bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparing the American Joint Committee on Cancer (AJCC) breast cancer staging eighth versus seventh edition and breast cancer biology in large databases.
Authors: Young Jessica S. , Takabe Kazuaki , Asaoka Mariko , Edge Stephen B.
Published: May 2019

e12077

Background: The AJCC 8th edition Breast Cancer Staging system includes biomarkers (estrogen receptor, progesterone receptor, Her2), grade and a genomic assay, to better reflect outcomes, compared to the 7th edition. We used databases with anatomic, biomarker and genomic information to determine if the 8th edition reflects biology better than the 7th edition. Methods: 696 breast cancer patients in The Cancer Genome Atlas (TCGA) and Text Information Extraction System (TIES) were staged both with 7th and 8th edition. Results: From the 7th to 8th editions, 66% of stage 2 patients migrated (64% to stage 1, 1.5% to stage 3). 36% of stage 3 patients migrated (22% to stage 1, 13% to stage 2). We analyzed the differences between stage 1 and 2 in both editions, and the overall survival hazard ratio calculated using Cox regression was greater in the 8th edition than the 7th (HR=1.50, HR=1.22 respectively). We performed Gene Set Enrichment Analysis (GSEA) and found that gene sets related to cell cycle and cell proliferation (E2F targets, G2M checkpoint) were significantly enriched in higher stage in 8th edition but not 7th. Mutant Allele Tumor Heterogeneity (MATH) and Homologous Recombination Defects (HRD) were elevated in higher stages in the 8th edition (p=0.022, p<0.001 respectively), but not the 7th. Immune cells (CD8 Tcell, NK cell) as well as CYT (Immune cytolytic activity score), and Tcell exhaustion markers (PD1, PDL1) were all found to be elevated in higher stage in 8th edition, but not 7th. Conclusions: The 8th edition AJCC Breast Cancer Staging system categorizes cancers by aggressive biology better than the 7th edition. We also found that higher stage tumors trigger an enhanced immune response, but are unable to overcome the aggressive cancer biology.
Impact of discordance in estrogen receptor, progesterone receptor, and Ki-67 after neoadjuvant chemotherapy in breast cancer on survival.
Authors: Ding Yu-Qin , Ding Xiaowen , Ding Kaijing , Cao Wen-Ming , Zou Dehong , Yang Hongjian , Zhang Fanrong , He Xiangming , Mo Wenju , Qin Chengdong , Zheng Yurong
Published: May 2019

e12079

Background: The expression status of estrogen receptor (ER), progesterone receptor (PR), and Ki-67 antigen (Ki-67) divides breast cancer into different subtypes. Changes in these biomarkers during treatment alter the overall treatment decision and affect prognosis. To date, few studies have investigated the effects of changes in these biomarkers throughout neoadjuvant chemotherapy (NAC) on patient prognosis. Methods: A total of 482 patients who received NAC were enrolled. The expression of ER, PR and Ki-67 between pre- and posttherapy specimens was studied by immunohistochemical methods. Physical and imaging examinations based on the Response Evaluation Criteria in Solid Tumors guidelines version 1.1 were utilized to assess the treatment response. The impact of these biomarkers status changes on survival was then tested for statistical significance using a Cox proportional hazards regression model for univariate and multivariate analyses. Results: The rate of discordance for ER, PR and Ki-67 was 10.37%, 17.01% and 77.39%, respectively, in which the PR positive-to-negative conversion was the most common change. A statistically significant differential overall survival (OS) related to biomarkers status throughout NAC (P<.01) was noted. The risk of death in patients with a PR positive-to-negative conversion was 6.58 times greater than that of stable PR expression (P=.002). The risk of disease recurrence in patients with increased Ki-67 expression was 1.91 times greater than that of stable Ki-67 expression (P=.02). Furthermore, we validated both of them as independent predictors of poor prognosis. Conclusions: We concluded that inconsistent expression of biomarkers can significantly affect patient prognosis. We suggest that biomarkers investigations during NAC may potentially improve patient management and survival. Survival result that compared with concordance and discondance in ER, PR and Ki-67. (N=482).*P<.05. [Table: see text]
Outcomes of Hispanic/Latino women with triple-negative breast cancer who achieve a complete pathologic response after neoadjuvant chemotherapy.
Authors: Philipovskiy Alexander , Corral Javier Chavez , Heydarian Rosalinda , Dwivedi Alok Kumar , Xiaoming Gong , Leelani Sajid , Gaur Sumit
Published: May 2019

