bluuebunny/crossref_metadata_2025 huggingface dataset:
Sequential versus concurrent use of chemotherapy and endocrine therapy in the adjuvant treatment of ER-positive breast cancer: A systematic review and Bayesian network meta-analysis.
Authors: Li Tianfu , Shan Zhen , Yu Liang , Kuang Xiaying , Zhang Deyuan , Lu Sihong , Zhang Qi , Shao Nan , Lin Ying
Published: May 2019

e12040

Background: Chemotherapy followed by endocrine therapy is the standard adjuvant treatment strategy for estrogen receptor-positive breast cancer patients. However, no direct evidence so far demonstrated better efficacy of sequential use of chemotherapy and endocrine therapy over concurrent. Objective: To evaluate the efficacy between sequential and concurrent use of chemotherapy and endocrine therapy in the adjuvant treatment of ER positive breast cancer. Methods: Randomized clinical trials comparing chemotherapy and/or endocrine therapy in the adjuvant treatment of ER positive breast cancer were included. Hazard ratios (HRs) of disease-free survival (DFS) and overall survival (OS) were extracted and analyzed in Bayesian analysis. Patients were stratified by menopause status for subgroup analysis. Results: 37 trials were identified with 37225 patients enrolled in total, 37 trials with DFS results and 24 with OS. 3 comparisons were done between sequential and concurrent arms. In DFS analysis, no statistical significance was found in all 3 comparisons [CHE seq/con TAM (HR 1.01, 95%CI 0.8497 - 1.199); CHE seq/con OFS+TAM (HR 0.9119, 95%CI 0.5666 - 1.49); CHE seq/con OFS+AI (HR 1.032, 95%CI 0.6291 - 1.776)]. The same were seen in OS analysis [CHE seq/con TAM (HR 0.9512, 95%CI 0.8053 - 1.125); CHE seq/con OFS+TAM (HR 1.065, 95%CI 0.6344 - 1.789); CHE seq/con OFS+AI (HR 1.069, 95%CI 0.665 - 1.717)]. Rankings were done for preferable treatment recommendations. In DFS analyses, sequential arms ranked higher than concurrent arms [CHE seq/con OFS+AI (1 vs. 3); CHE seq/con OFS+TAM (6 vs. 7); CHE seq/con TAM (8 vs. 8)]. The same tendency was seen in OS analyses [CHE seq/con OFS+AI (1 vs. 2); CHE seq/con TAM (4 vs. 5)] except for CHE seq/con OFS+TAM (11 vs. 6-9). In subgroup ranking results, CHE seq/con OFS+AI and CHE seq/con OFS+TAM showed consistency among comparisons with concurrent arms ranked higher than sequential arms. However, CHE seq TAM ranked higher than CHE con TAM in all comparisons. Conclusions: The combination of chemotherapy and endocrine therapy in the adjuvant treatment of ER positive breast cancer demonstrated equal efficacy either used sequentially or concurrently. However, concurrent arms were recommended over sequential arms in premenopausal patients for better DFS and OS, except for the combination of chemotherapy and tamoxifen which was recommended to be used sequentially. Others: This study has been registered in PROSPERO (CRD42018104889).
The prognostic role of the androgen receptor in patients with triple-negative early breast cancers and primary surgery.
Authors: Jongen Lynn , Floris Giuseppe , Wildiers Hans , Claessens Frank , De Sutter Luna , Croes Romaric , Decloedt Jan , Laenen Annouschka , Ardui Jan , Punie Kevin , Berteloot Patrick , Vergote Ignace , Neven Patrick
Published: May 2019

e12042

Background: The prognostic value of androgen receptor (AR) expression in triple-negative breast cancer (TNBC) is debated and might be partially masked by the use of adjuvant chemotherapy, which might benefit AR-negative TNBC more than AR-positive cases. We compared the prognostic value of AR in a case control study of consecutive women with TNBC treated or not with adjuvant chemotherapy (ACT). Methods: We retrospectively studied AR expression by immunohistochemistry in all consecutive patients with a secondary metastatic TNBC treated in UZ-Leuven between 2000 and 2009. The control group were cases of TNBC never developing secondary metastatic disease during a long follow-up period matched 1:1 for age and tumor grade. Relations between demographics and clinical pathological features and AR protein expression were studied, including stromal tumor infiltrating lymphocytes (sTILs). Secondary metastatic disease connections with AR protein expression was assessed using the Akaike information criterion; time-to metastasis (TTM) was studied using a linear model with and without ACT correcting for lymph node involvement. We explored whether results differed by AR protein expression levels (0%, 1-34%, ≥34% of tumor cells) and body-mass index (BMI) comparing normal ( < 25kg/m2) with overweight/obese patients BMI. Results: We included 139 patients (69 metastatic and 70 non-metastatic; median age 51.0 years); median follow-up for both groups was 8 years. AR protein expression level ≥ 1% was observed in 25% (n = 34) and ACT was given in 73% (n = 101). AR-positive as compared to AR-negative TNBC patients were older (p = 0.04). Results based on multivariable models including lymph node status and ACT as confounders showed that AR-negative cases have a higher metastasis risk compared to AR-positive patients (3.015 odds ratio (95% CI 1.199-7.582), p = 0.02); this difference was more significant in ACT-naive patients (10.823 odds ratio (95% CI 1.897-61.740), p = 0.007). ACT-treated patients had the best outcome if AR was low (1≤ and < 34%) followed by those with a normal weight and an AR-negative high sTIL TNBC. Conclusions: The AR is prognostic in TNBC and this is clearer in non-ACT treated patients with a TNBC. Our results might suggest that if ACT is given, only the AR-positive TNBC with low AR-expression do well.
Oncotype DX score in hormone receptor-positive/HER2-positive breast cancer: A SEER analysis.
Authors: Qasrawi Ayman , Myint Zin , Alnimer Yanal Mufeed , Romond Edward H.
Published: May 2019

