, E2 &amp;gt;20 pg/ml), 8.0%; and group 4 (FSH ≥30 mIU/ml, E2 ≤20 pg/ml), 35.6%. During the 24-month follow-up, the prevalence of menstruation restoration was higher in group 1 (71.6%) than in the other three groups. Restoration of serum E2 and menstrual bleeding occurred in 44% and 33% of patients in group 2, respectively; the corresponding percentages in group 4 were 40.6% and 28.7% (P&amp;lt;0.001). CONCLUSIONS Ovarian function should be monitored using serum FSH, serum E2, and menstruation history for at least 24 months after completing chemotherapy during tamoxifen treatment to establish eligibility for ovarian suppression. Citation Format: Kim HJ, Ahn SH, Nam SJ, Park SH, Ro JS, Im SA, Jung YS, Noh WC. Time course of changes in serum FSH, serum estradiol, and menstruation in premenopausal patients with breast cancer taking tamoxifen after completing chemotherapy: A report from the ASTRRA study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-12-08.

Abstract ES8-3: Endocrine management of premalignant lesions and DCIS

Abstract It has been recognized for many years that there exist pathological entities associated with an increased risk of invasive breast cancer. The most frequently encountered are atypical hyperplasia (AH), lobular carcinoma in situ (LCIS) and ductal carcinoma in situ (DCIS), although other diagnoses have also been identified. Often these lesions are discovered incidentally, and when diagnosed are found to confer a wide range of elevated breast cancer risk. Clinical management of these conditions has largely consisted of surveillance, sometimes with the addition of endocrine therapy. The selective estrogen receptor modulators (SERMs), including tamoxifen and raloxifene, have been the mainstay of endocrine therapy in this setting. A prospective randomized trial, NSABP P-1 randomized over 13,000 high risk women, defined by a Gail score &amp;gt;1.66, to either 5 years of tamoxifen or placebo.1 Tamoxifen reduced the risk of invasive breast cancer by 49% (p&amp;lt;.00001), with the greatest risk reduction seen in women with ADH or LCIS. The IBIS I study also compared to tamoxifen to placebo and confirmed a risk reduction with tamoxifen, although lower than that reported initially in the P-1 trial (hazard ratio [HR] 0.72 [95% CI 0.59-0.88], p=0.001).2 Most recently, the role of aromatase inhibitors as chemoprevention in this setting has been studied; the results of IBIS II trial, which randomized 3864 high risk postmenopausal women to anastrozole or placebo, found a substantial risk reduction in the AI group (hazard ratio 0.47, 95% CI 0.32-0.68, p&amp;lt;0.0001).3 Endocrine therapy in the adjuvant setting has been reported for DCIS in two prospective clinical studies, the NSABP-B24 and UK/ANZ trials. A meta-analysis of these two trials demonstrated that tamoxifen after lumpectomy for DCIS reduced recurrence of both ipsilateral (HR 0.75; 95% CI 0.61 to 0.92) and contralateral (RR 0.50; 95% CI 0.28 to 0.87) DCIS.4 There was a trend towards decreased ipsilateral invasive cancer (HR 0.79; 95% CI 0.62 to 1.01) and reduced contralateral invasive cancer (RR 0.57; 95% CI 0.39 to 0.83). In addition, the findings of NSABP B-35 randomizing postmenopausal women with ER-positive DCIS reported that 10-year point estimates for DFS were 77.9% for tamoxifen and 82.7% for anastrozole.5 Future challenges for this field will include more precise patient selection for these treatments, as all confer risk of side effects. These have resulted in poor uptake of chemoprevention despite the definitive benefit demonstrated in the large randomized studies. In addition, the utility of endocrine therapy as primary treatment for low risk DCIS or in the neoadjuvant setting are important questions which are currently under investigation. More precise quantification and communication of the risks and benefits of the endocrine therapies will be increasingly needed in order to maximize the benefits of endocrine intervention in this setting. 1Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90:1371-88, 1998 2Cuzick J, Sestak I, Cawthorn S, et al: Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial. Lancet Oncol 16:67-75, 2015 3Cuzick J, Sestak I, Forbes JF, et al: Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. Lancet 383:1041-8, 2014 4Staley H, McCallum I, Bruce J: Postoperative tamoxifen for ductal carcinoma in situ. Cochrane Database Syst Rev 10:CD007847, 2012 5Margolese RG: Primary Results of NRG Oncology/NSABP B-35: A Clinical Trial of Anastrozole vs Tamoxifen in Postmenopausal Patients with DCIS. J Clin Oncol 33, 2015 (suppl; abstr LBA500), 2015. Citation Format: Hwang ES. Endocrine management of premalignant lesions and DCIS. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr ES8-3.