e12081

Background: The aim of this study was to determine the efficacy of neoadjuvant chemotherapy (NACT) versus adjuvant chemotherapy (ACT) in Hispanic/Latino (H/L) women with triple negative breast cancer (TNBC). Methods: We retrospectively reviewed 104 records of female patients diagnosed with TNBC, stages I–III, treated at Texas Tech Breast Care Center from 2006 to 2016. Pathological complete response (pCR), overall survival (OS) and progression-free survival (PFS) were estimated and compared between two treatment groups. Kaplan Meier survival curve and Cox proportional hazards regression analyses were conducted to determine unadjusted and adjusted effects of NACT compared to ACT. Results: Of 104 TNBC patients with median duration of follow up of 6 (range 2-11) years, 30 (29%) received NACT and 74 (71%) received ACT. Women undergoing NACT were mostly younger, with a mean age of 50.8 (range 40-67) years, compared with those in the ACT group, mean age of 53 (range 32-80) years. Additionally, women in the NACT group had more advanced cancer, stage III (61%) and stage II (33%), in contrast to the ACT group, who had stage III (23%) and stage II (55%). Of 30 patients received NACT,twelve (40%) had pCR. The (median 6 years/range 2-11 years Women who achieved pCR had better PFS and OS compared with patients who received ACT. On the other hand, women with residual cancer after NACT had worse survival outcomes compared with women who received ACT (Hazards Ratio-HR = 0.1, p = 0.001). Conclusions: In our study, we observed that the patients in the NACT group with residual cancer had statistically significantly worse survival outcomes compared with ACT group. Patients who received NACT and had pCR had no relapse over the observation period. Our study suggests that there is a need of a prospective study to better understand the biology of TNBC among H/L women in order to individualized NACT to population of patients with “chemosensitive” subtype of TNBC.
Quality of life after preoperative radio-/chemotherapy in locally advanced breast cancer patients.
Authors: Matuschek Christiane , Nestle-Kraemling Carolin , Wollandt Sylvia , Speer Vanessa , Boelke Edwin , Roth Stephan L. , Audretsch Werner , Tamaskovics Balint , Lammering Guido , DjiepmoNjanang Freddy Joel , Budach Wilfried , Haussmann Jan
Published: May 2019

e12083

Background: Preoperative radiotherapy and chemoradiotherapy (PRT/PCRT) represents an increasingly used clinical strategy in different tumor sites. However, concerns regarding a possible unfavorable influence on the clinical outcome still exist. The aim of the current study was to examine the long-term global health status in our series of LABC patients treated with PRT/PCRT followed by breast-conserving surgery (BCS) or mastectomy (ME). Methods: Of the 315 patients treated with PRT/PCRT in the years 1991 and 1999, 203 patients were still alive at long-term follow up of mean 17.7 years (range 14-21). Thirty-seven patients were lost to follow up and 58 patients refused to be contacted, which resulted in 107 patients (64 patients after BCS and 43 after mastectomy) being available and willing to undergo further clinical assessment. PRT/PCRT consisted of external beam radiation therapy (EBRT) with 50 Gy (5 × 2 Gy/week) to the breast and the supra-/ infraclavicular lymph nodes combined with a consecutive electron boost or (in case of BCS) a 10-Gy interstitial brachytherapy boost with Ir-192 prior to EBRT. Overall, chemotherapy was administered either prior to RT or concomitantly in the majority of patients. Quality of life (QoL) was assessed by EORTC QLQ-C30 questionnaires for overall QoL and EORTC QLQ-BR23 for breast-specific QoL. Results are reported using functional scales (body image, sexual functioning, sexual enjoyment, and future perspective) and symptom-related items (systemic therapy side effects, breast symptoms, arm symptoms, and upset by hair loss). The results were compared to a published reference cohort of n=2028 healthy adults (16-92 years), including n=1139 women (age 16-92 years). EORTC QLQ-C30 functional scales were also analyzed between different subgroups including an age-matched analysis with a two sided paired t-test. Results: In comparison with this healthy control group of 1139 women, we did not detect any significant differences for the functional scales measured by physical function, emotional well-being, cognitive, and social function as well as the symptom scales: fatigue, nausea, vomiting, pain, diarrhea and financial difficulties for both groups. However, significant inferior scores were found in the present study group regarding obstipation (p=0.013), loss of appetite (0.038), sleeping disorder (p=0.01) and dyspnoe (p=0.01). Conclusions: Taken together, retrospective as well as prospective data underline the feasibility of preoperative radiotherapy in breast cancer.
Nomogram for predicting axillary lymph node pathological complete response in node-positive breast cancer patients after neoadjuvant chemotherapy.
Authors: Wang Wenyan , Wang Xin , Wang Xiang , Liu Jiaqi , Zhang Pin
Published: May 2019