e12044

Background: The recurrence score Oncotype DX (RS) predicts the need for adjuvant chemotherapy in hormone receptor positive (HR+) early stage breast cancer (BC). However, it has not been validated for HR+/HER2+ BC cases. We aim to evaluate the results of RS in HR+/HER2+ BC by using the Surveillance, Epidemiology, and End Results Program (SEER) national database. Methods: We identified patients with non-metastatic HR+/HER2+ BC with reported RS scores from the national SEER database between 2010 and 2015. Data obtained included demographics, histologic subtypes, grading, tumor size, nodal status, HR status and overall survival (OS) outcomes. RS scores were divided into low/intermediate (≤30) and high ( > 30). Histologic subtypes were further categorized into favorable (lobular, tubular, mucinous, and cribriform) and unfavorable (infiltrating ductal, mixed ductal, and micropapillary). We used Kaplan-Meier & Cox regression to analyze the survival outcomes. Logistic regression analysis was used to analyze the correlation between variables and different RS scores. Results: A total of 1537 patients were included. Median age was 61 (25-90). Majority of the patients presented with node negative disease (85%), low/intermediate grade (71%), tumor size < 20 mm (73%), unfavorable histology (89%), and only 15% had negative progesterone receptor (PR –). High RS score ( > 30) was seen in 24% of cases. After a median follow-up of 38 m (1-72), the five-year OS was 94.5%. Chemotherapy was given to 71% and 35% of those with RS > 30 and ≤30, respectively. There was a strong correlation between age > 60 ([hazard ratio, HR] = 4.9, p < 0.0001) and RS > 30 (HR = 2.4, p = 0.004) with worse outcomes on multivariate analysis. However, there were no associations between histologic subtype, tumor size, grade, nodal status and chemotherapy with survival. Tumor size > 20 mm (OR = 1.5), unfavorable histology ([odds ratio, OR] = 3.5), PR – (OR = 4.3) and high grade tumors (OR = 4.5) were independent predictors of RS > 30 (p < 0.0001). Conclusions: Our study shows that large tumor size ( > 20 mm), higher grade, PR –, and unfavorable histology were independent risk factors for higher RS in patients with localized early stage HR+/HER2+. High RS was associated with worse outcome.
Chemotherapy-related outcomes in triple-negative breast cancer.
Authors: Wellmann Rebecca M. , Ghafouri Sanaz N. , McAndrew Nicholas Patrick , Hurvitz Sara A.
Published: May 2019

e12049

Background: Triple-negative breast cancer (TNBC) is associated with a poor prognosis when compared to hormone receptor positive breast cancers. Anthracycline-based regimens (ABRs) are mainstays of treatment for non-metastatic TNBC. However, anthracyclines are associated with an increased risk of potentially life-threatening adverse effects. We sought to compare survival outcomes in patients with early TNBC treated with ABRs versus those treated with anthracycline-sparing regimens (ASRs). Methods: All patients treated for stage I-III TNBC who had undergone curative-intent surgery at a large academic medical center between January 2013-May 2018 were included in the study. Event-free survival (EFS) and disease-free survival (DFS) were the primary endpoints, with overall survival (OS) as a secondary endpoint and were defined as per standardized STEEP criteria. Kaplan-Meier, multivariable Cox regression, and log-rank tests were used to define key survival and treatment related differences between subjects treated with ABRs vs ASRs. Results: 137 patients met inclusion criteria with a median follow-up of 39 months. 21 patients (15%) recurred and 16 (12%) died. Patients treated with ABRs (n = 26, 19%) compared with ASRs (n = 111, 81%) had significantly shorter median EFS (38 months vs not-yet-reached, NYR, p < 0.001), DFS (37 months vs NYR, p < 0.001), and OS (50 months vs NYR, p < 0.001). Though patients in the ABR vs the ASR group were more likely to be node-positive (Odds Radio 3.46, p = 0.006), shorter survival estimates in the ABR group were observed after adjusting for nodal status. 27% of patients (7/26) had an anthracycline added after suboptimal response to an ASR. After adjusting for these patients, the survival findings were similar. 43 patients (31%) received a platinum containing ASR. In the platinum subgroup, ASRs were associated with longer EFS and DFS compared to ABRs, but this effect was not statistically significant in the node-positive group. No cardiac or secondary leukemic events were observed in either group. Conclusions: ABRs were associated with shorter EFS, DFS and OS, even after adjusting for certain high-risk clinical features. Larger studies are needed to identify the role of platinum containing ASRs in patients with early TNBC.
Does the time to initiate adjuvant chemotherapy effect outcome in patients with breast cancer? A National Cancer Database-based retrospective analysis.
Authors: Ashok Kumar Prashanth , Wang Dongliang , Sinha Shreya , Sivapiragasam Abirami
Published: May 2019

e12054

Background: The Early Breast Cancer Trialists Collaborative Group showed that adjuvant therapy for breast cancer (BC) significantly reduces the 5-year recurrence and 15-year mortality rates. After surgery, it usually takes around 4-6 weeks to begin adjuvant chemotherapy and delay in initiating the same is believed to lead to poorer outcomes. A number of studies have sought to evaluate the role of delayed initiation of chemotherapy on survival but results have remained controversial and an optimal time has not been defined. Methods: Our aim was to determine the effect of delay in starting chemotherapy from the date of surgery on survival of patients with early BC using the National Cancer Database (NCDB) data. From the database, we selected patients aged >18 years with stage 1-3 BC who received adjuvant chemotherapy. We included all ER/PR statuses. A total of 544,005 patients were divided into 3 groups based on the time of initiating chemotherapy from the date of surgery i.e., 0-60 days, 60-90 days and >90 days and had a distribution of 38.07%, 35.90% and 26.03 % respectively. Results: Estimates from cox models showed the following adjusted Hazard Ratios(HR): 0-60 days vs >90 days (HR 0.976, CI 0.955-0.998), 60-90 days vs >90 days (HR 0.899, CI 0.879-0.920). Kaplan Meier Survival estimates revealed that the 0-60 days and the 60-90 days groups had a better 10 year survival estimate than the > 90 days group with a p<0.0001. The factors that correlate with delay in initiating adjuvant chemotherapy are African American race, poor Charlson Deyo Score, uninsured or government insurance holders, well differentiated tumors and ER/PR positive status. Conclusions: Based on our analysis from a large national database, we hypothesize that delaying adjuvant therapy for more than 90 days may have worse outcomes due to reasons like rapid growth of micro metastasis following removal of the primary tumor. Thus for stage 1-3 BC, the ideal time to start adjuvant chemotherapy from the date of surgery is before 90 days. Survival estimates from Kaplan-Meier analysis. [Table: see text]
Is it possible to predict the prognostic values of Oncotype Dx using the results of web-based mathematical prognostic value models?
Authors: Iwatani Tsuguo , Tsugawa Koichiro
Published: May 2019

