bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between weight gain during adjuvant chemotherapy (CTx) for early-stage breast cancer (BC) and survival outcomes.
Authors: Gutierrez-Barrera Angelica M. , Schvartsman Gustavo , Song Juhee , Ueno Naoto T. , Peterson Susan K. , Arun Banu
Published: September 2018

e12057

Background: Obese and overweight women have an increased risk of BC and worse outcomes at the time of diagnosis compared to those at normal weight. Studies suggest that women tend to gain weight after BC cancer diagnosis and during CTx for early-stage disease, which may in turn increase risk for worse outcomes. We examined if weight gained during adjuvant CTx was associated with worse outcomes. Methods: We queried the prospectively maintained UT MD Anderson Cancer Center Breast Cancer (UTMDACC) Database for data on patients (pts) who received adjuvant third-generation CTx for early-stage BC cancer, including: demographics; tumor characteristics; and, body mass index (BMI) at diagnosis, pre- and post-CTx and one year after completion of treatment. Univariate and multivariate analysis (MA) by Cox regression were performed for survival outcomes across 3 categories according to BMI variation from start to end of CTx: >0.5-point loss or gain and stable BMI (± 0.5). Results: We included 1998 pts in this study. Women over 50 years old and post-menopausal were more likely to lose weight during adjuvant CTx, whereas women under 30 years old gained more weight (p<0.0001). At one year post-CTx, all pts tended to return to their original weight (ρ=0.3, p<0.0001). On MA, a BMI increase of 0.5 points was o associated with increased loco regional recurrence risk for both the entire cohort (HR 2.4; 95% CI, 1.122-5.166; p=0.0241) adjusting for grade and stage and for post-menopausal women (HR 3.774, 95% CI 1.241-11.447, p=0.0193) adjusting for Her2 status. Age <30 years old (HR, 2.52; 95% CI, 1.009-6.293; p=0.0478) and tumor stage 3 comparing to 1 (HR, 4.598; 95% CI, 2.754-7.677; p<0.0001) were associated with increased risk of death and tumor grade 2 (vs 3; HR, 0.547; 95% CI, 0.353-0.847; p=0.0069) was a protective factor on MA for the entire cohort. Conclusions: Weight gain during adjuvant CTx was associated with increased loco regional recurrence for the entire cohort and post-menopausal women, including pts who at year 1 returned to their normal weight. The effect of increased BMI during CTx on breast stroma, molecular profile and how it affects local recurrence is intriguing and needs to be further evaluated.
Neoadjuvant treatment of HER2 positive breast cancer with concomitant nonpegylated liposomal doxorubicin (NPLD), docetaxel and dual blockade with trastuzumab and pertuzumab: A retrospective analysis of pCR and cardiac safety.
Authors: Egle Daniel , Brunner Christine , Czech Theresa , Jaeger Thomas , Lang Alois , Hager Christopher , Poisl Clemens , Volgger Birgit , Marth Christian
Published: September 2018

e12061

Background: Neoadjuvant treatment in HER2 overexpressing early breast cancer (EBC) has increased considerably. The Neosphere study, in which dual blockade of HER2 was combined with docetaxel resulted in favorable pCR rates. The addition of anthracyclines could play an important role in enhancing the effectiveness. The use of NPLD might be valuable in combination with HER2 targeted therapies. Safety and efficacy of NPLD, taxotere and trastuzumab was reported in the ABSCG 32 study. There is only little data about the cardiac safety and efficacy in combination with dual HER2 blockade. We report pCR-rate and cardiac safety of a single arm, retrospective, multicenter analysis of neoadj. treatment for HER2+ EBC. Methods: In this study 98 women with HER2+ EBC were investigated in 4 oncological departments in Austria. All patients were treated with NPLD (50 mg/m²), docetaxel (75 mg/m²) concurrent with trastuzumab and pertuzumab in standard dosage for 6 cycles as neoadjuvant therapy. All patients were free of cardiovascular disease and had a left ventricular ejection fraction (LVEF) of ≥50%. Cardiac function was measured by LVEF. All patients underwent surgery after neoadjuvant chemotherapy. The absence of any residual invasive cancer in the breast and axilla was defined as pathological complete response (pCR). Median follow up was 1.7 years. Results: Median age was 49 years. pCR rate was 73%. In this cohort a negative estrogen-and progesteron receptor was predictive for pCR (p<0.001). These patients achieved pCR in 89%. No patient progressed during treatment. Only one patient(1%) suffered symptomatic heart failure after surgery. Conclusions: We observed a considerably high rate of pCR in HER2-positive EBC treated with a combination of NPLD, docetaxel, trastuzumab and pertuzumab. Hormone receptor negativity was highly predictive for pCR. The addition of NPLD entails a very favorable cardiotoxicity profile. This regimen is a safe and highly effective treatment option in patients with HER-2 positive EBC.
Weight trajectories during first two years of endocrine treatment: Premenopausal compared to postmenopausal early breast cancer survivors.
Authors: Nyrop Kirsten A , Deal Allison Mary , Lee Jordan T , Muss Hyman B. , Choi Seul Ki , Wheless Amy , Carey Lisa A. , Shachar Shlomit S.
Published: September 2018