e12090

Background: Pathological complete response (pCR) of axillary lymph nodes (ALNs) is frequently achieved in patients with clinically node-positive breast cancer after neoadjuvant chemotherapy (NAC), and ALN status is an important prognostic factor for breast cancer patients. Our goal is to develop a new predictive clinical model to assess the axillary lymph node pCR rate after NAC. Methods: A retrospective series of 547 patients who had biopsy-proven positive ALNs at diagnosis and undergoing axillary lymph node dissection from 2007 to 2014 in National Cancer Center/Cancer Hospital of Chinese Academy of Medical Sciences. We analyzed the clinicopathologic features and developed a nomogram to predict the probability of ALN pCR. Univariate assessment was performed using a logistic regression model. A multivariate logistic regression stepwise model was used to generate a nomogram to predict ALN pCR in node positive patients Variables with P < 0.05 on multivariable analysis were included in the nomogram. The adjusted area under the receiver operating characteristic curve (AUC) was calculated to quantify the ability to rank patients by risk. Internal validation was estimated using 50-50 hold out validation method. Nomogram was validated externally with the prospective cohort of 167 patients from 2016 to 2018. Results: In retrospective study, there were 172 (31.4%) patients achieved axillary pCR after NAC. Multivariate analysis indicated that clinical nodal (N) stage, hormone receptor (HR) status and clinical response of primary tumor after NAC were significant independent predictors for axillary pCR ( P< 0.05). The NAC nomogram was based on these three variables. In the internal validation of performance, the AUCs for the training and test sets were 0.719 and 0.753, respectively. The nomogram was validated in an external cohort with an AUC of 0.734. Conclusions: We developed a nomogram to predict the likelihood of axillary pCR in node positive breast cancer patients after NAC. The predictive model performed well in prospective external validation. This practical tool could provide information to surgeons regarding whether to perform additional ALND after NAC.
Pathological complete response rate (pCR) in thirty-three women with triple-negative breast cancer (TNBC) treated with a neoadjuvant carboplatin-based regimen.
Authors: Chopra Avani , Wojtowicz Mark , Manikowski Jesse , Maddineni Bhumika , Kirchner Lester , Panikkar Rajiv Prasanna , Vogel Victor G.
Published: May 2019