e12058

Background: The goal of the study was to determine whether the prognostic values for ER+ HER2- breast cancer can be calculated based on a test of gene expression profiles in tumors using Oncotype Dx or by entering clinicopathological factors into a web-based model. We evaluated the correlation between these results to shed light on whether the results from web-based models could serve as representative indices for Oncotype Dx. Patients: Two hundred two primary breast cancer patients whose prognostic value was evaluated using Oncotype Dx between May 2010 and October 2018 in St. Marianna University Hospital. Methods: The patients’ clinicopathological factors were extracted from their medical records. Then, the 5- and 10-year breast cancer-specific mortality rates were calculated using PREDICT (www.predict.nhs.uk/tool), while the 5–10 year distant recurrence rate was calculated using CTS5 (www.cts5-calculator.com/). The correlations with the Oncotype Dx prognostic values were evaluated by calculating the Spearman’s rank correlation coefficient, and JMP.ver13.0 (SAS Institute Inc., Cary, NC, USA) was employed for the analysis. Results: The patients’ median age was 49. There were 78 lymph node(LN)-negative patients and 124 LN-positive patients. For the disease stages, 51 patients were stage I, 99 patients were stage IIA, 41 patients were stage IIB, and 11 patients were stage III or above. All patients of the correlation between the Oncotype Dx recurrence score (RS) and the 10-year breast cancer-specific mortality rate was r = 0.1616. The correlation of LN-Negative patients of the 10-year distant recurrence rate between Oncotype Dx and CTS5 was r = 0.1768. The correlation of LN-Positive Cases of the 5-year distant recurrence rate between Oncotype Dx and CTS5 was r = 0.3374. The correlation of these cohort between the 5-year mortality rate from Oncotype Dx and PREDICT was r = 0.4298. Conclusions: There was no correlation between the Oncotype Dx RS and prognostic values calculated from web-based models, and there was also no correlation for prognostic values of lymph node-negative cases. However, there was a correlation for prognostic values of lymph node-positive cases, but the correlation was too weak to use the results from web-based models as representative indices for Oncotype Dx.
Clinical relevance of 21-gene recurrence score with lymph node involvement in HR+HER2- early breast cancer: A tumor size-match paired cohort study.
Authors: Yu Xingfei , Wang Chen , Chen Bo , Pan Xiaodan , Yang Hongjian
Published: May 2019

e12059

Background: Axillary lymph node (LN) involvement is significantly related with high recurrent risk and influenced by tumor size, histologic grade and subtype in early breast cancer. For hormone receptor positive (HR+) and human epidermal growth factor receptor-2 negative (HER2-) breast cancer without LN involvement, 21-gene recurrence score (RS) provides an effective method evaluating the risk of recurrence and metastasis. But the correlation between RS and LN involvement is not clear currently. To investigate the effect of RS on LN involvement, we designed a retrospective cohort study based on the data of tumor size-match LN+/- HR+HER2- breast cancer. Methods: The luminal type (ER+, PR+ and HER2-) early breast cancer (cT1-2) patients with 1~3 LN+ were enrolled and were tumor size-match paired (1:3) with those LN- during the same period. We compared the 21-gene RS between the LN+ and LN- group by univariate and multivariate analyses. Results: From April 2016 to May 2018, there were 65 LN+ cases undergoing 21-gene test included and 195 LN- cases were paired. With tumor size matched, the LN+ group had significantly younger age, more positive family history, higher histologic grade and higher RS than LN- group. All those factors, excepted histologic grade, were further confirmed in multivariate analysis (Table). Conclusions: After adjusted by tumor size, RS may have a significantly independent correlation with LN involvement in HR+HER2- early breast cancer. Total HR+HER2- cases’ tumor size-match paired (1:3) clinic pathologic and RS data. Clinical trial information: NCT03638648. [Table: see text]
Evaluation of immunotherapy (I-O)-associated immune cell (IC) dynamics and PD-L1 expression using multispectral immunohistochemistry (mIHC) and single-cell hierarchical regression modeling in early-stage breast cancer (ESBC).
Authors: Sanchez Katherine , Martel Maritza , Chang Shu-Ching , Wu Yaping , Sun Zhaoyu , Nyberg Richard , Redmond William L , Pucilowska Joanna , Aliabadi-Wahle Shaghayegh , Imatani James , Conlin Alison Katherine , Bernard Brady , Shah Monil , Wadell Dottie , Laxague Deborah R. , Wen Lu , Li Qiao , Wolf Gregory T. , Urba Walter John , Page David B.
Published: May 2019