e12069

Background: Obesity and weight gain in breast cancer survivors (BCS) can impact prognosis, survival, and quality of life. Women who were premenopausal (PreBCS) or postmenopausal (PostBCS) at BC diagnosis are compared regarding weight change during the first 2 years of endocrine treatment (ET) and factors associated with > 2kg weight gain. Methods: Data were gathered by retrospective chart review, with weights assessed by nursing staff during routine clinic visits. Chi-squared and t-tests were used to compare PostBCS and PreBCS characteristics, and log-binomial regression models to evaluate factors associated with > 2kg weight gain. Results: In a final sample of N = 447 BCS, 33% were PreBCS (mean age 44) and 67% were PostBCS (mean age 65). PreBCS had lower BMI at diagnosis (p = 0.003), lower proportion of white (p = 0.04), fewer comorbidities (p < 0.0001); higher stage (p < 0.0001), grade (p = 0.008), node positive (p < 0.0001), PR positive (p = 0.03), and HER2 positive (p = 0.03) BC tumors; higher proportion of mastectomies (p < 0.0001), axillary node dissection (p = 0.005), chemotherapy (p < 0.0001), radiation treatment (p = 0.009), and Tamoxifen use (p < 0.0001); and less weight loss between diagnosis and start of ET (p = 0.013). After 2 years of ET, 48% of PreBCS and 39% of PostBCS had gained > 2kg (p = 0.08). In univariate analysis, factors associated with > 2kg weight gain were: weight loss between BC diagnosis and ET start (p < .0001), lower age at start of ET (p = .002), higher tumor size (p = .003), increasing stage (p < .0001), mastectomy (p = .0002), axillary node dissection (p = .005), positive nodal status (p = 0.0003), and chemotherapy (p < .0001). In multivariable analysis controlling for covariates that differed between PreBCS/PostBCS, only weight change between BC diagnosis and ET start was associated with > 2kg weight gain (p = 0.0005). Conclusions: In our sample, neither menopausal status nor type of ET was significantly associated with weight gain during ET. Our research suggests that BC survivors with higher risk tumors and associated treatments may experience higher weight gain during ET and warrant weight management counseling.
Network meta-analysis of adjuvant chemotherapy in early breast cancer.
Authors: John Preethi , Bannuru Raveendhara R , Cohen Joshua T. , Buchsbaum Rachel J. , Erban John Kalil
Published: September 2018

e12071

Background: The NCCN recommends several adjuvant regimens for early stage breast cancer (ESBC) that have not been directly compared in randomized clinical trials (RCTs) making the optimal regimen unclear. Regimens of interest include dose dense doxorubicin/cyclophosphamide followed by paclitaxel (DDAC-T), doxorubicin/cyclophosphamide followed by weekly paclitaxel (ACwkT), docetaxel/doxorubicin/cyclophosphamide (TAC), and docetaxel/cyclophosphamide (TC) x 4 cycles. This is the first network meta-analysis (NMA) to compare the effectiveness of these regimens. Methods: A systematic literature review was performed to identify RCTs that included the above regimens. To complete the network, doxorubicin/cyclophosphamide (AC), doxorubicin/cyclophosphamide followed by paclitaxel (AC-T) every 3 wks, and doxorubicin/cyclophosphamide followed by docetaxel (AC-D) every 3 wks were included. Primary outcomes were progression free survival (PFS) and overall survival (OS) estimated as odds ratios (OR). OR > 1 indicates better survival. Bayesian random effects model with non-informative priors was used. Results: 5 RCTs involving 12,579 females with mainly node positive, Her2- ESBC were analyzed. Although there were no statistically significant differences in PFS or OS among these regimens, AC-D, ACwkT, DDAC-T, TAC, and TC demonstrated better survival outcomes compared to AC and AC-T (not shown). Survival outcomes among DDAC-T, ACwkT, TAC, and TC were comparable. DDAC-T survival outcomes were marginally better than the other regimens. Conclusions: DDAC-T, ACwkT, TC, and TAC were similar in efficacy. Final results with at least one additional RCT will be presented. Although NMA is not a substitute for direct comparison RCTs, it allows indirect comparisons to aid in decision making. Future results from ongoing RCTs will refine estimates of anthracycline vs non anthracycline efficacy and toxicity. [Table: see text]
Complementary medicine use during adjuvant radiotherapy of breast cancer.
Authors: Buecker Rebecca , Schafer Ulrich
Published: September 2018

e12088

Background: Complementary medicine (CM) is used widely in cancer patients, mostly in palliative treatment regimes or during chemotherapy. In contrast, the use of CM during curative Radiotherapy (RT) is less frequent.The aim of this study was to evaluate the influence of CM with regard to toxicity and recurrence during postoperative radiotherapy for breast cancer. Methods: Between 2010 and 2013 all patients intended for adjuvant radiotherapy for breast cancer received a questionnaire concerning the use of CM e.g. Vitamins, trace elements, enzymes, natural herbs etc. (yes / no) and if yes what kinds. Radiotherapy was applied with 50.4 Gy to the whole breast and a Boost of 10.8 Gy in 6.5 weeks.6 weeks after radiotherapy the side effects were analyzed. Follow up for progression rates was done yearly. Results: A total number of 879 patients with breast cancer completed the questionnaire, 641 (73%) did not take any CM and 238 (27%) took CM. There were almost 40 different products mentioned and the most common were magnesium (n=71) and selenium (n=38). The RT side effects (Dermatitis RTOG grade 0, I, II, III/IV) 6 weeks after completion of RT were as follow: in the non CM group 53% grade 0, 41% grade I, and 6% grade II, 0% grade III/IV. And in the CM group 54%, 39%, 9%, and 0% respectively. The corresponding side effects for the group taking magnesium were 35% 42%, 6% and 1% and for the selenium group 47%, 47%, 5% and 0%. There was no significant difference in side effects between the non CM and CM patients, respectively magnesium and selenium group . The sum of all registered disease progression (0 years – 5 years) were in the non CM group 6.4%, in the CM group 6.3%, in the magnesium group 5.6% and in the selenium group 7.9%, no significant difference could be detected between all groups. Conclusions: In this cohort, 27 % of patients used CM during adjuvant radiotherapy of breast cancer. The most commonly product is magnesium followed by selenium. A measurable influence of CM on RT side effects or disease progression could not be identified.
Relationship between the pre-operative background enhancement coefficient under MRI of breast cancer and recurrence of postoperative chest wall.
Authors: Ren Ruimei , Lin Haimin , Zhao Tianshu
Published: September 2018