Abstract P5-08-03: Prognostic impact of the combined risk groups by breast cancer index and HOXB13/IL17BR ratio in hormonal receptor positive, node negative breast cancer: A TransATAC study

Abstract Background: Breast Cancer Index (BCI) is a gene expression-based assay that reports two distinct results: 1) BCI predictive based on HoxB13/IL17BR ratio (H/I), and 2) BCI prognostic based on an algorithm incorporating H/I with the Molecular Grade index (MGI). Both biomarkers have been validated independently in randomized trial cohorts. However, integrated results to better correlate recurrence risk with endocrine response have not been evaluated. The aim of this post-hoc analysis was to examine patient outcomes within BCI prognostic and predictive groups using the translational arm of the Arimidex, Tamoxifen, Alone or in Combination trial (TransATAC). Methods: Primary tumor samples (N=742) from hormonal receptor-positive, N0 breast cancer patients treated with 5 years of tamoxifen (TAM) or anastrozole (ANA) in the ATAC trial were examined. Kaplan-Meier analysis was used to examine the risk of distant recurrence (DR) in patient subgroups derived from BCI and H/I results. A separate series of clinical cases submitted for BCI testing (N=853) were analyzed to determine distribution of the combined BCI and H/I groups in clinical practice. Results: Summary of patient distribution across the 6 BCI clinical subgroups showed that a large number of patients (331/742, 45%) were BCI low risk with low likelihood of benefit, whereas 108/742 (15%) of patients with endocrine responsive disease (High H/I) were classified as BCI low risk (Table 1). Kaplan-Meier analysis demonstrated that patients classified as BCI low risk had a very similar 10-year risk of DR irrespective of H/I status (H/I low: 5.5% vs. H/I high: 4.0%), indicating that prognosis was largely determined by BCI vs H/I. Table 1: Distribution of BCI and H/I risk groups in TransATAC BCI: PrognosticH/I: PredictiveLow RiskIntermediate RiskHigh RiskTotalLow Likelihood3318717435 (59%)High Likelihood10895104307 (41%)Total439 (59%)182 (25%)121 (16%)742 In 853 node negative cases submitted for BCI clinical testing, the distribution of BCI and H/I risk groups were similar to that from the TransATAC cohort (Table 2). Table 2: Distribution of BCI and H/I risk groups in clinical cases submitted for BCI testing BCI: PrognosticH/I: PredictiveLow RiskIntermediate RiskHigh RiskTotalLow Likelihood36410523492 (58%)High Likelihood96107158361 (42%)Total460 (54%)212 (25%)181 (21%)853 Discussion: Both prognostic and predictive components reported from the BCI assay may be used to stratify patients into 6 clinical subgroups based on prognostic risk of distant recurrence and endocrine responsiveness. Findings from this analysis indicate that patients classified as BCI low risk, regardless of H/I status, had sufficiently low DR rates and identifies patients that may be adequately treated with 5 years of endocrine therapy. Citation Format: Zhang Y, Sestak I, Schroeder BE, Dowsett M, Cuzick J, Schnabel CA, Sgroi DC. Prognostic impact of the combined risk groups by breast cancer index and HOXB13/IL17BR ratio in hormonal receptor positive, node negative breast cancer: A TransATAC study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-08-03.

Abstract P2-08-12: Integration of tumor size and grade with the breast cancer index (BCI) for prediction of distant recurrence in hormone receptor-positive breast cancer with 1-3 positive lymph nodes