e12070

Background: In triple negative breast cancer (TNBC), anti-PD-L1 is associated with gains in overall survival, however only in tumors with > 1% PD-L1+ ICs. Locoregional cytokine therapy is being evaluated as a method of priming and redirecting ICs to tumors, which may increase I-O benefit particularly in PD-L1 negative tumors. We report a sensitive method of quantifying I-O-related changes in PD-L1 and ICs using mIHC and single-cell hierarchical regression, which controls for within-tumor and across-patient PD-L1/IC heterogeneity. Methods: Pre-treatment and resection tissues from a phase Ib trial of locoregional cytokines (IRX-2, n = 16 subjects) in ESBC were analyzed. IRX-2 contains immunostimulatory cytokines (GM-CSF, IL-2, IFN-α, INF-γ, and IL-12) and was injected in peri-areolar tissue, which communicates directly with tumor-draining lymphatics. Specimens were analyzed for 1) H&E stromal TILs score; 2) clinical PD-L1 IC expression (Ventana SP142, 2 blinded pathologists); and 3) mIHC (PerkinElmer Vectra). InForm software was used to obtain geospatial outputs of tumor cells (CK+) and ICs (CD3, CD8, CD163) across multiple regions of interest (mean:18; range: 9-32). Mixed-effects modeling was used to evaluate for changes in PD-L1, ICs, and IC/tumor distance metrics. Results: PD-L1 and IC quantity by mIHC was highly concordant with clinical PD-L1 IC classification (JT test = 211, p < .001) and TIL score (r = 0.77). Cytokine therapy was associated with higher PD-L1 IC classification in 9/13 tumors, and increased PD-L1 ICs by mIHC in 14/15 (+337%, 95% CI: 120,769%). After adjusting for heterogeneity, cytokine therapy increased CD3+CD8+ ICs (+173%, CI: 93,287%) and CD3+CD8- ICs (+120%, CI: 21,301%). Therapy was also associated with increased effector-helper T-cell clustering (nearest-neighbor distance, -40%, CI: -29,-50%) and effector cell tumor localization (stromal-tumor interface CD8+ density +90%, Cl: 74, 305%). Conclusions: Our method is concordant with clinical PD-L1 and sTILs scores, and can additionally quantify IC and IC distances. This assay may allow for comparative I-O assessments with increased resolution, and will be used in a randomized phase II trial of pembrolizumab, chemo +/- IRX-2 in stage II/III TNBC.
Predicting response to neoadjuvant chemotherapy in nonmetastatic hormone receptor-positive breast cancer using 21-gene Breast Recurrence Score test.
Authors: Thekkekara Romy Jose , Bharadwaj Sushma , Yadav Udit , Baranwal Anmol , Peace David , Rogowski Wendy , Sekosan Marin , Lad Thomas E. , Marcus Elizabeth A. , Ferrer Karen , Shah Mousami , McDunn Susan H.
Published: May 2019

e12093

Background: The Recurrence Score (RS) result based on the 21-gene Oncotype DX Breast Recurrence Score assay is standard of care in deciding adjuvant chemo-hormonal therapy versus hormone therapy alone in hormone-receptor positive (HR+), HER 2 negative, node–negative breast cancer. This study explores the role of RS result in predicting the response to neoadjuvant chemotherapy (NACT). Methods: In this retrospective single institution cohort study, electronic medical records of 148 women with HR+, HER 2 negative, non-metastatic breast cancer who received NACT from 2006 onward were screened. 38 patients were excluded due to lack of tissue for testing. Pretreatment biopsy blocks were sent to Genomic Health, Inc. for Oncotype Dx testing. Low RS result was defined as ≤25. Pathologic complete response (pCR) was defined as no residual tumor. Partial response (PR) was residual tumor with > 25% decrease in the largest dimension. No response (NR) was defined as < 25% decrease in the tumor post NACT. Progression (PD) was defined as increase in size of original tumor or new site(s) of disease. Results: Of the 110 patients studied, 58% were postmenopausal women. Fifty percent were African American, 12% were Caucasian and 27% were Hispanic. Invasive ductal carcinoma was the predominant histology (86%). Most patients had > T2 disease (97%) with 73% being clinically node positive. Adriamycin based NACT regimen was used in treating 86.3% of the women. Forty patients (36.4%) had tumor with RS≤25. NR/PD was significantly higher in tumors with RS≤25 (27/40) vs RS > 25 (13/70) (OR: 9.1, 95% CI: 3.7-22.2, P< 0.001). pCR was seen in 16% with RS > 25 and 0% with RS ≤25. Response to NACT (pCR/PR) was 32.5% in RS≤25 vs 81.4% in RS > 25. In tumors with response, RS > 25 was associated with a greater percent decrease in the tumor size compared to RS≤25 (median decrease of 71% vs 52%, P= 0.033). Conclusions: HR+, HER 2 negative, RS≤25 breast cancer is associated with increased rates of NR/PD and is unlikely to respond to NACT. Recurrence Score result determination in pretreatment breast cancer biopsy samples can be an effective tool to select patients with non-metastatic breast cancer for NACT. Studies are needed to determine novel neoadjuvant therapeutic approaches in patients who are candidates for neoadjuvant therapy but are unlikely to benefit from NACT.
Biomarkers involved in the neoadjuvant therapy response in triple-negative and Her2+ subtypes breast cancer.
Authors: Bofill Salvador , Benavent Marta , Gil Ana , Pineda Antonia , Molina-Pinelo Sonia , Gonzalez Rosario , Montaño Alvaro , Ruiz Borrego Manuel , Falcon Alejandro , Garrigos Carmen
Published: May 2019

