Premenopausal Early Breast Cancer Patients Research Articles

Long-Term Outcomes With Pharmacological Ovarian Suppression During Chemotherapy in Premenopausal Early Breast Cancer Patients.

Although use of gonadotropin-releasing hormone agonist (GnRHa) during chemotherapy is an established strategy to protect ovarian function in premenopausal breast cancer patients, no long-term safety data are available, raising some concerns in women with hormone receptor-positive disease. There are controversial data on its fertility preservation potential. The Prevention of Menopause Induced by Chemotherapy: a Study in Early Breast Cancer Patients-Gruppo Italiano Mammella 6 (PROMISE-GIM6) trial is a multicenter, randomized, open-label, phase III superiority trial conducted at 16 Italian centers from October 2003 to January 2008. Eligible patients were randomly assigned to (neo)adjuvant chemotherapy alone (control arm) or combined with the GnRHa triptorelin (GnRHa arm). The primary planned endpoint was incidence of chemotherapy-induced premature ovarian insufficiency. Post hoc endpoints were disease-free survival (DFS), overall survival (OS), and post-treatment pregnancies. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Of 281 randomly assigned patients, 80.4% had hormone receptor-positive breast cancer. Median follow-up was 12.4 years (interquartile range = 11.3-13.2 years). No differences in 12-year DFS (65.7% [95% CI = 57.0% to 73.1%] in the GnRHa arm vs 69.2% [95% CI = 60.3% to 76.5%] in the control arm; HR = 1.16, 95% CI = 0.76 to 1.77) or in 12-year OS (81.2% [95% CI = 73.6% to 86.8%] in the GnRHa arm vs 81.3% [95% CI = 73.1% to 87.2%] in the control arm; HR = 1.17, 95% CI = 0.67 to 2.03) were observed. In patients with hormone receptor-positive disease, the hazard ratio was 1.02 (95% CI = 0.63 to 1.63) for DFS and 1.12 (95% CI = 0.59 to 2.11) for OS. In the GnRHa and control arms, 9 and 4 patients had a posttreatment pregnancy, respectively (HR = 2.14, 95% CI = 0.66 to 6.92). Final analysis of the PROMISE-GIM6 trial provides reassuring results on the safety of GnRHa use during chemotherapy as a strategy to preserve ovarian function in premenopausal patients with early breast cancer, including those with hormone receptor-positive disease.

Final analysis of the PROMISE-GIM6 phase III trial assessing GnRH agonist use during chemotherapy as a strategy to preserve ovarian function in premenopausal patients with early breast cancer.

516 Background: Current guidelines recommend GnRH agonist (GnRHa) use during chemotherapy (CT) as a strategy to reduce the risk of premature ovarian insufficiency (POI) in premenopausal patients with early breast cancer (EBC). However, no long-term safety data are available raising some concerns on concurrent use of GnRHa during CT in patients with hormone receptor-positive disease. In addition, there is no evidence on the protective role of this strategy in patients with germline BRCA mutations ( mBRCA). Here, we report the final analysis of the PROMISE-GIM6 phase III randomized study, the largest trial addressing the role of GnRHa use during CT in premenopausal EBC patients (Del Mastro et al, JAMA 2011 & Lambertini et al, JAMA 2015). Methods: From October 2003 to January 2008, 281 premenopausal patients aged 18 to 45 years with stage I-III EBC candidates for (neo)adjuvant CT were randomized to receive CT alone or combined with the GnRHa triptorelin. Primary endpoint was incidence of CT-induced POI (defined as amenorrhea and post-menopausal FSH/estradiol levels 1 year following CT). This final analysis reports on post-treatment pregnancies, disease-free survival (DFS) and overall survival (OS). An exploratory descriptive analysis in mBRCA patients is also reported. (ClinicalTrial.gov: NCT00311636) Results: Of the 281 randomized patients (CT+GnRHa arm = 148; CT alone arm = 133), 80% had hormone receptor-positive disease. At the time of this final analysis, 38 (13.5%) patients were lost to follow-up. Median follow-up was 12.4 years (IQR: 11.3-13.2 years). In the CT+GnRHa and CT alone arms, respectively, 9 (10-year cumulative incidence of pregnancy 6.5%, 95% CI 3.5%-12.3%) and 4 (10-year cumulative incidence of pregnancy 3.2%, 95% CI 1.2%-8.3%) patients had a post-treatment pregnancy (HR 2.14, 95% CI 0.66-6.92). No differences in 10-year DFS (72.4% in CT+GnRHa arm vs. 71.2% in CT alone arm: HR 1.16, 95% CI 0.76-1.77) nor in 10-year OS (82.0% in CT+GnRHa arm vs. 85.9% in CT alone arm: HR 1.17, 95% CI 0.67-2.03) were observed. There was no interaction between treatment effect and hormone receptor status. In patients with hormone receptor-positive disease, HR was 1.02 (95% CI 0.63-1.63) for DFS and 1.12 (95% CI 0.59-2.11) for OS. Out of 43 patients tested for BRCA, overall incidence of POI, irrespective of treatment arm, was 20% in mBRCA patients (n = 10) and 12% in patients without mBRCA (n = 33). In mBRCA patients, incidence of POI was 0% and 33% in the CT+GnRHa and CT alone arms, respectively. One post-treatment pregnancy was described in a patient with mBRCA1 in the CT alone arm. Conclusions: The final analysis of the PROMISE-GIM6 trial at a median follow-up of 12.4 years provides reassuring evidence on the safety of GnRHa use during CT as a strategy to preserve ovarian function in premenopausal patients with hormone receptor-positive EBC. Clinical trial information: NCT00311636.