e12091

Background: With the rapid development of MRI scanning technology , DCE-MRI in breast cancer has been one of the most sensitive examinations for the reason of allowing precise imaging, which can be helpful to demonstrate and evaluate the anatomical structures of breast cancer and its surrounding. What is more,through application of postprocessing technique of MRI,quantitative and half-qualitative data can be obtained for the diagnosis and the differential diagnosis of breast cancer. It is reported that the recurrence of breast cancer after breast conserving surgery is related with elevated BEC of MRI before operation as the result of the difficulty to find the micro-lesions and the margin of infiltrative lesions. Objective: Study on the relationship between the background enhancement coefficient of breast cancer under MRI before operation and recurrence of postoperative chest wall. Material and Methods: 194 cases of breast cancer patients undergoing radical surgery were retrospectively analyzed, all of which were confirmed by pathology and molecular classification.Before surgery all the patients did MRI and the BEC was measured.Aim for study on the relevance of the elevated BEC and chest wall recurrence,we investigate the relationship between the stage, grade,molecular subtype of breast cancer and the elevated BEC statistically. Results: The elevated BEC of the breast before operation is associated with chest wall recurrence after operation (P=0.045), and high expression of HER-2 (P=0.07). Multiple lesions of breast cancer and Ki-67>14% also appeared to be associated with the elevated BEC (P=0.08).While there seem to be no correlation between the size of tumor ,LN metastases, nuclear and pathological grade,molecular typing, PR expression,ER expression, status of the LN capsule and the elevated BEC. Conclusions: The elevated BEC of breast before operation is an independent prognostic factor for chest wall recurrence after operation.Given BEC get a potential to make a brand new biomarker for breast cancer,further relevant research is needed.
Areola sparing mastectomy without preservation of nipple: A clinicopathological assessment and a case series.
Authors: Yang Houpu , Wang Shu , Xie Fei , Guo Jiajia , Chen Xiaoyong , Yu Changjiang , Wang Chuan , Zhang Zhiqiong , Yu Xiaoxia
Published: September 2018

e12099

Background: Preservation of the nipple-areolar complex has gained worldwide popularity due to significantly improved cosmetic result of mastectomy, while 4% to 58% involvement of nipple and assumed increased recurrence risk made it controversial on the oncological safety of nipple sparing mastectomy. This study focuses on the oncological feasibility of areola sparing mastectomy without preservation of nipple by evaluating involvement of the areola and nipple separately in consecutive mastectomy specimens. Methods: During Aug 3, 2016 to Jan 25, 2017, consecutive specimens from women underwent traditional mastectomy were analyzed. Areolae and nipples were resected and sectioned separately. Involvement of nipple and areola and clinicopathological data were analyzed. The results of 4 patients underwent areola sparing mastectomy were studied. Results: The overall frequency of malignant involvement of the areola among the breasts was 3 of 127 (2.3%), which was significantly lower than that of the nipple (11 of 127, 8.7%, p = 0.03). In patients whose tumors were ≤3cm, outside areolar area, and without dimpling of areola or inflammatory appearance, the incidence of areolar involvement was low to zero. A total of 4 patients received areola sparing mastectomy by “nipple coring” and immediate implant based reconstruction. No patients desired nipple reconstruction. Cosmetic results were all good. Conclusions: Areolae were rarely involved in breasts with tumor ≤3cm, and without inflammatory skin, dimpling of areola or retro-areolar tumor. Areola sparing mastectomy might be oncologically safe and should be a potential treatment in selected patients.
BRCAness and prognosis of triple-negative breast cancer patients treated with neoadjuvant chemotherapy.
Authors: Akashi-Tanaka Sadako , Tanino Yuichi , Yamamoto Yutaka , Nishimiya Hiroshi , Yamamoto-ibusuki Mutsuko , Iwase Hirotaka , Nakamura Seigo
Published: September 2018

e12111

Background: Triple-negative breast cancers (TNBCs) consist of patients which are recalcitrant to chemotherapy. Dysfunction of BRCA, called “BRCAness” may be predictive of sensitivity to DNA repair inhibitors. However, adequate assay of “BRCAness” are still not confirmed. Multiplex ligation-dependent probe amplification (MLPA) with the Probemix P376-B2 BRCA1ness (MRC-Holland, The Netherlands) can be one method to determine BRCAness. We previously reported that “BRCAness” by MLPA predict resistance to taxane during neoadjuvant chemotherapy (NAC) and poor outcome. In the present study, we evaluated the clinical significance of BRCAness in a multicenter retrospective study. Methods: The data on 94 patients with TNBC treated with NAC were obtained from 3 hospitals in Japan. Most of them were treated by anthracyclines plus taxanes in 86 patients between 2005 and 2015. BRCAness was determined by core needle biopsy (CNB) specimens prior to NAC and surgical specimens. Genes from those specimens were amplified by MLPA, and the amplicons were scored. BRCA1-like type (BRCAness) was determined by tumors with greater than 0.5 Results: pCR (ypT0/Tis/N0) rate was 46%. Recurrence occurred in 22 patients, 11 of whom died from breast cancer. (1) BRCA1-like type accounted for 51 patients while the sporadic type in 43 patients in CNB specimens. No major differences in pCR rates and recurrence were observed between the BRCA1-like type and sporadic type (19/51 vs. 24/43), respectively. Patients with BRCA1-like tended to resist taxane than those with sporadic type when treated with taxane first. Among the 51 non-pCR patients, 19 were BRCA1-like type and 31 were sporadic type upon surgical specimens. Patients with a BRCA1-like tumors had more recurrences, than non-BRCA-1-like (13/19 vs. 9/31, respectively, P < 0.01). Conclusions: Tumors with BRCA-1 like tended to resist taxane than sporadic type when treated by taxane first. Anthracycline first might mask the progression during taxane regimen. Patients with BRCA1-like after NAC had more recurrences than those with sporadic type. Further study is needed to evaluate the significance of BRCAness.
A population model to predict progression free survival in breast cancer patients treated with neoadjuvant chemotherapy ñ vaccines based on tumour growth inhibition metrics.
Authors: P.Solans Belen , Salas Diego , Abengozar Marta , Pina Luis Javier , Elizalde Arlette , Cosgaya Maria Cruz Martinez , De La Cruz Susana , Salgado Pascual Esteban , Gil-Bazo Ignacio , Aramendia Jose Manuel , Troconiz Inaki F , Santisteban Marta
Published: September 2018