e12098

Background: Neoadjuvant systemic therapy for breast cancer is used increasingly for patients with breast cancer. One of the more compelling theoretical arguments for primary systemic therapy is its value as an in vivo test for drug sensitivity. The oncogenesis of breast cancer, progression and development of metastasis is influenced by the deregulation of a multitude of processes. Several long non-coding RNAs (LncRNAs) and genes are important regulators of gene expression, acting at almost all regulatory levels: transcriptional, posttranscriptional, epigenetic, and protein translation. Our main objective was to identify the differential expression of genes and LncRNAs in paraffin-embedded breast cancer samples Her2+ and triple negative (TN) subtypes in responders (R) and non-responders (NR) patients (pts) to neoadjuvant therapy. Methods: The expression RNAs was analyzed by ClariomD Asssay (ThermoFisher). Results were analyzed with Transcriptome Analysis Console and with in-house scripts in R (version 3.5.1). Data were corrected and normalized using Robust Multichip Average method from the oligo package. Expression was summarized at gene level using the corresponding annotation for ClariomD array BrainArray. Expression analyses were performed with limma package. We defined R (RCB 0; n = 29) and NR (RCB III; n = 11) pts. Results: The differential expression (p < 0.01) of two LncRNAs (RP1-213J1P_B.1 and AC053503.12), one miscellaneous RNA (miscRNA) (Metazoa_SRP) and five genes (STMND1, C8orf33, RP11-144G6.12, ZNF555, RGS2) were found between R and NR. Among others, we highlighted one of these LncRNAs (AC053503.12) and one gene (Metazoa_SRP) that were also identified in TN R (n = 11) vs NR (n = 6). In the Her2+subtype, STMND1 gene also showed a differential expression in R (n = 18) vs NR (n = 5). Conclusions: We found these LncRNAs, miscRNA and genes were involved in different cancer pathways and the their differential expression in R vs NR pts suggest that they could be involved in the response to neoadjuvant therapy in TN and Her2+ subtypes breast cancer. LncRNAs, miscRNA and genes differentially expressed are being independently analyzed by individual qPCR assays in the study cohort.
Association of pathologic non-complete response of axillary node with outcome after neoadjuvant chemotherapy in node positive breast cancer.
Authors: Chen Shin-Cheh , Chang Hsien-Kun , Lin Yung-Chang , Lin Yung-Chang , Shen Shih-Che , Kuo Wen-Lin , Yu Chi-Chang , Chou Hsu-Huan , Chu Chia-Hui , Huang Yi-Ting , Ueng Shir-Hwa
Published: May 2019

e12101

Background: The pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) correlates with better outcome in specific subtype of breast cancer and the axillary nodal pCR (N-pCR) rate are more common than breast pCR (B-pCR). While only a few studies to compare the survival in terms of B-pCR and N-pCR, and no study compare between the outcome for those non pCR either in breast or axillary node. Methods: A cohort of 968 cytologically proved nodal metastatic breast cancer (cT1~4N1~2) received NAC in a single medical center between 2005~2017 were analyzed retrospectively. NAC regimen included anthracycline and taxanes in all patients, Trastuzumab was used in 308(70.3%) HER2(+) patients. The percentage of both breast and axillary pCR (T-pCR) 、B-pCR and N-pCR were compared in different subtypes. The impact of T-pCR、B-pCR and N-pCR to DFS and OS were analyzed using univariate and multivariate Cox proportional hazard model. Results: The median follow-up time was 45 months. The median age was 49 years old, average tumor size was 4.2cm, and 543 (56.1%) patients were N1 disease. 382(39.5%) patients were HR(+) HER2(-), 222(22.9%)were HR(+)HER2(+),216(22.3%) were HR(-)HER2(+) and 148(15.3%) were HR(-)HER2(-). After NAC, T-pCR was found in 213 (22.0%) patients, B-pCR and N non-pCR in 31 patients, N-pCR and B non-pCR in 245 patients and T non-pCR in 479 patients. N-pCR rate(47.3%) were significantly higher than B-pCR(25.2%) and this trend found in all subtypes ( P<0.0001).The predicting factors of N-pCR were N1,HER2(+) and HR(-). In survival analysis the pCR (either T,B or N) patients had significantly better 5-year DFS and OS than non- pCR(T-pCR v.s T non-pCR, DFS,85.1% v.s 58.4%;OS,91.2% v.s 73.6%,p<0.0001). B-non pCR had a significant better DFS than T non Pcr(65.1% v.s 58.4%,p=0.041) and non- significant. Cox better 5-year OS(78.9% v.s73.6%,p=0.059). Cox regression model demonstrated that T4,N2,grade 3, HR(-) and T non-pCR were poor prognostic factors in DFS and OS. Conclusions: The study demonstrated higher N-pCR rates than B-pCR in all subtypes after NAC, either T-pCR;B-pCR or N-pCR were associated with better outcome than non pCR. The worst outcome found in those T non-pCR or N non-pCR.
HER2 cluster amplification as a factor of an especial sensitivity for anti-HER2 neoadjuvant therapy with biosimilar of trastuzumab in Russian women with breast cancer stage II-III.
Authors: Kolyadina Irina Vladimirovna , Gordeeva Olga , Ganshina Inna , Zavalishina Larisa , Andreeva Yulia , Frank Georgy , Savelov Nikita , Tuzova Elena , Zhukova Lyudmila , Vishnevskaya Yana , Arkhipov Aleksandr , Bokhian Vahan Yurikovich , Komov Dmitry , Poddubnaya Irina
Published: May 2019