Abstract Background: BCI is a genomic signature (Molecular Grade Index (MGI) and HOXB13/IL17BR (H/I)) that significantly predicts risk of distant recurrence (DR) in hormonal receptor-positive, lymph node negative (LN-) breast cancer. As previously shown in the TransATAC and MA.14 studies, BCI was also prognostic for DR in lymph node-positive (LN+) patients. Here, a distinct BCI model that integrates tumor size and grade was evaluated for prediction of DR in women with 1-3 lymph node positive disease. Methods: 219 primary tumor samples from hormonal receptor-positive patients with 1-3 positive lymph nodes treated with 5 years of tamoxifen or anastrozole were examined. Women with four or more positive lymph nodes were excluded. BCI was combined with tumour size and grade into a comprehensive risk score, BCIN+. Kaplan-Meier (KM) estimates of 10 year DR and hazard ratios (HR) and 95% confidence intervals (CI) were estimated. Change in likelihood ratio 2 (LR-2) values were used to measure prognostic information of each variable alone or combined in new score. New cutpoints for low versus high risk groups for the new model were determined to ensure the low risk patients had minimal 10-year residual disease. Results: In 219 LN+ patients, BCI alone provided substantial additional prognostic information to tumor size (LR-2=11.83, P=0.0006) and grade (LR-2=8.33, P=0.004). Both clinical variables provided additional significant prognostic information to BCI alone (BCI alone: LR-2=9.59, P=0.0004; T: LR-2=7.09, P=0.008; G: LR-2=27.59, P&amp;lt;0.0001). Integration of tumor size and grade with BCI (BCIN+) provided additional highly significant prognostic information compared to BCI alone (Interquartile HR=3.15 [95% CI: 1.54-6.04]; LR-2=33.89, P&amp;lt;0.0001). A cut-point for a very low risk group in this LN+ population was determined, and included 55 (25%) women with no DR within 10 years. In contrast, 51 (31.1%) women developed a DR in the high risk group (N=164). 10-year DR risk for those in the high risk group was 35.4% (95% CI 28.0-44.1%). Discussion: Integration of tumor size and grade significantly enhanced the prognostic ability of BCI to predict 10 year DR risk in hormonal receptor-positive patients with 1-3 positive nodes. A significant number of patients have been identified to have a very low 10-year risk for DR, who may choose to safely forego unnecessary adjuvant chemotherapy or extended adjuvant endocrine therapy. Validation of BCIN+ in other datasets is ongoing. Citation Format: Sestak I, Zhang Y, Schroeder B, Dowsett M, Sgroi D, Cuzick J, Schnabel CA. Integration of tumor size and grade with the breast cancer index (BCI) for prediction of distant recurrence in hormone receptor-positive breast cancer with 1-3 positive lymph nodes. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-08-12.

Abstract PD1-03: Cholesterol, cholesterol lowering medication use, and breast cancer outcomes in the BIG 1-98 study

Abstract Background: Cholesterol lowering medications (CLM)—statins in particular—may exert anti-cancer effects. A proposed mechanism involves attenuated signaling through the estrogen receptor by the cholesterol metabolite, 27-hydroxycholesterol, which correlates with systemic total cholesterol. Assessment of cholesterol levels and use of cholesterol-lowering medications among breast cancer patients receiving endocrine treatment may enrich our understanding of factors affecting endocrine therapy effectiveness and the role of statins and cholesterol in cancer survival. Aim: To investigate the prognostic effect of baseline cholesterol level and baseline CLM use, and to study the effect on outcome of concurrent use of CLM and endocrine therapy in the BIG 1-98 study. Design and Methods: The BIG 1-98 study enrolled 8,010 postmenopausal women with early-stage, estrogen receptor-positive invasive breast cancer from 1998-2003. Participants were randomized to five years of tamoxifen, letrozole, or their sequence. Cholesterol levels and use of CLM were assessed at baseline and every six months up to 5.5 years. Multivariable prognostic models of baseline cholesterol or baseline CLM use were adjusted for patient- and tumor characteristics and treatment regimen. Prognostic analyses of baseline cholesterol were restricted to women not taking CLM at baseline. Marginal structural modeling was used to investigate the relationship between initiation of CLM during endocrine therapy and outcome. Median follow-up was approximately 8 years. Endpoints were: disease-free survival (DFS), breast cancer-free interval (BCFI), and distant recurrence-free interval (DRFI). Results: Among 7,963 women who received at least one dose of endocrine therapy, 637 reported use of CLM at baseline, including statins (n=490) and non-statins (n=147). Compared with non-users, women on CLM at baseline were older, more often had a history of diabetes, were more likely to use hormone replacement therapy, and were more often diagnosed with smaller tumors or node-negative disease. During follow-up, 2,005 DFS-events, 1,303 BCFI-events and 1,004 DRFI-events were reported. Among non-users of CLM at baseline, baseline cholesterol levels showed a significant U-shaped association with BCFI and DRFI when grouped according to the quartiles of the distribution; however, these results were not maintained using cardiovascular risk-based cholesterol cut points. Prognostic models also suggested that use of any CLM at baseline was associated with better DFS compared with non-use (HRadj=0.82, 95% CI: 0.68, 0.99); similar, but non-significant associations were seen for BCFI (HRadj=0.83, 95% CI: 0.65, 1.06) and DRFI (HRadj=0.81, 95% CI: 0.61, 1.09). Results from the marginal structural modeling showed no differences in outcomes for women who initiated CLM during endocrine therapy compared with those who did not. Conclusions: In the BIG 1-98 study investigating the use of tamoxifen, letrozole or their sequence as endocrine therapy in the adjuvant setting, use of cholesterol-lowering therapy at baseline was associated with beneficial tumor characteristics. The effects on clinical outcome need further investigation. Citation Format: Borgquist S, Giobbie-Hurder A, Ahern T, Garber JE, Colleoni M, Láng I, Debled M, Ejlertsen B, Coates AS, Goldhirsch A, Price KN, Gelber RD, Regan MM, Thürlimann B. Cholesterol, cholesterol lowering medication use, and breast cancer outcomes in the BIG 1-98 study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD1-03.