e12114

Background: Breast cancer (BC) is the most commonly diagnosed malignancy in women. Neoadjuvant chemotherapy selects patients with optimal pathological responses and increases tumorectomy versus total mastectomy. Changes in tumor size (CTS) are related to an early clinical benefit and to Progression Free Survival (PFS) and Overall Survival (OS) in BC patients. Thus, the identification of new prognostic factors in the neoadjuvant scenario is crucial. Objectives:To assess the link between tumor growth inhibition metrics (TGI) and progression free survival (PFS) based on data obtained from BC patients with neoadjuvant therapy Methods: Data were obtained from 218 patients with BC treated at the University Clinic of Navarra, diagnosed from January 2008 to February 2016, with a median age of 49 years (range 25 to 84). Classification of molecular subtypes was based on IHC and found as follows: Her2 (6%), LA ( 23%), LB ( 36%), LB-Her2 (10%) and TN ( 25%). Patients were treated with ddECx 4 followed Docetaxel x 4. Her2 patients had therapy with Trastuzumab. 18% of the patients (LB and TN) received vaccination with dendritic cells. Data were analysed under the population approach with NONMEN 7.3. A model accounting for the dynamics of tumor growth and antitumor effect of the neoadjuvant therapy was developed. The model describes tumor size as the sum of the longest diameters of target lesions as a function of time and drug exposure. A PFS model was developed to describe the PFS time distribution as a function of covariates Results: The TGI was able to individually and accurately describe the tumor shrinkage. Vaccinated patients had an increased shrinkage rate of 36% (p < 0.001) than those who were not (p < 0.001). PFS (months) was best described by a Weibull model, and greater tumor size at diagnosis (p < 0.05), smaller CTS (p < 0.05) and TN subtype (p < 0.001) were identified as poor prognostic factors Conclusions: A PFS model that uses a model-based estimate of tumor growth to predict the PFS of BC patients receiving neoadjuvant therapy has been developed. This model helps to gain early understanding of potential clinical benefit to facilitate go/no-go decision making.
Genomic predictors of neoadjuvant chemotherapy (NACT) response in breast cancer (BC).
Authors: Wong Andrea Li Ann , Tan Kar Tong , Sundar Raghav , Ow Samuel , Pang Angela , Yap Hui-Ling , Chan Ching-Wan , Hartman Mikael , Iau Philip , Buhari Shaik Ahmad , Mogro Maria Jannet , Tan Iain BeeHuat , Wang Ling-Zhi , Yang Henry , Goh Boon C. , Lee Soo-Chin
Published: September 2018

e12122

Background: We assessed effects of NACT on BC mutational landscape. Methods: Baseline (BL) and post-NACT tumor / matched normal DNA from 12 newly diagnosed BC patients on NACT (4 x doxorubicin/cyclophosphamide + low dose sunitinib; NCT01176799) were subject to whole exome sequencing. Nonsynonymous somatic single nucleotide variants from 34 genes in known BC signaling pathways were evaluated for changes in mutant variant allele frequency (VAF) according to clinical outcome. Poor outcome was defined as <50% target lesion reduction after NACT or BC relapse / progression (PD) within 2 years; significant change was defined as > 0.2 difference in BL vs post-NACT mutant VAF. Results: Mean tumor size was 6.4 + 2.9cm; 50% were N+; 8% were M1; 7/12 patients had poor outcomes. Tumors harbored mutations in PI3K (58%), NOTCH (42%), Wnt (42%), TP53 (33%) and FOXA (17%) pathways. Change in no. of somatic mutations post-NACT correlated with outcome (mean percent change +14% vs -30% in patients with poor vs good outcome, p=0.04). 11 patients had >1 of 23 putative driver mutations identified ( Table 1). Mutant VAF declined significantly in those with good outcomes, except for a new NOTCH2 mutation in A2 and rise in mutant VAF in A4. In patients with poor outcomes, mutant VAF persisted or rose, and emergent mutations (AKT1, PIK3CA) occurred in 2 patients. Conclusions: Chemoresistance and emergent mutations were revealed by tracking mutant VAF in BC patients on NACT. Clinical trial information: NCT01176799. [Table: see text]
Optical blood irradiation in improving the effectiveness of neoadjuvant polychemotherapy for breast cancer.
Authors: Sheiko Elena A. , Shikhlyarova Alla Ivanovna , Vashchenko Larisa Nikolaevna , Babieva Stella
Published: September 2018