Predictors of weight gain in a cohort of premenopausal early breast cancer patients receiving chemotherapy

AimIn breast cancer patients, post chemotherapy weight gain is linked with increased risk of cancer recurrence. We prospectively studied a cohort of premenopausal women receiving contemporary chemotherapy following a diagnosis of breast cancer to examine factors predicting weight increase. MethodsBetween May 2005 and January 2008, 523 patients from the Prospective Outcomes in Sporadic versus Hereditary (POSH) breast cancer study entered this sub-study comparing weight prior to chemotherapy and weight and waist/hip measurements 12-months following chemotherapy. ResultsData from 380 patients were available. Mean (standard deviation [SD]) pre-treatment body mass index (BMI) was 26.3 (5.6) kg/m2; 30% women gained > 5% body weight during the study period. Lower BMI at diagnosis predicted greater subsequent post treatment weight gain (4.3% relative weight gain for those in the 1st quartile of BMI compared to 0.8% for those in the 4th quartile; r = −0.22; p < 0.001). No link to chemotherapy regimens, cigarette smoking, previous parity or chemotherapy induced amenorrhoea was noted. A total of 44% of women had central obesity (post-treatment waist measurement of ≥88 cm). ConclusionsAlmost a third of premenopausal patients receiving adjuvant chemotherapy for breast cancer will gain clinically significant weight and over 40% will have central obesity 12-months following diagnosis. A greater weight gain is predicted by lower pretreatment BMI.

Abstract GS4-01: Pooled analysis of five randomized trials investigating temporary ovarian suppression with gonadotropin-releasing hormone analogs during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal early breast cancer patients

Abstract Background The role of temporary ovarian suppression with gonadotropin-releasing hormone analogs (GnRHa) during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal early breast cancer patients remains highly controversial. This option is considered experimental by the ASCO and ESMO guidelines on fertility preservation in cancer patients. The present pooled analysis aimed at elucidating the efficacy and safety of temporary ovarian suppression with GnRHa during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal early breast cancer patients. Patients and methods This study included individual patient data from 5 trials (PROMISE-GIM6, POEMS/SWOG S0230, Anglo Celtic Group OPTION, GBG-37 ZORO, Moffitt-led trial) in which premenopausal women with early breast cancer were randomized to receive (neo)adjuvant chemotherapy alone or with concurrent administration of GnRHa. Efficacy endpoints were premature ovarian insufficiency (POI, according to the definition used as primary endpoint in the included trials), 1- and 2-year amenorrhea rates and post-treatment pregnancy rate. Safety endpoints were disease-free survival (DFS) and overall survival (OS). Odds ratio (OR), incidence rate ratio (IRR) and hazard ratio (HR) with 95% confidence intervals (CI) were calculated for the effect of adding GnRHa to chemotherapy alone. As each study represents a cluster, statistical analysis has been performed using a random effects model. The study is registered with the PROSPERO registration number CRD42014015638. Results A total of 873 patients from 5 randomized trials were included. Median age was 38 years (interquartile range: 34-42 years). POI rate was 14.1% in the GnRHa group and 30.9% in the control group (adjusted OR 0.38; 95% CI 0.26-0.57; p &amp;lt; 0.001). The incidence of 1-year amenorrhea was 36.8% in the GnRHa group and 40.4% in the control group (adjusted OR 0.92; 95% CI 0.66-1.28; p = 0.623). The incidence of 2-year amenorrhea was 18.2% in the GnRHa group and 30.0% in the control group (adjusted OR 0.51; 95% CI 0.31-0.85; p = 0.009). A total of 37 patients had at least one post-treatment pregnancy in the GnRHa group and 20 in the control group (IRR 1.83; 95% CI 1.06-3.15; p = 0.030). There were no significant differences in DFS (adjusted HR 1.01; 95% CI 0.72-1.42; p = 0.999) or OS (adjusted HR 0.67; 95% CI 0.42-1.06; p = 0.083) between the GnRHa and control groups. Subgroup analyses of both efficacy and safety endpoints according to age of the patients, hormone receptor status, type and duration of chemotherapy will be presented at the conference. Conclusions This study provides level 1A of evidence for the efficacy and safety of temporary ovarian suppression with GnRHa during chemotherapy in premenopausal early breast cancer patients. Given the findings of this pooled analysis, temporary ovarian suppression with GnRHa during chemotherapy should be considered as a new standard option to reduce the likelihood of chemotherapy-induced POF and possibly improve future fertility in premenopausal early breast cancer patients. Citation Format: Lambertini M, Moore HCF, Leonard RCF, Loibl S, Munster P, Bruzzone M, Boni L, Unger JM, Anderson RA, Mehta K, Minton S, Poggio F, Albain KS, Adamson DJA, Gerber B, Cripps A, Bertelli G, Seiler S, Ceppi M, Partridge AH, Del Mastro L. Pooled analysis of five randomized trials investigating temporary ovarian suppression with gonadotropin-releasing hormone analogs during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal early breast cancer patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS4-01.