e12102

Background: Effect of neoadjuvant chemotherapy (NACT) is extremely important for patients with HER2-positive breast cancer stage II-III as it correlates with long-term outcomes. However, predictive factors for achieving complete pathologic response (pCR) remain unclear. Aim of the study: Assess an impact of clinical, morphological and genetic factors on pCR achievement in patients with HER2-positive breast cancer stage II-III treated by biosimilar of trastuzumab. Methods: We studied treatment results in 73 patients with HER2-positive breast cancer (BC) stage II-III (aged 29-71, median – 51 years), treated with NACT with anti-HER2 therapy and radical surgery in “N.N. Blokhin National Medical Research Center of Oncology” оf the Ministry of Health of the Russian Federation in 2015-2018. After radical surgery pathologic response was assessed. Initially operable tumors were observed in 45,2% patients, locally advanced - in 53,4%. Luminal HER2-positive BC was diagnosed in 41,1%, non-luminal HER2-positive in 58,9%. Ki67 was high (≥ 20%) in 91,5%. NACT included anthracycline and non-antracycline regimens with addition of biosimilar of trastuzumab ± pertuzumab. Radical mastectomy was performed in 78,8% patients, 21,2% had breast-conserving surgery. We studied biopsies obtained before the start of treatment in all women, HER2 amplification was detected by HER2 IQFISH pharmDx (DAKO) kit in accordance with ASCO/CAP 2018 guidelines. In 87,1% HER2+ status was defined as ASCO/CAP 2018 category 1; cluster amplification was detected in 30,1% patients. We analyzed the rate of bpCR и tpCR achievement depending on clinical, pathological data and amplification of HER2. Results: Pathologic complete response in primary tumor (bpCR) was achieved in 57,4%, both in primary tumor and lymph nodes (tpCR) – in 48,9% patients; bpCR achievement depended on age, NACT regimen, addition of pertuzumab and HER2 copy number ( < 0,05). The highest rate of bpCR was noted in women aged 50 and older (71,9%, p = 0,026); in patients received TCH±Р regimen (80,0%, p = 0,045); with addition of pertuzumab (88,9%, p = 0,049); and if cluster amplification was detected (81%, p = 0,013). Cluster amplification was the only one significant predictive factor for achieving tpCR: with cluster amplification - 68,8%, without - 38,7% (p = 0,049). Conclusions: Cluster amplification of HER2 is the most significant factor of especial sensitivity for NACT with biosimilar of trastuzumab in HER2-positive BC stage II-III.
Retrospective single-center outcome analysis of neoadjuvant and palliative treatment with dual trastuzumab and pertuzumab in HER2-positive breast cancer.
Authors: Marhold Maximilian , Ionce Lea Roxana , Christ Alexandra , Aretin Marie-Bernadette , Sagaster Verena , Exner Ruth , Wimmer Kerstin , Devyatko Yelena , Fitzal Florian , Steger Guenther G.
Published: May 2019

e12114

Background: Her2-positive (Her2pos) breast cancer (BCa) is the second most lethal subtype of BCa. The treatment of Her2-positive BCa was revolutionized due to the dual use of trastuzumab and pertuzumab (T+P) in recent years both in the neoadjuvant and the palliative setting. Although several years have passed after initial approval of these drugs, single-center outcome data as reported by clinicians is sparse. In this retrospective study, we set to assess outcomes measures at our institution, Austria’s largest academic hospital, for the use of T+P in early and metastasized BCa. Methods: We acquired records on combined pertuzumab and trastuzumab orders from our intramural drug order software (CATO, Cato Research, Durham, NC, USA) for the time period of May 2013 to March 2018. Further, using electronic patient histories, we described both the neoadjuvant and palliative patient groups by assessment of body weight/size, tumor stage, histology including immunohistochemistry (IHC), lines of oncological therapies received, ejection fraction (EF) drops>10%, deaths and most importantly the outcomes measures pathological complete response (pCR, neoadjuvant cohort) rate and progression-free survival (PFS, palliative cohort). Results: 120 breast cancer patients were given dual therapy with T+P. The neoadjuvant cohort contained 63 patients, while the palliative cohort included 57 patients. All patients included were female. Full histology including IHC data was available for 47 of 63 patients in the neoadjuvant cohort and 30 of 57 patients in the palliative cohort. BMI was 25.6 and 23.3, respectively, on average. The mean age was 54 years in the neoadjuvant and 56 years in the palliative cohort. 73.6% (39/53) and 65.9% (29/44) of tumors were ER positive as determined by IHC. While neoadjuvant patients obtained an average of 6.5 cycles, patients within the palliative cohort received a mean of 17.3 cycles of T+P. 0 and 17 deaths were observed in the respective cohorts. Data on pCR and PFS was available for 95.2% and 91.2% of patients, respectively. The pCR rate within the neoadjuvant cohort was 46.7% (28/60), and mean PFS across all treatment lines of the palliative cohort was 10.2 months. Conclusions: We report retrospective single-center outcome data for the combined use of trastuzumab and pertuzumab in both early and metastatic Her2pos BCa in line with previously published data.
Doxorubicin response prediction in neoadjuvant breast cancer therapy.
Authors: Buhl Anna Sofie Kappel , Christensen Ib Jarle , Knudsen Steen , Jensen Peter Buhl
Published: May 2019

e12119

Background: Neoadjuvant treatment for breast cancer (BC) is an important remedy if the tumors are responding adequately. Still, there is no biomarker guidance resulting in many patients receiving chemotherapy with no efficient antitumor effect. We study a multigene mRNA-based technology for drug response prediction (DRP). DRP has been thoroughly validated in other settings, latest in prediction of epirubicin efficacy in advanced BC [1]. Here are the results of the DRP method in the prediction of response to neoadjuvant doxorubicin in early BC. Methods: The DRP correlates sensitivity of the applicable drug in cell lines with background mRNA. This is combined with gene expression patterns from >2.000 tumors of different origin to ensure clinically usefulness. The higher DRP score, the higher likelihood of response. Blinded predictions of doxorubicin DRP scores were compared to response data which originated from a phase II trial [2], where the study population received neoadjuvant doxorubicin and cyclophosphamide (N=279). The patients had histologically confirmed primary invasive breast adenocarcinoma (T2-3, N0-3, M0, tumor size ≥ 2.0 cm, ER+/- and HER2+/-). Statistical analysis was done using logistic regression. Results: Table shows the distribution of response and DRP scores, showing higher DRPs are correlated to better clinical outcome. This is demonstrated by logistic regression ( p=0.002), odds ratio for response 2.2 (95% CI:1.3-3.4). Multivariate analysis showed that the DRP was independent of other covariates. Conclusions: The DRP can predict which patients will be high likelihood responders to neoadjuvant doxorubicin. Modern multigene technologies may help assist clinicians in choosing between upfront surgery or neoadjuvant chemotherapy. Complete response (CR), Partial response (PR), Stable disease (SD), Progression of Disease (PD). 1. Buhl ASK, et al. (2018): Predicting efficacy of epirubicin by a multigene assay in advanced breast cancer within a Danish Breast Cancer Cooperative Group (DBCG) cohort: a retrospective-prospective blinded study. Breast cancer research and treatment. doi: 10.1007/s10549-018-4918-4. 2. Horak CE et al. (2013): Biomarker analysis of neoadjuvant doxorubicin/cyclophosphamide followed by ixabepilone or Paclitaxel in early-stage breast cancer. Clinical cancer research. doi: 10.1158/1078-0432.ccr-12-1359.[Table: see text]
Biological behavior of HER2+ breast cancer: Differences based in hormone receptor expression.
Authors: Da Silva Maria Joao Ribeiro , Abreu Miguel Henriques , Azevedo Sergio Xavier , Alpoim Tiago , Sousa Susana , Pereira Deolinda
Published: May 2019