e12124

Background: Breast cancer (BC) incidence rates are increasing worldwide. Development of multicomponent programs, in particular polychemotherapy combined with technologies of quantum medicine, can help increase BC treatment effectiveness. The purpose of the study was to assess clinical efficacy of neoadjuvant polychemotherapy (PCT) modified with extracorporeal optical blood processing in BC. Methods: The study included 90 patients, mean age 48 years, with stage IIIB BC: nodular BC with secondary edema – 80 (88.8%) patients, edematous-infiltrative BC – 10 (11.2%) patients. Menstrual function was preserved in 20 (22.3%) patients; the other 70 (77.7%) women were menopausal. The control group (30 patients) received PCT with the total course doses of cytostatics: doxorubicin - 200 mg, 5-fluorouracil - 3000 mg, cyclophosphan - 100 mg, methotrexate - 100 mg. The main group (60 patients): 200 ml of blood from a peripheral vein was obtained into tubes with Glugicir, and then doxorubicin 50 mg/m2, methotrexate 25 mg/m2, 5-fluorouracil 750 mg/m2 and cyclophosphan 600 mg/m2 were added and incubated for 40 min at 37оC. The blood was continuously irradiated for 3 minutes using red light λ=0.67 µm, W=5 J/cm2. After that, the blood was transfused back to the patient intravenously. Each course included 3 procedures with a 3-day interval, and patients received 2-3 courses with a 3-week interval. Results: The assessment of neoadjuvant chemotherapy modified with extracorporeal optical blood processing showed increased rates of resectable BC by 2.8 times; an objective antitumor effect increased by 20%, and tumor growth rates reduced by 3.5 times. Conclusions: This technology can become an effective additional factor improving the effectiveness of anticancer therapy.
Phase II trial with letrozole as neoadjuvant treatment in postmenopausal and premenopausal patients with highly endocrine responsive operable breast cancer.
Authors: Cheng Min-Yi , Zhang Yi-Fang , Yang Ci-Qiu , Zhang Liu-Lu , Zhu Teng , Gao Hong-Fei , Chen Fu-Long , Xiong Qian-Qian , Zhang Yi , Wang Kun
Published: September 2018

e12125

Background: Neoadjuvant endocrine therapy (NET)is effective in postmenopausal patients with breast cancers expressing oestrogen receptor. However, the therapeutic benefit of NET in premenopausal population is not fully characterized. We aimed to assess the efficacy and safety of endocrine therapy between the postmenopausal and premenopausal patients with highly endocrine responsiveoperable breast cancer for primary systemic therapy. Methods: Previously untreated patients with operable breast cancer and highly endocrine responsive breast cancer (ER/PR≥50% and Her2-) were recruited. Patients were assigned to receive letrozole 2.5mg daily (combined with triptorelin in premenopausal patients) for a period of at least 6 months. The primary end point of the study was the objective response rate (ORR) measured by breast ultrasound. Secondary end points included safety, pathologically complete response (pCR) rate, breast conservative surgery (BCS) rate. Results: Between September 2012 and December 2016, 41 patients were enrolled in the study (16 postmenopausal, 25 premenopausal ). The total ORR of this study was 73.2% (30 of 41). No significant differences were seen in the ORR, 76.0% (19 of 25 premenopausal patients) and 68.8% (11 of 16 postmenopausal patients) (P = 0.723). The pCR rate was 8% (2 of 25) for the premenopausal and 0%(0 of 16) for the postmenopausal (p=0.512). The BCS rate was 40% (10 of 25) for the premenopausal and 37.5%(6 of 16) for the postmenopausal (P = 0.873). No treatment-related grade 3/4 adverse events were recorded in both groups. Conclusions: Letrozole shows a high activity and excellent tolerability as neoadjuvant therapy in both postmenopausal and premenopausal patients with highly endocrine responsive operable breast cancer.
Phase II study of eribulin with trasutuzumab for pretreated locally advanced or metastatic HER2-positive breast cancer.
Authors: Tsunoda Nobuyuki , Hattori Masaya , Murata Toru , Akahane Kazuhisa , Kamei Keitaro , Goto Yasutomo , Amemiya Takeshi , Nishimae Kazumi , Kubota Tomoyuki , Ito Yuko , Kurumiya Yasuhiro , Yoshihara Motoi , Nakanishi Kenichi , Kikumori Toyone , Ando Masahiko , Nagino Masato
Published: September 2018

e12505

Background: Eribulin mesylate demonstrated a survival benefit in patients with locally recurrent or metastatic breast cancer who previously received 2 or more chemotherapy regimens. There are limited studies reported about the efficacy of eribulin with trastuzumab as first-line therapy for locally advanced or metastatic HER2-positive breast cancer. The aim of this study was to assess the efficacy and safety of eribulin with trastuzumab as late-line therapy for locally advanced or metastatic HER2-positive breast cancer. Methods: In this multicenter, phase II, single-arm study, patients with locally advanced or metastatic HER2 positive breast cancer who previously received at least one chemotherapeutic regimen, received eribulin at 1.4 mg/m2 intravenously (I.V.) on days 1 and 8 of each 21-day cycle with an initial trastuzumab dose of 8 mg/kg I.V. on day 1, followed by 6 mg/kg of trastuzumab on day 1 of each subsequent cycle. The primary end point was ORR, and secondary end points included PFS and safety. Results: Thirty-six patients (median age: 60.5 years) were enrolled. The median number of prior treatment regimens was 4 (range, 1‐8). Twenty-two patients (61.1%) had received prior pertuzumab treatment, 10 patients (27.8%) had prior T-DM1. Patients received a median of 6 cycles of eribulin with trastuzumab (2-13 cycles). The ORR was 17% (CR 0, PR 6) with median PFS of 4.6 months (3.3-7.0 months). The clinical benefit rate was 33%. The most common Grade 3/4 treatment-emergent adverse events were neutropenia in 22 (61%) patients, peripheral neuropathy in 3 (8%; all Grade 3) patients, fatigue in 1 (3%) patients. Five (13.9%) patients had asymptomatic LVEF decline. However, no grade 3 LVEF decline or symptomatic congestive heart failure was observed. The reasons for treatment discontinuation were disease progression in 27 (75%) patients and adverse events in 8 (22%) patients. Conclusions: Eribulin with trastuzumab is an acceptable option in late-line treatment for locally advanced or metastatic HER2-positive breast cancer. Clinical trial information: 000012350.
Duration of second-line T-DM1 therapy: Is it associated with duration of first-line anti-Her2 therapy in metastatic HER2 + breast cancer?
Authors: Katz Daniela , Feldhamer Ilan , Greenberg-Dotan Sari , Hammerman Ariel
Published: September 2018