Abstract P5-12-09: A novel commercial LC-MS/MS assay for tamoxifen (TAM) and its major metabolites

Abstract The standard of care for women presenting with early stage- ER-positive breast cancer (BC) following "curative" surgery has been 5 years of TAM. Adjuvant treatment with TAM has changed the natural history of BC, producing a significant reduction in 5- and 10-year recurrence rates; however, because of its adverse effects, many women (approx. 40%) do not complete the recommended 5 years of treatment. Furthermore, since TAM is a pro-drug that needs to be converted to endoxifen to be effective, inter-individual variability in endogenous enzymatic activity (i.e., CYP2D6) can affect endoxifen exposure. Certain drugs (e.g., SSRIs) can also reduce endoxifen exposure by inhibiting CYP2D6. It is thought that a reduction in endoxifen exposure reduces the efficacy of TAM treatment and increases recurrence risk. However, several recent studies contradict this hypothesis and suggest that a) there is more than one pathway to get to endoxifen, even in the presence of variant CYP2D6; and b) TAM may act through its other metabolites as well, not just endoxifen. Thus, a CYP2D6 genetic test may overly simplify our understanding of TAM metabolism and prompt clinicians to draw the wrong conclusions. As such, it would seem useful to develop an assay to directly measure each patient's unique serum metabolite levels. The ability to quantitate all the major TAM metabolites would also allow researchers to assess which metabolite level(s) most closely correlates with both recurrence and toxicity, allowing individualized patient dosing. In this regard, results from the BIG1-98 study suggest that some metabolites may be more closely associated with adverse effects than others. This finding could be clinically useful when combined with outcomes data, as poor adherence to TAM may be an unrecognized reason for a number of recurrences that could potentially be avoided by therapeutic drug monitoring (TDM) using a sensitive and specific assay. With this in mind we developed an HPLC-MS/MS method that quantitatively measures TAM and 6 of its major metabolites in a single assay. This high-throughput assay has been validated to CLIA '88 standards and is run in a high-volume commercial CLIA certified laboratory. Although some of the metabolites had been measured previously by HPLC or LC-MS/MS, this is the first assay that measures all of the major metabolites, including the newly identified norendoxifen. Results Serum from 100 women taking TAM at 20 mg/d for &amp;gt; 6 months was tested using this assay, and observed ranges were calculated for this patient cohort. The observed ranges from the analysis are shown in Table 1, along with the lower limit of quantitation (LLOQ) for each analyte. Table 1. Observed ranges and LLOQs for Tamoxifen and MetaboliteAnalyteLLOQ (ng/mL)Observed Range (ng/mL)Endoxifen0.40.93-43.19Tamoxifen1.512.5-233.1N-Desmethyl Tamoxifen1.53.0-374.04-Hydroxy Tamoxifen0.20.24-5.05N-Desmethyl 4'- Tamoxifen0.41.17-19.954'-Hydroxy Tamoxifen0.40.4-6.33Norendoxifen1.2&amp;lt;7.3 Conclusions A novel commercial assay has been developed for TAM and its metabolites, which for the first time allows physicians to use a TDM approach for their TAM-treated patients. Citation Format: Clarke NJ, Weber DM, Goldman SM, Morton JW, Lagier RJ, Birse CE, Bender RA, Waldman FM. A novel commercial LC-MS/MS assay for tamoxifen (TAM) and its major metabolites. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-12-09.