e12120

Background: Breast carcinoma is a heterogeneous disease whose therapeutic approach idepends on the classification into molecular subtypes. Despite the impact the expression of hormone receptors (HR) among patients with overexpression of HER2 is already the target of some studies, there is a lack of analysis in the era of treatment with adjuvant trastuzumab. Methods: This stydy consists in a retrospective analysis of cases of tumors with overexpression of the HER2 receptor (HER2 +), and HR- treated at an oncological center, comparing their biological behavior with cases of HR +/ HER2 + tumors, thus controlling for classic prognosis. Results: We analised a total of 420 patients, of whom 210 with HR+/HER2+ tumors and 210 HR- / HER2 +, with median ages of 52 years and 53 years, respectively. They accounted for 89.5% of cases of stage I to III disease. The groups were balanced in clinical characteristics. There was a higher proportion of undifferentiated and inflammatory tumors in the RH-/ HER2 + group, and in this group higher rates of complete pathological responses to treatment were observed (50.8% vs. 30.0%, p < 0.001). During the follow-up 30 recurrences occurred, 18 in the HR- / HER2 + group, and 12 in the HR + / HER2 +. There was lower disease-free survival in the HR-/HER2 +, on average 69.1 months, compared to 74.3 months in the group HR+/HER2 + (p = 0.001). The first metastatic site involved visceral location in 13 cases (72.2%) in HR- / HER2 + tumors (CNS involved in 8 cases), and in 8 cases (66.6%) in HR + / HER2 + tumors (CNS in 1 case). There was an association between relapse and response to primary systemic treatment (p = 0.003), with no relation demonstrated with other clinicopathological characteristics. In the global sample, there were 28 deaths, corresponding to 17 in the HR-/HER2 +, and 11 in the HR+/HER2 + group. There were significant diferences in OS, showing worse prognosis of HR- disease (mean of 70.7 months vs. 106.6 months, p = 0.001). There was an association of mortality with the presentation as an inflammatory tumor and involvement of the CNS. Conclusions: This study supports the concept of two distinct entities according to the expression in HER2 + disease, justifying therapeutic approaches and eventually different follow-up strategies.
Combining denosumab (D) and trastuzumab (T) as a novel treatment strategy in HER2-positive (+) breast carcinomas (BC).
Authors: Karamouzis Michalis , Zoi Ilianna , Xingi Evangelia , Thomaidou Dimitra , Papavassiliou Athanasios G.
Published: May 2019

e12506

Background: HER-2 is overexpressed in 20–30% of BC, indicating poor prognosis. RANKL/RANK pathway is implicated in HER-2(+) BC. The molecular mechanism and the potential of dual targeting have been evaluated and showed promising results. Methods: We used SKBR3, BT474, MCF7, MDA-MB-453 human BC cell lines. We examined the expression of RANK and RANKL using RT-PCR, Western-Blot and immunofluorescence. The interaction between RANK and HER-2 was detected using Proximity Ligation Assay (PLA) which enables the visualization of interacting proteins. NF-κB pathway activation was studied using Western-Blot. We used inhibitors of both pathways. Cell viability and cell migration was evaluated using XTT and scratch assay, respectively. Results: Cell lines differentially express RANK and RANKL. RANK receptor dimerizes with HER-2. RANK/ HER-2 dimer number depends on HER-2 expression (SKBR3: 5.4, BT474: 8.2, MCF7: 0.7, MDA-MB-453: 0.3). RANK/HER-2 dimers are decreased in the presence of the inhibitors D and T, while they are increased after RANKL (R) treatment in SKBR3 (m:5.4, D:1.2, T:1.9, DT:0.6, R:11.8,) and BT474 (m:8.2, D:3.1, T:4.3, DT:0.7, R:11.6). MCF7 and MDA-MB-453 do not correspond to inhibitors. The combination treatment of SKBR3 with the inhibitors further decreased NF-κB pathway activation compared to single targeting. SKBR3, after inhibitors treatment, also exhibit reduced cell proliferation (m:100%, D:84.7%, T:51.57%, DT:48.61%, R:111%) and lower metastatic potential (m:26.02%, D:33.56%, T:16.54%, DT:13.75%, R:32.36%) compared to mock cells (m) and increased values in RANKL presence. The combination treatment of SKBR3 with D and T has an advantage in functional proliferation assays compared to single targeting. Conclusions: The results indicate a direct association between HER-2 and RANKL/RANK pathway in HER-2(+) BC growth. We also present data suggesting that the combination of trastuzumab and denosumab may have therapeutic benefit in certain BC patients.
HER2 testing: Insights from pathologists’ perspective on challenging HER2 cases.
Authors: Grimm Erin V , Swenson Karen K , Krueger Janet , Hicks David G. , Allison Kimberly H. , Yaziji Hadi , Rendi Mara Hester , Susnik Barbara , Downs-Kelly Erinn , Tsai Michaela L. , Lillemoe Tamera J
Published: May 2019