Prediction of Postmenopausal Status in Premenopausal Early Stage Breast Cancer Patients after Adjuvant Chemotherapy

Prediction of Postmenopausal Status in Premenopausal Early Stage Breast Cancer Patients after Adjuvant Chemotherapy

P007 - Survival outcome of combined GnRH agonist and tamoxifen is comparable to that of sequential adriamycin and cyclophosphamide chemotherapy plus tamoxifen in premenopausal early breast cancer patients

P007 - Survival outcome of combined GnRH agonist and tamoxifen is comparable to that of sequential adriamycin and cyclophosphamide chemotherapy plus tamoxifen in premenopausal early breast cancer patients

Abstract P5-15-04: Zoledronic acid combined with adjuvant tamoxifen with or without ovarian function suppression in premenopausal early breast cancer patients

Abstract Background: Bisphosphonates can delay the onset and reduce the risk of skeletal related events in patients with bone metastatic breast cancer; it can prevent and controlcancer treatment-induced bone loss. Zoledronic acid (ZOL) plus adjuvant endocrine therapy significantly improved disease free survival. The aim of the study is to evaluate the benefits of ZOL combined with adjuvant therapy in premenopausal early breast cancer patients. Patients and methods: Patients were premenopausal females who had undergone primary surgery for stage I, II ER +ve and/or PR +ve breast cancer with &amp;lt; 10 positive lymph nodes. All 300 patients were scheduled for standard tamoxifen 20mg/day for five years plus goserelin 3.6 mg every 28 days and were randomized to ZOL 4mg every 6 months for 3 years (group A) and without ZOL (group B). The primary end points were toxicity and disease-free survival (DFS), while overall survival (OS) was the secondary end point. Results: Between April 2005 and March 2012, 300 patients were enrolled, the median follow up duration was 98.4 months (range 14-120 months), adding ZOL to endocrine therapy strongly suggests improved DFS versus endocrine therapy alone (90% versus 85% for an absolute increase of 5%). There were fewer disease recurrences in the ZOL group versus no ZOL group (12% vs. 16%) with the greatest reductions in the loco-regional recurrence (3% vs. 5%), distant metastasis (6% vs. 7%) and bone metastasis (3% vs. 5%). Conclusion: ZOL with adjuvant endocrine therapy were generally well tolerated with no reports of renal failure or osteonecrosis of the jaw. So, a twice yearly ZOL enhanced the efficacy of adjuvant endocrine treatment, and this benefit is maintained for long time. Citation Format: El-Ibrashi MM, El-Sadda WM, Abdel-Halim II, Elashri MS. Zoledronic acid combined with adjuvant tamoxifen with or without ovarian function suppression in premenopausal early breast cancer patients. [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 P5-15-04.

Abstract P1-11-01: Depression and anxiety after adjuvant ovarian function suppression in premenopausal breast cancer patients

Abstract Purpose The results of the Suppression of Ovarian Function Trial (SOFT) and the Tamoxifen and Exemestane Trial (TEXT) showed that ovarian function suppression (OFS) in premenopausal early breast cancer patients improves disease control. However, mood swings after OFS is one of the chief complaints to make patients stop undergoing endocrine therapy. Studies about complications of OFS in breast cancer patients are not established well. We designed this randomized controlled trial to evaluate psychological functioning of patients after undergoing adjuvant OFS by goserelin. Patients and Methods We randomly assigned 64 premenopausal women with hormone receptor positive early breast cancer to the tamoxifen or tamoxifen plus goserelin group for a period of 1 year. Participants were screened for depression and generalized anxiety disorder using Hamilton Rating Scale for Depression (HAMD), Hamilton Rating Scale for Anxiety (HAM-A), Anxiety Sensitivity Index (ASI) and Albany panic and phobia questionnaire (APPQ) at baseline, 6 months and 12 months. Brain-derived Neurotrophic Factor (BDNF) levels were measured, as well. The results were analyzed by using a linear mixed model and a generalized linear mixed model. Results Thirty two patients were distributed in each group, equally. Linear mixed-mixed model analyses revealed that, compared with HAM-A scores of each group at baseline, HAM-A scores at 12 months showed increments (p=0.0078). Among HAM-A questions, Questions for intellectual, sensory and autonomic status were scored significantly high at 12 months (p=0.0018, p=0.0132, p=0.0006). Platelet BDNF levels reported a statistically significant rise at 12 months (p=0.0006). There was no significant time-by-study group effect in all scales. Conclusion Compared with the patients without OFS, patients with Goserelin showed no difference in anxiety or depression scales. Thought the levels of anxiety of each group at 12 months were increased, they do not indicate medical interventions. Patients with increased levels of BDNF at 12 months are expected to have good recovery from anxious and depressive symptoms. Citation Format: Yi HW, Nam SJ, Kim SW, Lee JE, Lee SK, Bae SY, Park S, Paik H-J, Ryu JM. Depression and anxiety after adjuvant ovarian function suppression in premenopausal breast cancer patients. [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 P1-11-01.