e12099

Background: The purpose of this retrospective case series was to assess pCR rate, progression-free survival and prognostic factors in TNBC. Methods: We reviewed medical records for 33 consecutive female patients with TNBC (41% node+) treated between July 2015 and April 2018 with neoadjuvant paclitaxel 80 mg/m2 IV weekly plus concurrent carboplatin (AUC 4) every 3 weeks for a total of 12 weeks followed by dose-dense doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 every 2 weeks for a total of 4 cycles. Surgical pathology was studied to determine the presence or absence of residual disease at surgery. Age at treatment, tumor stage, subsequent hospitalizations, and genetic testing were recorded. Patients with residual disease were treated with adjuvant capecitabine 1500 mg PO BID, one week on, one week off, for 6 monthly cycles ± radiation; some patients with a complete pathological response also received postoperative radiation. Results: Among 33 patients, 17 patients had pCR (52%, median age 58 yrs), 10 had a partial response and 6 had no response or progression (median age 63.5). After surgery 24 patients received radiation therapy (XRT). There were 6 hospitalizations, 3 that were treatment related, 2 for neutropenic fever and one for renal failure induced by carboplatin; all 3 resulted in chemotherapy dose reductions; all 3 had pCR. 3 progressions/recurrences were recorded: 2 after treatment and 1 progression during treatment. Two deaths occurred, 1 secondary to progressive disease. Median progression free survival time was 8.5 months (range 0.1 to 24.0 mos). Median time since diagnosis is 16.7 months (range 8.1 to 37.6 mos). There was no significant difference in the median age of patients who had a pCR compared with patients with residual disease. Conclusions: We observed pCR in patients with TNBC treated with a pre-operative carboplatin-containing regimen (superior to historical pCR rates in patients receiving taxanes and anthracyclines only). Although there are insufficient data to demonstrate increased overall survival, we show an improvement in prognosis with a carboplatin-containing regimen for TNBC.
Sequence of anthracyclines and taxanes in the neoadjuvant chemotherapy of HER2-negative breast cancer: Experience of a Brazilian oncological center.
Authors: Preto Daniel D’Almeida , Sanches André Octavio Nicolau , Barroso Alison Wagner Azevedo , Carbinatto Alessandra Caroline Moretto , Veneziani Ana Lima , Kons Georgia , BUDIB MARIA , Safro Maria Augusta Zaffari , Pinto Gustavo Sanches Faria , Bello Secco Alan Felipe , Zorzetto Marina Moreira Costa , Lacerda Domicio , Paiva Carlos Eduardo , Souza Cristiano de Pádua
Published: May 2019

e12105

Background: The best sequence of anthracyclines and taxanes in the neoadjuvant chemotherapy of HER2-negative breast cancer is still unknown. The aims of this study were to assess the impact of the sequence order in the pathological complete response (pCR) rate, and in the disease free survival (DFS) and overall survival (OS). Methods: We retrospectively reviewed 235 HER2-negative breast cancer women treated with neoadjuvant chemotherapy from 2003 to 2011 at our cancer center. The patients were pooled in two groups: anthracycline-based followed by taxanes (AC-T) and the reverse sequence (T-AC). The chi-square test was performed to verify the homogeneity between the groups and to compare pCR rate among the treatment groups. Cumulative survival probabilities were calculated using the Kaplan-Meier method. Differences between survivals were tested using the log-rank test. Results: The AC-T (n = 161) and T-AC (n = 74) groups were balanced for age, staging, receptor profile and histologic grade. The follow-up was at least five years for each patient. The median age was 50.1 years. Most patients (97%) had stage III tumors and 72 (30%) had triple negative disease. pCR rate was higher in triple negative compared with luminal cases (16.3 vs. 7.3%; p = 0.049). Treatment sequence did not influence the occurrence of pCR (10.5 vs. 8.5%; p = 0.8) or median survival times (DFS: 87.9 vs. 64.1, p = 0.85; OS: 91.1 vs. 71.6 months, p = 0.15), in the AC-T and T-AC groups, respectively. Conclusions: The sequence of neoadjuvant taxane-anthracycline-based chemotherapy regimen in daily practice did not show difference in the evaluated clinical outcomes. The retrospective design and the low number of patients may limit the power of the study to detect statistically significant differences. Phase III trials should be stimulated in this context. [Table: see text]
Genomic profiling of residual tumor after neoadjuvant chemotherapy for breast cancer.
Authors: Hattori Masaya , Rajagopal Padma Sheila , Sveen Lise , Khramtsova Galina , Yoshimatsu Toshio , Beaubier Nike , Barber Mathew , Abboushi Taylor , Fang Liu , Zheng Yonglan , White Kevin , Huo Dezheng , Olopade Olufunmilayo I.
Published: May 2019