e12512

Background: Tumors with HER2 overexpression usually respond to HER2-targeted therapies. Since the CLEOPATRA and EMILIA trials, a taxane plus trastuzumab and pertuzumab (TTP) are the first-line standard for the management of HER2 + metastatic breast cancer (MBC) and trastuzumab emtansine (TDM-1) is the second-line standard. Intrinsic subtypes existing within HER2+ tumors may impact the degree of a patient’s response to anti HER2 therapy; however HER2 subtyping for predicting response is still experimental and not in routine clinical use. In this retrospective population-based study, we aimed to assess whether duration of treatment (DOT) of second-line TDM1 is associated with the DOT of first-line TTP, and might serve as a hint for a HER2 subtype. Methods: Clalit Health Services (CHS) manages health care of 52% of the Israeli population. We identified 113 HER2+ CHS MBC patients, treated with TTP as first-line treatment that initiated TDM1 as second-line, until Dec. 31, 2016. Patient's (pts) demography, HER2 and HR status were recorded. A Cox proportional hazard model, stratified by HR status, adjusted for age and prior adjuvant trastuzumab, was used to explore the association between second-line and first-line DOT in HR positive and negative pts. Results: Pts baseline characteristics and DOT in first- and second-line treatment are presented in the table. A statistically significant association between DOT of both treatment lines was found in HR positive pts with a trend also in HR negative pts. Conclusions: The observed association between first- and second-line DOT, unrelated to hormonal status, may result from a primary characteristic of the intrinsic tumor subtype, that impacts acquired resistance. Longer observations in larger patient cohorts are required to confirm this observation. [Table: see text]
A real-world registry to evaluate HER2-directed therapy in Australian patients with metastatic breast cancer (MBC).
Authors: Lee Margaret , Lok Sheau Wen , Turner Natalie Heather , Day Daphne , Greenberg Sally , Green Michael , Foo Serene S. , Yip Desmond , Nott Louise M. , Gibbs Peter , De Boer Richard H.
Published: September 2018

e12515

Background: The management and outcomes of HER2 positive MBC have dramatically evolved with the introduction of HER2-targeted therapies. However, limited data regarding the uptake, impact and safety of these treatments in the real-world context, prompted us to initiate a comprehensive registry across multiple settings in Australia. Methods: We examined the multisite electronic registry TABITHA (Treatment of Advanced Breast Cancer in the HER2 positive Australian Patient) to capture clinical data of consecutive patients diagnosed with HER2 positive MBC between Jan 2016-Jan 2017. Patient demographics, use and outcomes of treatment were explored. Results: An initial cohort of 74 patients was identified, 28 (38%) with de novo metastatic and 46 (62%) with relapsed disease. The median age at presentation with MBC was 57 years (range 27-83), with main metastatic sites being bone (n = 41, 55%), major organs (n = 40, 54%), locoregional (N = 26, 35%) and central nervous system (n = 13, 18%). In total, 64 (86%) patients had received first-line HER2 therapy, including trastuzumab plus pertuzumab (n = 48, 75%), trastuzumab alone (n = 10, 16%) and trastuzumab-emtansine (n = 6, 9%). Ten patients had not received any HER2 therapy, of which 8 received best supportive care alone, 1 received endocrine therapy, and 1 received anti-resorptive therapy. The median age of non-HER2 treated patients was 61 (range 44-81) and 40% were ECOG 2+ compared to 25% of patients receiving HER2 therapy (p = NS). First-line HER2 therapy had been discontinued in 20/63 (32%) patients, due to progressive disease (n = 18, 90%) or toxicity (n = 2, 10%). Median time to progression was 12.7+ months (range 2.0-81.9+). Conclusions: Whilst trials of HER2 directed therapies have demonstrated a substantial impact on survival outcomes for MBC with modest toxicity, a proportion of HER2 positive patients in routine care may not receive these agents. Poor performance status contributes to non-HER2 therapy use, however data collection is ongoing and other potential drivers will be further examined. Where HER2 directed therapies are used, the preliminary data indicates good activity with the majority of patients still currently on treatment.
CLIA validation of a novel HER2 FISH test involving image-based cell-sorting to recover pure tumor cell populations from formalin fixed paraffin embedded tissue.
Authors: Bischoff Farideh Z. , Gerber Amanda , Sero Valeria , Khurana Aditi , Ting Marc , Webb Judy , Sims Cynthe , Verma Suman , Medoro Gianni , Manaresi Nicolò , Gunn Shelly , Moore Mathew , Cotter Philip
Published: September 2018

e12519

Background: The use of the DEPArray™ system to prepare pure tumor cell populations for more reliable and accurate downstream molecular sequence analysis has been previously demonstrated. To formally evaluate the utility of the DEPArray™ for sample preparation prior to molecular testing, we conducted a CLIA validation study to investigate the analytical performance of the instrument as well as accuracy in determining HER2 status in FFPE tumor specimens using a standard FISH assay. Methods: An initial cohort consisting of 93 FFPE samples (68 from Breast and 25 from Stomach) were selected based on defined inclusion criteria (tumor type and tumor content). For each sample, a single 50µm FFPE scroll was dissociated and then stained using fluorescently labeled Vimentin and Cytokeratin markers to distinguish between putative stromal and tumor populations, respectively. Following separation of these populations on the DEPArray™, a minimum of 100 single cells from each population was recovered and used for subsequent HER2 FISH testing. In addition, an H&E of each sample was evaluated by a Pathologist to confirm the presence of tumor content. Single-cell HER2-FISH analysis was then performed on the DEPArray™ processed samples to assess the number of signals present for each of the chromosome 17 and HER2 loci. Results were compared to the conventional tissue section FISH score. Results: Of the 93 specimens, 80 samples met pre-analytical acceptability criteria that were also confirmed by conventional methods to be either HER2-positive (n = 43) or HER2-negative (n = 37). Overall, a 95% concordance between HER2 results derived from the conventional as compared to the DEPArray™ method was observed. In addition, the instrument performance in terms of reproducibility and reliability was reported as 100%. Conclusions: DEPArray™ for preparation of FFPE-derived tumor cells was analytically validated and shown to yield high confidence in performing HER2-FISH analysis on recovered pure tumor cells. Current strategies to establish clinical utility and efficacy of this approach are underway for cases characterized as equivocal for HER2 or indeterminate by FISH.
Early-onset neutropenia-related events in eribulin monotherapy: A possible biomarker in the real world?
Authors: Watanabe Junichiro , Onozawa Yusuke
Published: September 2018