Abstract P4-10-05: Changes in metabolic syndrome components in breast cancer patients receiving neoadjuvant or adjuvant chemotherapy

Abstract Purpose. We sought to determine the impact of (neo)adjuvant chemotherapy on metabolic syndrome (MetS) components and related anthropometric and metabolic biomarkers among premenopausal and postmenopausal early stage breast cancer patients. Methods. Eighty-six women with early stage (I-III) breast cancer who were free from clinically diagnosed MetS (defined as 3 out of 5 components of MetS) and were planning to undergo chemotherapy, enrolled in the study. Participants were tested for MetS (blood pressure; BP, waist circumference; WC, fasting blood glucose; FBG, high-density lipoprotein cholesterol; HDL-C, and triglycerides; TG), anthropometrics (body weight; BW, percent body fat; BF, fat mass; FM), lipid profile (total cholesterol; TC, low-density lipoprotein cholesterol; LDL-C), glucose metabolism (insulin, homeostatic model- insulin resistance; HOMA-IR, glycosylated hemoglobin; HbA1c), and inflammation (C-reactive protein; CRP) within one week before and following the completion of chemotherapy. Fasting (12-hour) venous blood samples of the antecubital vein were drawn to measure glucose, insulin, lipid profile (TC, HDL-C, LDL-C, and TRI), HbA1c, and CRP. Blood samples were analyzed at the City of Hope Clinical Pathology Laboratory. Insulin resistance was calculated using the HOMA index: [(fasting glucose (mg/dL) x fasting insulin (mg/dL)/405]. Height, BW, and BP measurements were obtained by the nursing staff during pre-chemotherapy physical exams. Body composition (BF and FM) was measured using a portable hand-held bioelectrical impedance device (Omron®; Hoffman Estates, IL). WC was measured, using a fabric measuring tape, as the distance around the waist using the umbilicus as the reference point. One-way analysis of covariance (ANCOVA) using SPSS version 18.0 was used to compare means adjusting for covariates such as age, race, type of chemotherapy, duration of chemotherapy, BMI at baseline, and menopausal status. Results. The majority of the 86 women enrolled were Caucasian (44%) or Hispanic (30%), nonsmoking (96%), employed (84%), and well-educated (90%), with a mean age of 48.2 years. Women were most commonly undergoing Cytoxan/Adriamycin + Taxol (42%) or Taxotere/Cytoxan (36%) chemotherapy regimens, lasting on average 15.3 (±2.7) weeks. Overall the population was sedentary, averaging 7.2 (±5.8) minutes of physical activity/week. Following chemotherapy, all MetS components and overall MetS score (out of 5) significantly increased (p&amp;lt;0.01). Additionally, BW, BF, FM, lipids (TC, LDL), glucose metabolism (HOMA-IR, insulin, HbA1c), and inflammation (CRP) significantly increased (p&amp;lt;0.01). Conclusion. In women without MetS, (neo)adjuvant chemotherapy negatively altered MetS components, related anthropometrics, and biomarkers of glucose metabolism and inflammation, within 12 -18 weeks. Studies that test the impact of lifestyle interventions, such as diet and exercise, should be explored in this population of breast cancer patients to reduce the onset of MetS. Citation Format: Dieli-Conwright CM, Wong L, Waliany S, Bernstein L, Salehian B, Mortimer JE. Changes in metabolic syndrome components in breast cancer patients receiving neoadjuvant or adjuvant chemotherapy. [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 P4-10-05.

New insights on the role of luteinizing hormone releasing hormone agonists in premenopausal early breast cancer patients.