e12106

Background: Patients who have residual disease after neoadjuvant chemotherapy (NAC) have a higher risk of metastatic recurrence. Residual disease likely includes therapy-resistant subclones of breast cancer cells, which untreated lead to metastases. The aim of this study was to identify additional adjuvant therapies based on genomic profiling of residual disease post NAC therapy. Methods: Next-generation sequencing of tumor samples from patients (pts) with residual invasive breast cancer after NAC was performed using a Tempus xT, 595 gene panel on matched tumor-normal samples. All samples were obtained from the University of Chicago Breast Cancer tissue bank. Clinical information was obtained from electronic health records and the cancer registry. Results: Of 23 evaluable patients enriched for African Americans, 65% were HER2-positive, 22% TNBC and 13% ER+/HER2-. At a median follow up of 2.9 years, 8 pts (35%) have recurred and 8 were dead. We identified 119 clinically actionable variants in 22 tumors, and the most commonly altered genes were TP53 (18 alterations, 74% of cases), ERBB2 (8, 26%), PIK3CA (7, 30%), CDK4 (4, 17%), MCL1 (4, 17%), and MDM2 (4, 17%). Of significance, 67% of HER2-positive pts had no detectable ERBB2 copy number gain in the residual tumor. 78% of pts had at least one potential druggable target according to CIViC and/or OncoKB: 19 variants in HER2-positive, 8 in HER2-negative. The mean estimated tumor mutation burden (TMB) was 4.34 m/MB (range: 0-26.7), and 13% were considered TMB-high ( > 9 m/MB). No patients had high-microsatellite instability type residual tumors. Conclusions: Many potentially targetable alterations reside in residual disease of both HER2-positive and -negative breast cancer after NAC. Post-NAC treatment targeting these harbored alterations and post-NAC immunotherapy could have impact on the prognosis of breast cancer patients who have residual disease after NAC. [Table: see text]
FDG uptake to reflect NLR and expression levels of TILs and PD-L1 in patients with primary breast cancer: Tumor inflammation and immunity.
Authors: Fujii Takaaki , Hirakata Tomoko , Kurozumi Sasagu , Katayama Ayaka , Yanai Keiko , Tokuda Naoko , Nakazawa Yuko , Obayashi Sayaka , Yajima Reina
Published: May 2019

e12110

Background: 18F-Fluorodeoxyglucose-positron emission tomography(FDG-PET) is used to evaluate the glucose metabolic rates of cancers. Several studies have reported that high FDG uptake is predictive of poor prognosis and aggressive features in patients with breast cancer (BC).However, FDG-uptake is influenced by many factors, including inflammation and immunity. In this study, we investigated the relationship between FDG uptake and inflammation and immunological factors, including Neutrophil/lymphocyte ratio (NLR) and degrees of Tumor-infiltrating lymphocytes (TILs), programmed cell death ligand 1 (PD-L1). Methods: We retrospectively investigated the cases of 96 consecutive invasive ductal carcinoma patients who underwent surgery andunderwent FDG-PET preoperatively. The evaluation of PET was determined using standardized uptake value max (SUVmax). We divided the cases into two groups based on the value of SUVmax; low (<2.5) and high (≥2.5) and the value of NRL; low (<1.7) and high (≥1.7). Grade of stromal-TILs was immunohistochemically (IHC) evaluated using the criteria of the International Working Group for TILs in BC: low (10-20%), intermediate (20-40%) and high (50-90%). PD-L1 positive were evaluated by IHC. The relationships between SUVmax and NLR and expressions of TILs, PD-L1 were investigated. Results: Among the 96 patients, 52 (54.2%) had high SUVmax in the primary tumor. The multivariate analysis revealed that large tumor size (p<0.001), high nuclear grade (p=0.016), high NLR (p=0.037), and PD-L1 (p=0.003) were significantly associated with high SUVmax in the primary tumor.There were associations between SUVmax and NLR(r=0.319, p<0.001) and TILs (r=0.298, p<0.001). Among the 96 cases with, there was 4 cases (4.2%) had recurrent disease, while 3 cases among the 4 cases with recurrent disease was low TILs and the one case was high TILs and PD-L1 psitive. disease recurrence.It is interesting to note that the group with high SUVmax and low NLR had no recurrent disease. Conclusions: The present study demonstrated thatthe finding of preoperative FDG uptake in BC may be reflective of poor prognosis and high NLR and the grades of high TILs and expression of PD-L1in the tumor. From these findings, preoperative high FDG uptake in BC may be reflective of tumor microenvironmentincluding inflammatory or immunological features in addition to aggressive features among patients with BC.
Circulating cell-free DNA (ctDNA) assessments before, during, and after neoadjuvant therapy (NAC) in nonmetastatic inflammatory breast cancer (IBC).
Authors: Hall Carolyn S. , Meas Salyna , Sarli Vanessa Nicole , Lucci Anthony
Published: May 2019