e12529

Background: Eribulin mesylate (eribulin) showed antitumor activity via the anti-tubulin effect, and improved overall survival (OS) in HER2-negative (HER2-) metastatic breast cancer (MBC) patients without extending progression-free survival (PFS) in a phase 3 trial. On the other hand, according to the published data (Watanabe J, Springerplus, 2015), eribulin monotherapy improved OS in the clinical setting, and PFS is a possible surrogate for OS in HER2-, hormone receptor-positive (HR+) MBC patients. However, there is no practical biomarker for PFS in relation to eribulin monotherapy in patients with HER2-HR+MBC. Methods: Eribulin was administered according to the instructions in the package insert (1.4mg/m2 on days [D] 1 and 8, and a 21-day cycle [C]). The medical records of the patients who received eribulin monotherapy were reviewed. Results: From August 2011 to December 2016, 90 HER2-HR+MBC patients received eribulin monotherapy as daily practice at our institution, and 84 (93.3%) patients terminated their therapy. Lung and/or liver metastasis was observed at the induction of the therapy in 68 (86.7%) of the patients. The median relative dose of eribulin on C1D1 was 95.3% (1.33mg/body). Fever was observed during C1 in 23 (25.6%) patients, and grade (G) 3/4 neutropenia was observed on C1D8 in 28 (31.1%) patients. In contrast, only 4 (4.4%) patients developed febrile neutropenia within C1. Due to the delayed recovery of neutrophils, the second cycle of treatment was suspended in 8 (8.9%) patients. With regard to liver test abnormalities, an elevation of one grade in comparison to baseline, which resolved afterward without specific treatment, was observed during C1 in 24 (26.7%) patients. A multivariate Cox regression analysis revealed that G3/4 neutropenia on C1D8 and a delay of C2D1 were strong predictors of PFS (hazard ratio [HR] 0.53; p < 0.05, HR 0.42; p < 0.05, respectively). A chi-squared test revealed no statistically significant differences between the two subgroups in the relative dose on C1D1. Conclusions: This retrospective, observational study revealed that early-onset neutropenia-related events may be a biomarker for eribulin therapy that can be applied in the clinical setting.
The role of mitochondrial estrogen receptor β in relapse of breast cancer.
Authors: Kim Tae Hyun , Song In-Sung , Han Jin
Published: September 2018

e12540

Background: Breast cancer is the most common non-skin cancer in women. Breast cancers are heterogeneous, and treatment by subgroup based on hormone receptor and HER2 made a significant difference in clinical outcomes. Several studies have reported that estrogen receptor beta (ERβ) decreases during tumor development in the breast epithelium. However, the role of ERβ in relapse and metastasis of breast cancer is poorly understood. Methods: In this study, we retrospectively studied 30 case breast carcinomas divided luminal, HER2, and triple negative subtype. Among them, patients relapsed within 5 years are 6 cases. The expression of ERβ gene in breast cancer tissues (30 cases) was estimated using a quantitative PCR, and other marker (ERα, HER2, PR etc) was measured anonymously in formalin-fixed paraffin-embedded tumor sections, by using specific antibodies. Results: A low level of ERβ expression and mitochondrial translocation of ERβ was associated with relapse/metastasis of breast cancer. The ERβ depletion resulted in resistance in response to tamoxifen treatment of MCF-7 breast cancer cells. Conversely, the overexpression of mitochondrial ERβ enhanced the cell death by treatment of tamoxifen in MCF-7 cells. We found that ERβ localizes to the mitochondria via the interaction with Grp75 and improves mitochondrial oxygen consumption rate and ATP production in breast cancer cells. Finally, we showed that ERβ level was a low in the breast cancer stem cells (CD24-CD44+ cells) compared with breast non-cancer stem cells (CD24+CD44- cells), whereas ERα level was a high. The overexpression of mitochondrial ERβ contribute to a decrease of sphere formation showing a tumorigenic ability. Conclusions: The mitochondrial ERβ contribute to suppress survival and stemness of cancer stem cells for relapse/metastasis, promising to the development of novel strategies for the treatment of breast cancer patients.
Identification of differentially expressed genes associated with clinical response after treatment of breast cancer skin metastases with imiquimod.
Authors: Rozenblit Mariya , Heguy Adriana , Chiriboga Luis , Loomis Cynthia , Darvishian Farbod , Egeblad Mikala , Shao Yongzhao , Adams Sylvia
Published: September 2018