Luteinising hormone releasing hormone agonists (LH-RHa) are effective in the treatment of advanced endocrine-sensitive breast cancer in premenopausal patients, but their role in the adjuvant setting has remained controversial for a long time. Tamoxifen for 5 years has been traditionally considered the standard endocrine therapy for premenopausal patients and this is still valid for many patients. However, the recently reported SOFT trial has suggested that adding ovarian function suppression (OFS) to tamoxifen could improve DFS in women at sufficient risk to warrant adjuvant chemotherapy and who remained premenopausal after this therapy. The administration of an aromatase inhibitor plus OFS represents an additional therapeutic option for hormone-receptor positive premenopausal breast cancer patients, according to the combined analysis of the SOFT and TEXT trials. Temporary ovarian suppression induced by LH-RHa has been recognized as an effective strategy to preserve ovarian function from the toxic effects of chemotherapy and is now recommended in young breast cancer patients with endocrine-insensitive tumors. In this review, we discuss recent data on the role of LH-RHa in combination with tamoxifen or with an aromatase inhibitor, and we comment on its role as a strategy to preserve ovarian function in young patients candidates for adjuvant or neo-adjuvant chemotherapy.

Clinical utility of exemestane in the treatment of breast cancer.

Breast cancer is the most prevalent cancer in women, causing a significant mortality worldwide. Different endocrine strategies are available for the treatment of hormone-sensitive breast cancer, including antiestrogen tamoxifen and fulvestrant, as well as third-generation aromatase inhibitors (AIs), such as letrozole, anastrozole, and exemestane. In this review, we will focus on exemestane, its clinical use, and its side effects. Exemestane is a steroidal third-generation AI now used in all treatment settings for breast cancer. In the metastatic disease, it has been extensively investigated as the first-, second-, and further-line treatment and it is now registered for the treatment of postmenopausal women with advanced estrogen-receptor-positive breast cancer whose disease has progressed following antiestrogen therapy. A potential lack of cross-resistance with nonsteroidal AIs has been described, giving additional therapeutic opportunities in sequences of endocrine agents. Exemestane is also approved for the adjuvant treatment of postmenopausal early breast cancer, either as upfront monotherapy for 5 years, as a switch following 2–3 years of tamoxifen, or as extended therapy beyond 5 years of adjuvant treatment. New promising data also showed a beneficial effect in young premenopausal early breast cancer patients, when administered together with ovarian suppression. Interesting results have also emerged when exemestane has been investigated as neodjuvant treatment as well as preventive agent in healthy women at high risk for breast cancer. Exemestane is generally well tolerated, with a side effect profile similar to that of other AIs, including menopausal symptoms, arthralgia, and bone loss. In conclusion, exemestane can be considered an effective and well-tolerated endocrine treatment option for all stages of breast cancer.

Abstract P6-08-47: Androgen receptor expression in pre-menopausal early breast cancer patients treated with endocrine therapy within the ABCSG-12 trial - a single center pilot analysis

Abstract Background: Estrogen-receptor (ER) positive breast cancer co-expresses androgen receptor (AR) in 75% to 95% of cases. The Austrian Breast &amp; Colorectal Cancer Study Group (ABCSG) trial 12 compared anastrozole plus goserelin with tamoxifen plus goserelin in premenopausal patients with hormone receptor positive early breast cancer. In addition, patients were randomized to receive zoledronic acid or not. The aim of this analysis was to investigate the effect of AR expression on outcome in dependency of the treatment arm. Patients and methods: AR expression was analyzed by immunohistochemistry using a mouse monoclonal antibody (Novocastra) in formalin-fixed paraffin-embedded specimens from 194 early breast cancer patients treated within the ABCSG 12 trial at our institution. As there is no generally accepted cut-off level defining AR positivity, we used two definitions for this analysis: A) positive staining of ≥ 10% of tumor cells B) an immune reactive score (IRS; intensity of staining X percentage of stained cells) ≥ 3 according to the Remmele score used for ER/PR evaluation. Results: A total of 194 patients were included in this analysis. In tissue samples collected before 2001 AR staining was very weak, interpreted as a loss of antigenicity due to archival time and conditions. Therefore, 40 patients with tissue samples achieved earlier than 2001 were excluded from further analysis. Seventy-nine percent (122 of 154) and 63% (97 of 154) of tumors were AR positive by definition A and B, respectively. All except one of the AR positive tumors according to definition B, were also positive according to definition A. Disease free survival (DFS) and overall survival (OS) data N (%)DFSOSDefinition A (≥ 10%) AR positive122 (79)HR 0.61 (0.21-1.72) P=0.3428HR 0.17 (0.03-0.99) P=0.025AR negative32 (21) Definition B (IRS ≥ 3) AR positive97 (63)HR 0.88 (0.33-2.35) P=0.7994HR 0.39 (0.07-2.34) P=0.2846AR negative57 (37) DFS and OS did not differ between both endocrine treatment arms in a Cox regression model tested for interaction between AR expression and endocrine treatment. Conclusion: In this pilot study patients with AR positive disease had a numerically better DFS and OS compared to AR negative patients, but only prolongation of OS in patients with ≥ 10% AR positive tumor cells was statistically significant. AR expression did not influence outcome between tamoxifen and anastrozole treated patients, but based on the small number of events, this results have to be interpreted with caution. This data will be confirmed in a larger proportion of patients treated within the ABCSG-12 trial. Citation Format: Gabriel Rinnerthaler, Anna M Knopp, Cornelia Hauser-Kronberger, Simon P Gampenrieder, Patrick Morre, Brigitte Mlineritsch, Christian Fesl, Michael Gnant, Richard Greil. Androgen receptor expression in pre-menopausal early breast cancer patients treated with endocrine therapy within the ABCSG-12 trial - a single center pilot analysis [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-08-47.