e12113

Background: : IBC is a rare and aggressive subtype of breast cancer. A significant number of IBC patients who achieve pathologic complete response (no residual tumor in breast and axillary nodes, pCR) relapse after NAC. We hypothesized that circulating cell-free DNA (ctDNA) identified in blood before, during, and after NAC would identify novel ctDNA targets. Methods: Plasma ctDNA was extracted from 43 non-metastatic IBC patients (IRB: LAB04-0698) pre, mid, and post-NAC. The Oncomine Pan Cancer ctDNA Assay (ThermoFisher) was used for library preparation, and high throughput next generation sequencing was performed on a GeneStudio S5XL System (ThermoFisher), following manufacturer’s directions. ThermoFisher Ion Reporter 5.10 Software was used to analyze single nucleotide variants (SNVs), and copy number variants (CNVs). Results: Seventeen patients had pre-NAC ctDNA assessments; 7/17 (41%) had PIK3CA SNVs; 5/7 also had MYC or FGFR2 CNVs. Five of 17 (29%) had TP53 SNVs; 2/5 also had FGFR2 CNVs. Ten patients had mid-NAC ctDNA assessments; 9/10 (90%) had PIK3CA SNVs; 5/9 also had FGFR2 CNVs, 2/9 had FGFR2 and FGFR3 CNVs, 2/9 also had TP53 SNVs, 1/9 had FGFR2 and ERB2 CNVs. Thirty-one patients had post-NAC ctDNA assessments; 5/31 (16%) had PIK3CA SNVs; 2/5 had FGFR2 CNVs, 1/5 also had a TP53 mutation and an FGFR2 CNV, 1/5 had FGFR2 CNV, and FGFR3 CNV. Six of 31 (19%) had TP53 SNVs, 1/6 had CCND1 CNVs, no CNVs were detected in 6 patients with TP53 SNVs. Six of 31 (19%) had MAP2K1 SNVs. Three of 31 (10%) had MET SNVs; 1/3 had CCND3 CNVs, no CNVs were detected in 2 patients with MET SNVs. No SNVs or CNVs were detected in 10/31 (32%) of patients post NAC. Conclusions: ctDNA assessments before, during, and after NAC identified novel targets that could be tested in future adjuvant therapies trials in IBC patients who remain at high risk for relapse.
Efficacy and safety of intensified platinum-based neoadjuvant chemotherapy in locally advanced triple-negative breast cancer: Preliminary results of non-randomized phase II study.
Authors: Glazkova Elena , Frolova Mona , Stenina Marina , Ignatova Ekaterina , Rumyantsev Alexey , Petrovsky Alexander , Krohina Olga , Tjulandin Sergei
Published: May 2019

e12116

Background: patients with locally-advanced triple negative breast cancer (TNBC) have dismal prognosis with current standard of care therapy. Pathologic complete response (pCR) is the most important prognostic factor for long-term survival of these patients. Methods: this was non-randomized prospective single-center phase II study. Key inclusion criteria were histologically verified locally advanced TNBC, non-eligibility for primary surgical treatment (ie, TNM stage Т2-4N 2-3M0) and no evidence of metastatic disease. Patients were treated with 8 cycles of neoadjuvant doxorubicine, paclitaxel and cisplatin chemotherapy (ATP; doxorubicine 40 mg/m2 day 1, paclitaxel 160 mg/m2 day 1 and cisplatin 50 mg/m2 day 1 every two weeks) with G-CSF support (filgrastim 5 mcg/kg day 2-6). After 8 cycles of chemotherapy patients were referred for surgical treatment; adjuvant radiation therapy was prescribed to all patients. Primary end point was pCR assessed in modified intention-to-treat population (ie, in patients who underwent surgical treatment). Key secondary endpoints were disease-free survival (DFS) and pCR rate according to BRCA status. Results: we enrolled 80 patients, 79 (98.7%) of them underwent surgical treatment and were included in the analysis. Median age was 46 years (25-68), 22 (27.1%) patients had BRCA1 mutations, 5382insC was the most common mutation (17 [77.2%] of patients); 1 (1.2%) patient had CHEK2 mutation. pCR was achieved in 51 (64.5%) patients. In with BRCA1-mutation carriers pCR rate was 61.9%, in patients with 5382insC – 81.2%. 2-year DFS was 77.3%; 2-year overall survival was 91.0% . Most common grade 3-4 adverse events were anemia (29.3%), neutropenia (17.8%), neuropathy (4.9%), stomatitis (3.7%) and thrombocytopenia (1.8%). Conclusions: the ATP regimen was effective in treatment of locally-advanced TNBC, especially in patients with founder 5382insC BRCA1 mutation for Slavic population and deserves further investigation.
Survival and recurrence of breast cancer patients with pathologic complete response after neoadjuvant chemotherapy.
Authors: Lee Young Joo , Ahn Sei-Hyun , Sohn Byung Ho , Lee jong Won , Chung Il Yong , Ko Beom Seok , Kim Hee Jeong , Kim Jisun , Lee Sae Byul
Published: May 2019