Adjuvant endocrine therapy for postmenopausal women: Type and duration

Postmenopausal women with ER positive breast cancers benefit from adjuvant endocrine therapy. Most such patients should consider aromatase inhibitor therapy at some point in their treatment course as there are modest additional risk reductions over tamoxifen therapy, alone. Longer durations of therapy – beyond five years of tamoxifen – with either ongoing tamoxifen or an AI also improve cancer outcomes. Markers of risk for early recurrence are the same as those for late recurrence. Decisions regarding the optimal type and duration of therapy reflect patient preferences in light of well described side effects of tamoxifen and AI therapy, tolerability of treatment, and established clinical, pathological and genomic markers of risk.

Adjuvant endocrine therapy for premenopausal women with hormone-responsive breast cancer

Multiple strategies for endocrine treatment of premenopausal women with hormone-responsive breast cancer have been assessed and results have been presented over the last two years. These include tamoxifen for 5–10 years (ATLAS and aTTom), tamoxifen for 5 years followed by aromatase inhibitor (AI) for 5 years for women who have become postmenopausal (MA-17); ovarian ablation (OA) by surgery (EBCTCG overview); ovarian function suppression (OFS) by LHRH agonist (LHRH agonist meta-analysis); or combinations of approaches including OFS plus tamoxifen or AI (SOFT, TEXT, ABCSG 12 and E3193). Many of these trials have taken place in the backdrop of (neo)adjuvant chemotherapy which can confound interpretation because such therapy can suppress ovarian function either transiently or permanently. Nonetheless these trials suggest in aggregate that 10 years of tamoxifen are better than 5 years and that a program of extended adjuvant therapy of tamoxifen for 5 years followed by aromatase inhibitor for 5 years is effective for suitable candidates. The SOFT and E3193 trials do not show a major advantage for use of OFS + tamoxifen compared to tamoxifen alone. The joint SOFT/TEXT analysis and ABCGS12 trials both suggest that outcomes can be excellent with the use of combined endocrine therapy alone in properly selected patients but give conflicting results with regard to potential benefits for OFS + AI compared with OFS + tamoxifen. Further work will be needed to ascertain long-term outcomes, identify factors that predict who will benefit from extended adjuvant endocrine therapy, and assess role of OFS by medical or surgical means. It is clear, however, that endocrine therapy is a critical part of the adjuvant regimen for most premenopausal women with hormone-responsive breast cancer, and a subset of these women with luminal A-type tumors can be safely treated with endocrine therapy alone.

Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials

The optimal ways of using aromatase inhibitors or tamoxifen as endocrine treatment for early breast cancer remains uncertain. We undertook meta-analyses of individual data on 31,920 postmenopausal women with oestrogen-receptor-positive early breast cancer in the randomised trials of 5 years of aromatase inhibitor versus 5 years of tamoxifen; of 5 years of aromatase inhibitor versus 2-3 years of tamoxifen then aromatase inhibitor to year 5; and of 2-3 years of tamoxifen then aromatase inhibitor to year 5 versus 5 years of tamoxifen. Primary outcomes were any recurrence of breast cancer, breast cancer mortality, death without recurrence, and all-cause mortality. Intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded aromatase inhibitor versus tamoxifen first-event rate ratios (RRs). In the comparison of 5 years of aromatase inhibitor versus 5 years of tamoxifen, recurrence RRs favoured aromatase inhibitors significantly during years 0-1 (RR 0·64, 95% CI 0·52-0·78) and 2-4 (RR 0·80, 0·68-0·93), and non-significantly thereafter. 10-year breast cancer mortality was lower with aromatase inhibitors than tamoxifen (12·1% vs 14·2%; RR 0·85, 0·75-0·96; 2p=0·009). In the comparison of 5 years of aromatase inhibitor versus 2-3 years of tamoxifen then aromatase inhibitor to year 5, recurrence RRs favoured aromatase inhibitors significantly during years 0-1 (RR 0·74, 0·62-0·89) but not while both groups received aromatase inhibitors during years 2-4, or thereafter; overall in these trials, there were fewer recurrences with 5 years of aromatase inhibitors than with tamoxifen then aromatase inhibitors (RR 0·90, 0·81-0·99; 2p=0·045), though the breast cancer mortality reduction was not significant (RR 0·89, 0·78-1·03; 2p=0·11). In the comparison of 2-3 years of tamoxifen then aromatase inhibitor to year 5 versus 5 years of tamoxifen, recurrence RRs favoured aromatase inhibitors significantly during years 2-4 (RR 0·56, 0·46-0·67) but not subsequently, and 10-year breast cancer mortality was lower with switching to aromatase inhibitors than with remaining on tamoxifen (8·7% vs 10·1%; 2p=0·015). Aggregating all three types of comparison, recurrence RRs favoured aromatase inhibitors during periods when treatments differed (RR 0·70, 0·64-0·77), but not significantly thereafter (RR 0·93, 0·86-1·01; 2p=0·08). Breast cancer mortality was reduced both while treatments differed (RR 0·79, 0·67-0·92), and subsequently (RR 0·89, 0·81-0·99), and for all periods combined (RR 0·86, 0·80-0·94; 2p=0·0005). All-cause mortality was also reduced (RR 0·88, 0·82-0·94; 2p=0·0003). RRs differed little by age, body-mass index, stage, grade, progesterone receptor status, or HER2 status. There were fewer endometrial cancers with aromatase inhibitors than tamoxifen (10-year incidence 0·4% vs 1·2%; RR 0·33, 0·21-0·51) but more bone fractures (5-year risk 8·2% vs 5·5%; RR 1·42, 1·28-1·57); non-breast-cancer mortality was similar. Aromatase inhibitors reduce recurrence rates by about 30% (proportionately) compared with tamoxifen while treatments differ, but not thereafter. 5 years of an aromatase inhibitor reduces 10-year breast cancer mortality rates by about 15% compared with 5 years of tamoxifen, hence by about 40% (proportionately) compared with no endocrine treatment. Cancer Research UK, Medical Research Council.