ASCO 2014: highlights in breast cancer

While in general, not immediately praxis changing, results of various relevant clinical trials were presented at the 2014 ASCO Annual Meeting. Indeed, the ALTTO study provided first (albeit negative) data on the activity of dual Her2 inhibition with trastuzumab and lapatinib (either sequentially or concomitantly) in the adjuvant setting, while a combined analysis of the SOFT and TEXT studies suggested, for the first time, that a combination of ovarian function suppression (OFS) plus exemestane might be superior to OFS plus tamoxifen in premenopausal early breast cancer patients. Results of the POEMS trial investigating the role of the gonadotropin-releasing hormone-analog goserelin in the prevention of chemotherapy-induced amenorrhea led to lengthy debates, as the trial reported a survival benefit in hormone-receptor-negative breast cancer patients receiving goserelin. A subgroup analysis of German Breast Group trial GeparSixto as well as several other phase II trials again emphasized the role of carboplatin in neoadjuvant therapy of triple-negative breast cancer patients. These and other studies will be reviewed within this article.

269P - The Relationship Between Serum E2 Level and Recurrence During Endocrine Therapy for Er Positive Pre-Menopausal Early Breast Cancer Patients

ABSTRACT Aim: 10-year tamoxifen as adjuvant endocrine therapy become common for pre-menopausal ER-positive breast cancer patients according to the report from ATLAS trial (SABCS 2012) or aTTom study (ASCO 2013). On the other hand, it is generally believed that exposure to estradiol is strongly associated in breast cancer, however there are different opinions among experts voting in the duration of using LHRH agonist. The aim of this study is to evaluate the recurrence factor for endocrine therapy in ER positive pre-menopausal breast cancer patients. Methods: We chose 193 cases of premenopausal ER-positive early-stage breast cancer patients who received LHRH agonist and tamoxifen with 45 year-old or more younger onset. The median age was 40 years old (24-45) when the treatment started. They included 98 cases who were received pre-operative or post-operative chemotherapy as adjuvant systemic therapy. We studied about the relationship of local recurrence or distant metastasis and the duration of administration of the drug. We monitored of E2, FSH concentrations in blood before, during and after treatment. The median follow up period was 68 months (9-324 months). Results: We obtained the data of E2 dynamics during endocrine therapy from patients' sample. During LHRH agonist and tamoxifen therapy, serous E2 level decreased to the postmenopausal level, less than 31.0 pg/ml. However E2 concentration with tamoxifen and without LHRH agonist elevated to the average 58.1 pg/ml (10.0-5248.0 pg/ml). The duration of LHRH agonist was not the most important factor of breast cancer recurrence. There was a relation between continuous high serum level of E2 after LHRH agonist and metastasis regardless of the menstruation state. This phenomenon could be explained by the similar mechanism of low dose estrogen therapy after AI therapy for metastatic breast cancer. Conclusions: There might be association with breast cancer recurrence and E2 concentration in premenopausal ER-positive early-stage breast cancer. Disclosure: All authors have declared no conflicts of interest.

Abstract P1-08-13: Predictive value of intrinsic luminal subtypes in premenopausal women with endocrine-responsive early breast cancer: Results from Austrian breast and colorectal cancer study group trial 5