e12512

Background: HER2 status dictates treatment decisions in breast cancer making the precision and accuracy of laboratory testing essential. While most HER2 testing is straightforward using ASCO-CAP interpretation guidelines, 5% of cases fall into the less common categories (groups 2-4) and can present unusual diagnostic dilemmas. 6 high volume HER2 FISH laboratories evaluated 10 challenging HER2 cases. The results highlight the challenges and potential for variability in interpreting rare cases with unusual results. Methods: Ten diagnostically challenging HER2 FISH cases were selected from our breast cancer archives (41 months/3863 cases). Unstained slides were evaluated by 6 high volume laboratories. Laboratories performed HER2 FISH testing (along with HER2 IHC as needed) and rendered an interpretation. Participants discussed results during a conference call. Cases included the following situations: low-level amplification (ratio ≥ 2.0, mean HER2 signals/cell between 4.0-5.9), HER2 mean copy number or ratio near a clinically actionable threshold, complex heterogeneity or clones, and a technical challenge (signal clustering). Results: All laboratories elected to perform HER2 IHC in conjunction with FISH in all cases. Only 3/10 cases resulted in 100% agreement between the 6 institutions, all of which were in the category addressing complex heterogeneity. During the study, we identified a problematic subset (low amplified FISH cases) which may have discordant (negative) IHC results. Another problematic scenario is the finding of a small, highly amplified HER2 clone. Lastly, we identified cases with high cell to cell variability, and we saw discordant values resulting in disparate overall HER2 interpretations. Conclusions: Oncologists and pathologists should be aware of these challenges and the potential for variability in interpretation of these rare case scenarios. Evaluation for concordance between IHC and FISH results, correlation with other clinico-pathologic features and additional steps to ensure the accuracy of test results can help resolve unusual results, but grey zones may still remain and should be discussed when making clinical decisions based on HER2 test results.
Efficacy of abemaciclib (abema) after palbociclib (palbo) in patients (pts) with metastatic breast cancer (MBC).
Authors: Mariotti Veronica , Khong Hung T. , Soliman Hatem Hussein , Costa Ricardo L , Fisher Shanel , Boulware David , Han Hyo S.
Published: May 2019

e12521

Background: CDK 4/6 inhibitors (Abema and Palbo) have shown efficacy in patients with HR+/HER2- MBC. Abema is distinct from other CDK 4/6 inhibitors and was approved after the approval of Palbo. There is limited data on sequential use or cross resistance. The aim of this study was to analyze the response to Abema based therapy in MBC pts with prior exposure to Palbo. Methods: We queried our EMR database for pts who received Abema from 9/2017-9/2018 after having received prior Palbo. Under IRB approved protocol we retrospectively collected demographics, tumor characteristics, disease status, toxicities and survival. Results: 23 female pts were identified. Four patients discontinued Palbo due to toxicities: two of them remained on Abema for 8 months and the other 2 discontinued Abema due to toxicities. The remaining 19 pts (median age 57 years, range 39-76) received a mean of 5.6 prior therapies (range (1-11) including Palbo in combination with endocrine therapy (fulvestrant 9 in pts and Aromatase inhibitors (AI) in 10 pts) at the time of Abema based therapy. 73.6% had visceral involvement including brain metastasis in 26%. The median progression-free survival (PFS) of Palbo in combination with endocrine therapy was 8 months (range 2.3-14.3). Abema was given in combination with endocrine therapy in 15 pts (9 pts fulvestrant and 6 pts AI) and 4 pts received it as a single agent. The median PFS of Abema based therapy was 7.0 months (range 1.8-12.1). Four pts (21%) had a longer PFS on Abema compared to prior Palbo PFS (table). Abema was discontinued due to toxicities in 15.7%. No partial or complete response was observed but 33% had stable disease. Conclusions: Abema showed response in a significant number of pts previously exposed to Palbo and heavily treated with multiple lines of chemotherapy for widespread metastatic disease. Prospective studies are warranted to better assess the response to Abema after exposure to CDK4/6 inhibitors. [Table: see text]
Fulvestrant versus everolimus plus exemestane for patients with metastatic breast cancer resistant to aromatase inhibitors: Clinical experience from real world.
Authors: Li Yi , Xie Yizhao , Zhao Yannan , Hu Xi-Chun , Zhang Jian , Chen Shen , Gong Chengcheng , Zhang Sheng , Wang Leiping , Wang Biyun
Published: May 2019

e12522

Background: To present treatment patterns and the outcome of pure endocrine therapy fulvestrant (FUL) versus Exemestane (EXE)and target therapy everolimus (EVE) combination among hormone receptor-positive (HR+)/human epidermal growth factor 2 (HER2)-negative metastatic breast cancer (MBC) after progression on aromatase inhibitor (AI) in the real-life setting. Methods: Patients with HR+/HER2- MBC after AI who received FUL or EVE-EXE between June 2013 and June 2016 were identified from electronic database. Outcome measures included progression free survival (PFS), overall survival (OS) and safety profile. Propensity score matching (PSM) was applied to minimize potential confounders. Results: Among the 168 patients included, 124 patients received FUL and 44 patients treated with EVE-EXE. Patients that received EVE-EXE were significantly younger, more likely to have visceral, liver, multiple sites of metastases and had received more prior chemotherapy than FUL group. There was no significant difference in PFS after adjusted for propensity score between two groups (HR,1.173; 95%CI, 0.797-1.727; p = 0.419). In subgroup analysis, treatment effects were consistent across predefined subgroups except for the subgroup of multiple metastatic sites which the median PFS was significantly longer in EVE-EXE group than in FUL group (6.1vs3.2months, respectively; HR = 0.508;95%CI,0.299-0.862; p = 0.012). The toxicity of FUL regimen was more manageable. More patients discontinued the treatment due to intolerable toxicity in EVE-EXE group than FUL group. Conclusions: We observed substantial changes in treatment patterns in patients received EVE-EXE and FUL. Treatment outcomes were comparable between two schedules after adjusted for confounding factors, while FUL has been better tolerated. Clinical trial information: NCT03695341.