Sequelae of radiotherapy-induced coronary artery disease in breast reconstruction

Sir, Approximately 37% of breast cancer patients who undergo breast conserving surgery or are found to have positive lymph nodes receive adjuvant radiotherapy [1]. Known side-effects of radiotherapy include wound breakdown, scarring, and radiation-induced angiosarcoma [2]. Less commonly cardiovascular complications can occur secondary to unwanted indirect irradiation of the heart, including coronary artery disease, pericarditis, and cardiomyopathy [3]. Chemotherapy for breast cancer can also induce cardiotoxicity, mainly secondary to anthracycline chemotherapy, which can lead to irreversible heart failure [4]. Cardiotoxicity has also been described with fluorouracil (5-FU) as angina-like chest pain, with incidences ranging from 1 to 68 % in the literature; cardiac events occur generally within 5 days after first administration [4]. We present an interesting case of a 45-year-old lady who underwent left mastectomy for breast cancer. This was followed by non-anthracycline chemotherapy and adjuvant radiotherapy receiving a total of 40 Gy over a course of 3 weeks. Two years later, she underwent delayed left breast reconstruction with a pedicled extended latissimus dorsi (ELD) musculocutaneous flap with a 220 cc round textured implant. She completed 5 years of tamoxifen and breast follow-up without any complications and remained diseasefree. Seven years after completion of radiotherapy, she presented to the emergency department with syncopal episodes and a four week history of exertional angina. Although she thought this pain was implant-related, her blood results showed a positive troponin (peak of 75 ng/L) and ECG’s showed T wave inversion in all the anterior leads, indicating an acute myocardial infarction. Coronary angiogram revealed critical coronary disease involving the left anterior descending, left circumflex and right coronary arteries (i.e. triple vessel disease). Her general risk factors were that she was an ex-smoker (2 pack years) with a family history of coronary heart disease. The cardiologists believed that her left-sided breast radiotherapy was the main predisposing factor for such unique triple vessel disease in a young patient. She was referred for urgent coronary artery bypass graft (CABG). Though the preoperative CT showed that the medial margin of the left breast implant was near the mid-sternal line (Fig. 1), this was probably positional, as clinically it appeared aesthetically acceptable (Fig. 2a). The patient underwent an uncomplicated triple CABG, and the left breast implant was preserved as it had not encroached the median sternotomy incision. Her postoperative breast aesthetic appearance remained unchanged (Fig. 2b). This letter highlights an interesting case of radiotherapyinduced triple vessel coronary artery disease and subsequent acute myocardial infarction in a young woman, following left sided irradiation for breast cancer. Microscopically, endothelial injury may occur secondary to the formation of reactive oxygen species and the activation of lysosomal enzymes within intima and media. Radiation promotes the adhesion of endothelial cells and the release of VonWillebrand factor inducing a prothrombotic state. Overall, atherosclerosis is * Hazim Sadideen hazim.sadideen@doctors.org.uk