Abstract Purpose: The aim of the present study was to assess the predictive value of intrinsic luminal subtypes in premenopausal hormone receptor-positive early breast cancer patients who received adjuvant endocrine treatment or chemotherapy. Patients and Methods: Intrinsic luminal breast cancer subtypes were centrally assessed by immunohistochemistry on whole tissue sections of breast cancer patients who had been enrolled in the Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 5 and received either 3 years of goserelin plus 5 years of tamoxifen or six cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF). Luminal A disease was defined as Ki67 &amp;lt;20%, Luminal B/HER2-negative subtype as Ki67≥20%. Luminal B/HER2-positive subtype displayed HER2 overexpression by IHC or amplification by ISH. Recurrence-free survival (RFS) and overall survival (OS) were analyzed using Cox models adjusted for clinical and pathological factors. Results: 155 (36%), 217 (50%) and 59 (14%) of 431 tumors were classified as Luminal A, Luminal B/HER2-negative and Luminal B/HER2-positive, respectively. Luminal B subtypes were associated with poor outcome. Patients with Luminal B tumors had a significantly shorter RFS (adjusted hazard ratio [HR] for recurrence: 2.29, 95% confidence interval [CI] 1.44-3.64, P &amp;lt; 0.001) and OS (adjusted HR for death: 3.97, 95% CI 1.94-8.08, P &amp;lt; 0.001) as compared to patients with Luminal A disease. No interaction between intrinsic luminal subtypes and treatment was observed (test for interaction: P = 0.42 for RFS; P = 0.32 for OS). Combination endocrine treatment with goserelin/tamoxifen tended to be more effective than CMF chemotherapy in both luminal A and luminal B subtypes. Conclusion: Intrinsic luminal subtype is an independent prognostic factor for recurrence and death in premenopausal women with early-stage, hormone receptor positive breast cancer but is not predictive for outcome of adjuvant treatment with either goserelin/tamoxifen or chemotherapy with CMF. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-13.

Prevalence of bisphosphonate-associated osteonecrosis of the jaw after intravenous zoledronate infusions in patients with early breast cancer

The definite incidence rate of bisphosphonate-related osteonecrosis of the jaws (BRONJ) is still unknown. The aim of this study was to investigate prevalence of BRONJ in a group of breast cancer patients applying the classification of the Association of Oral and Maxillofacial Surgeons 2009. Between 2000 and 2008, 63 premenopausal early breast cancer patients who were free of metastases were treated with 4 mg zoledronic acid every 6 months over 3 years as participants of a multicenter, randomized, controlled, adjuvant breast cancer medication trial. Patients were not informed about the risk of jaw necrosis. None reported tooth or jaw complaints during the breast cancer follow-up examinations. In 2010, 48 patients of this cohort were investigated concerning BRONJ by clinical and radiological examinations. No advanced stages (AAOMS 2009)were detected. However, five patients (10.4%) presented purulent (2) and nonpurulent (3) fistulas and radiological signs correlating to BRONJ stage 0. Although no case of advanced BRONJ was detected, the study revealed a high prevalence of BRONJ stage 0. This supports the need for tight cooperation between dentists and medical specialists prescribing bisphosphonates including dental pre-therapeutic and follow-up examinations. Adaption of the BRONJ classification taking account to bone exposure via fistulas is recommended. BRONJ is said to be a complication linked to high-dosage bisphosphonate therapy. The study demonstrates that even after application of zoledronate in a low-dose protocol, early BRONJ occurred. Radiological signs solely are not sufficient to confirm BRONJ; clinical signs are mandatory.

P4-08-02: Estradiol (E2) Mediated Secretion of Vascular Endothelial Growth Factor (VEGF) and Stimulation of T-Regulatory Cells (T-Regs): Their Role for the Worse Prognosis of Breast Cancer (BC) in Premenopause.

Abstract Background: E2 plays a key role in all the phases of human reproduction, including promotion of uterine basal membrane erosion, embryo implantation, placental villi development, and pregnancy maintenance. E2 mediates all these functions through the induction of VEGF secretion and stimulation of T-Regs with increased tolerance for the eterologous embryo. BC might utilize the same pathways for its growth and for disease progression: Modulation of VEGF expression in BC cells through transcriptional activation and regulation of the peripheral development of CD4+CD25+ T-Regs cells. Both VEGF and T-Regs are important prognostic factors: In fact high levels of VEGF expression are associated with significantly worse survival in breast cancer patients, even in sub-groups expected to have a better prognosis and T-Regs quantification in breast tumors is valuable for assessing disease prognosis and progression. However few clinical studies investigated the association between E2, VEGF and T-Regs in humans. Objective of this study was to evaluate whether E2 suppression with an LH-RH analogue was able to down regulate VEGF expression, and decrease T-Regs in premenopausal patients with high-risk estrogen receptor positive (ER+) and negative (ER-) early BC. Material and Methods: From 04–2003 to 10–2008, 100 premenopausal early BC patients were entered into the study. At baseline, in the follicular phase of the menstrual cycle, after surgery, plasma E2, VEGF and T-Regs were measured. Measurements were repeated every six months. Treatment: LH-RH analogue for 5 years, chemotherapy tailored to the biological characteristics of each patient, radiation therapy, and 5-year hormonal therapy in ER+ tumors. Primary end-point was the evaluation of VEGF and T-Regs. Secondary end points were progression-free survival (PFS) and overall survival (OS). Results: Median age was 43 years (range 26–45). Median number of positive axillary nodes was 3.3. Eighty-three patients were ER+, 17 were ER - and progesterone receptor negative (PGR-), 10 were triple negative, 20 were Herb-2 positive. Median KI-67 was 33% (range 15%-100%). A statistically significant decrease of E2,VEGF and T-Regs was observed after 1 and 5 years, in ER+ and ER- patients: In particular, VEGF (P&amp;lt;0.001) and T-Regs (P&amp;lt;0.001) decreased in 95% of patients that were disease-free. No unexpected toxicity of chemotherapy was observed, while hot flashes and G1 osteopenia occurred after LH-RH analogues administration. After a median follow-up of 55 months (range 30–95), 5-year PFS and OS rate were 95% and 100%, respectively. Discussion: E2 deprivation with an LH-RH analogue is able to decrease plasma VEGF and T-Regs levels in premenopausal high risk ER+ and ER- BC patients. These data show how E2, through VEGF and T-Regs modulation, may be responsible for the worst prognosis that is observed in premenopausal BC. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-08-02.