e12541

Background: Imiquimod, a Toll-like receptor 7 agonist, activates innate immunity and has a response rate of 20% in breast cancer skin metastases. Tumor regression is associated with increased tumor infiltrating lymphocytes and increased Th1 cytokines in tumor supernatant, however gene expression changes are unknown. This is the first report of gene expression changes induced by imiquimod treatment in breast cancer skin metastases. Methods: FFPE-extracted mRNA from 8 patients pre and post 8 weeks of imiquimod treatment was analyzed using Nanostring PanCancer Immune Profiling Panel. Gene expression and pathway analysis was conducted with nSolver 3.0 with clinical response as outcome, controlling for HER2 ER/PR status, with 5% significance level used. Results: In all patients, imiquimod was associated with upregulation of genes in innate immunity such as TLR7, IL-1, T-cell, B-cell, and NK related genes. Three patients had a clinical response after imiquimod. Forty-two differentially expressed genes were identified in responders vs. non-responders after imiquimod. Reponders had up-regulation of T cell (CD2, SPN), NK cell (KLRC2), B cell (CD48), lymphocyte (LY96), and IL-2 (IL2RG) related genes. The top upregulated pathways were cytotoxicity, NK cell function, and antigen processing. Pre-treatment, the responders had upregulation of TNF and IL-17 related genes (TNFRSF10B, IL17RA) compared to non-responders. Comparing pre-treatment to post-treatment, Imiquimod was associated with mRNA expression changes in 72 genes in responders vs non responders. The top upregulated genes involved activation of lymphocytes (SH2D1A), NK cells (KLRC2), DCs (CLEC4C), several chemokines, IL7R and immune regulators PLD1 and IRF5. Conclusions: Clinical response to Imiquimod treatment of breast cancer skin metastases is associated with upregulation of genes in innate immunity suggestive of an anti-tumor immune response. Inhibition of negative feedback by addition of PLD1 inhibitors may enhance treatment response. Understanding the genetic signature of imiquimod can enhance prediction of response and inform possible combination therapies in the future.
Use of everolimus in advanced hormone receptor–positive metastatic breast cancer in a multicenter national observational study.
Authors: Cottu Paul H. , Lardy-Cleaud Audrey , Frank Sophie , Le Saux Olivia , Chabaud Sylvie , Parent Damien , Pistilli Barbara , Debled Marc , Mailliez Audrey , Veyret Corinne , Petit Thierry , Uwer Lionel , Guiu Lahaye Severine , Chamorey Emmanuel , Ung Mony , Arveux Patrick , Guesmia Tahar , Augereau Paule , Simon Gaetane , Bachelot Thomas Denis
Published: September 2018

e12548

Background: The everolimus-exemestane combination has been included in the International guidelines for advanced HR+ breast cancer (mBC) since the results of the Bolero-2 trial. Marketing authorization has been granted in France in July 2012 and reimbursement in Nov. 2014. Very few real life data of everolimus (EVE) use have been reported. Methods: All patients who initiated treatment for a newly diagnosed mBC between Jan. 2008 and Dec. 2015 in all 18 French Comprehensive Cancer Centers have been included in the real life ESME database, which collects retrospective data using a clinical trial-like methodology with quality assessments. Primary endpoint of the current analysis was to evaluate the incidence and indication of EVE use before and after marketing authorization and reimbursement Results: The ESME program included a total of 16,703 patients of which 9,921 had HR+/HER2- mBC. Median age at metastatic diagnosis was 62.0 year (range 23-96). Visceral metastases were present in 60.3% of cases. Only 4123 patients (41.6%) received endocrine therapy alone as first-line therapy, and 60% were deemed endocrine resistant Overall, 1,217 (12.3%) pts have received EVE during therapy as of Dec. 2015 (all lines). EVE was given as first line therapy in 117 pts (10% of all EVE pts and 1.2% of pts receiving a first line therapy). In 99/117 pts (85%) EVE was combined with exemestane. Before 2012, EVE was barely used and mostly within clinical trials. After 2012, use of EVE increased steadily (table). Percentages refer to the total of pts who received any kind of treatment during a given year of observation (e.g., 506/4435 pts took EVE in 2015). Median duration of EVE use was 6.0 months (0-65) as first line treatment and 3.9 months (0-65) in pretreated patients. Main causes of EVE cessation were recorded and will be detailed at the meeting. Conclusions: In this very large French national and representative cohort of HR+ HER2- mBC, EVE use rose quickly as soon as marketed. EVE was mostly used in pretreated mBC albeit in probably too advanced pts. These data underline the need for physician and patient education for oral therapies. [Table: see text]
Breast cancer and incidence of non-caseating granulomas diagnosed in PET avid chest lymphadenopahy.
Authors: Bechara Rabih , Rich Patricia , Parks Christopher , Bonta Dacian , Bonta Ioana
Published: September 2018

e12549

Background: Breast cancer is known to metastasize to the lung parenchyma and lymph nodes. Most breast malignancies are clinically staged using radiographic modalities (e.g. PET scans). Importantly, several inflammatory disorders will present lymph node FDG-uptake on PET, which can be mistaken for breast cancer metastasis. This may alter staging and implicitly treatment for individuals within whom both undiagnosed autoimmune disorders and breast cancer co-occur. We aim to examine the frequency of non-caseating granulomas diagnosed in PET avid mediastinal/hilar nodes in patients with known breast cancer. Methods: Between March 2013 and December 2015, 46 women diagnosed with breast cancer were staged by PET-CT. Those with positive result in the mediastinum/hilum underwent linear endobronchial ultrasound (EBUS) for pathologic diagnosis and ensuing treatment Results: Of the 46 patients with avid mediastinal/hilar adenopathy, 31 (67%) had malignant cytology on EBUS; the remaining 15 had positive PET but negative cytology for malignancy. Twelve of the 15 patients with false positive PET had reactive lymph nodes, and 3 had non-caseating granulomas on cytology (see table). Twenty percent of the patients with negative cytology and positive PET had non-caseating granuloma, and 6.5 % of all patients with positive PET had non-caseating granulomas. Conclusions: To our knowledge, this study represents the largest cohort of breast cancer patients, where the incidence of non-caseating granulomas is investigated in PET-positive mediastinal/hilar nodes. We conclude that in selected patients, in addition to imaging, pathologic staging should be done. Also, the finding of non-caseating granulomas in these patients may either indicate an incidental diagnosis of early stage sarcoidosis, or an inflammatory reaction to the current treatment (sarcomatoid reaction). We also suggest that these patients should be followed for any manifestations of sarcoidosis. [Table: see text]