Abstract 5055: The role of estrogens and vascular endothelial growth factor (VEGF) in premenopausal breast cancer carginogenesis and disease progression

Abstract Background. Estrogen is important in breast cancer development and there is evidence in vitro, that it modulates VEGF expression in breast cancer cells through transcriptional activation. However few clinical studies have investigated the association between VEGF and estrogens in humans. Objective of this study was to evaluate weather estrogen suppression with an LH-RH analogue was able to downregulate VEGF expression, and thus decrease its plasma concentration, in premenopausal patients with high-risk early breast cancer. Patients and methods: From April 2003 to October 2008 we conducted this study on 100 premenopausal early breast cancer patients. At baseline, after surgery, before any type of therapy, plasma VEGF and sex hormones (estradiol, progesterone, FSH, LH) were evaluated. Evaluation was repeated each year. Patients received an LH-RH analogue for 5 years, a chemotherapy that was tailored to the biological characteristics of each patient, radiation therapy, and hormonal therapy in estrogen receptor positive (ER+) tumors. Primary end point was the evaluation of VEGF. Secondary end points were progression-free survival (PFS) and overall survival (OS). Results: Median age was 43 years (range 26-45); mean number of positive axillary nodes was 3.3. (Range 0-25). Fifty-three patients were ER+ and progesterone receptor positive (PGR+), 17 were ER negative (−) and PGR-, 30 were ER+ and PGR-, Median KI-67 was 33% (range 15%-100%). Twenty patients were Herb-2 positive by FISH. A statistically significant decrease of VEGF was observed after 1 year. At 5 years and during the study period, plasma VEGF continued to decrease (p&amp;lt;0.001) in 94% of patients that were disease-free, while in 6% of patients with disease relapse, VEGF increased with respect to baseline values. No unexpected toxicity of chemotherapy was observed, while hot flashes and G1 osteopenia occurred after LH-RH analogues administration. After a median follow-up of 50 months (range 24-90), 8-year disease free survival and overall survival rated were 94% and 100%, respectively. Conclusion: Estrogen deprivation with an LH-RH analogue is able to decrease plasma VEGF levels in premenopausal high risk breast cancer patients. These data show how estrogens, through VEGF modulation, may be responsible for the worst prognosis that is observed in premenopausal breast cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5055. doi:10.1158/1538-7445.AM2011-5055

The association of HER-2 status with disease outcome in premenopausal early breast cancer patients treated with adjuvant ovarian ablation

The association of HER-2 status with disease outcome in premenopausal early breast cancer patients treated with adjuvant ovarian ablation

Adjuvant LH-RH agonists for premenopausal early breast cancer: A meta-analysis of randomized clinical trials (RCTs) exploring the magnitude of the disease-free and overall survival (DFS/OS) benefit

592 Background: LH-RH agonists are considered as a milestone for adjuvant treatment for premenopausal early breast cancer patients (pts). All RCTs in which ovarian ablation (OA) with/without tamoxifen (TAM) and/or chemotherapy (CT) was compared with tamoxifen (TAM) and/or chemotherapy (CT) were pooled to estimate the magnitude of the benefit in both DFS and OS. Methods: A literature-based meta-analysis was accomplished, and event-based relative risk ratios (RRs) with 95% confidence interval (CI) were derived. A fixed- (FEM) and a random-effect (REM) model according to the inverse variance and heterogeneity (Het) test were applied as well. Absolute benefits (AB) and the number of pts needed to treat (NNT) were calculated. A sensitivity analysis to test for effect robustness in 4 sub-populations (OA/OS vs CT; OA/OS + CT vs CT; OA + TAM vs CT; OA + TAM vs observation) was accomplished. Results: Fifteen RCTs were gathered (12,545 pts); one RCT did not report the OS result. Results are depicted in the table . Conclusions: Although differences across RCTs exist in median follow-up time (as demonstrated by heterogeneity), OA seems to significantly improve DFS when combined with CT over CT alone, when combined with TAM versus CT alone and when combined with TAM versus observation. Actually, these DFS benefits do not translate into an OS benefit, with the exception of the last subgroup. [Table: see text] No significant financial relationships to disclose.