e12121

Background: Patients with Pathologic complete response after neoadjuvant chemotherapy is known to have a good prognosis. However, there is a difference depending on how the complete remission is defined. Methods: We analyzed basic characteristics and outcomes of 295 patients who had pathologic complete response defined as ypT0 and ypTis after neoadjuvant chemotherapy for breast cancer at Asan Medical Center in Seoul, Korea. Results: Median follow up period was 66.5 month(6~128 month). Overall survival was 94% at 5-year and 10-year. No difference was shown in preoperative age, grade, HR/HER2 status, Ki-67 level. Clinical stage III showed worst outcome(85.8%). Survival rate between ypT0N0 (98.8%) and ypTis (89.1%, p=0.00) and between ypT0/TisN residual (85.7%, p=0.00) was shown, but no statistical difference between ypTis and ypT0/Tis with residual nodes(p=0.539). Disease free survival also showed no statistical significance between age, HR/Her2 status. But patients with low Ki-67 level(0~20%)(68.2%) at diagnosis had worse DFS compared to high Ki-67 level(>20%)(87.5%)(P=0.013). No difference between intrinsic subtypes was shown. Patients with residual nodal disease had worse DFS(66.1%) than ypN0(89.1%)(p=0.00). DFS of ypT0N0 was 92.7% and ypTisN0(75.5%), ypT0/Tis with residual metastatic nodes(71.4%). There was no significant difference in type of chemotherapy regimen. Conclusions: Overall survival and disease free survival was different in ypT0N0 with ypTis and residual nodal disease. Good prognosis of pathologic complete response should be limited to cases in which the cancer has completely disappeared.
Effect of additional administration of pertuzumab for the post-treatment in patients with HER2-positive locally advanced/metastatic breast cancer who were previously treated with pertuzumab.
Authors: Kubo Shinichiro
Published: May 2019

e12500

Background: Currently, there are no data related to re-administering trastuzumab (T) + pertuzumab (P) beyond the second-line therapy to patients with human epidermal growth factor receptor 2-positive advanced/metastatic breast cancer (HER2-MBC) who had previously received P. The present study targeted patients with HER2-MBC who were previously treated with P and aimed to evaluate the efficacy and safety of additional administration (top-up intervention) of P post-disease progression (PD) after standard treatment with T plus chemotherapy vinorerbine(VNR) or eribulin (ERI). Methods: SBP-08 was a multicenter, collaborative, single-arm phase II study of HER2-MBC patients who had previously received P. After standard treatment with T and chemotherapy, P was additionally administered (top-up intervention) post-PD. Results: Eleven HER2-MBC patients, recruited between June 2016 and June 2018, who had previously received P participated in this study. Their mean age was 63.5 years, and 45% were estrogen receptor (ER)-negative, while 55% were ER-positive. The mean chemotherapy history was 3.6 regimens, with a median of four regimens. Previous treatment regimens with P had been effective in all patients. All patients had organ metastasis and treatment histories with TDM-1. Initially, during the two-year case collection period, registration of 30 patients was planned. However, the study was terminated because the interim analysis did not demonstrative effectiveness, and it was decided that there were no potential benefits to the patients. The overall response rate (ORR) of the standard treatment was 0%, stable disease (SD) was 36%, PD was 55%, and the clinical benefit rate (CBR) was 0%. The following combination anticancer agents were used: VNR (10 patients) and ERI (one patient). The intervention treatment (top-up with P) achieved the following: ORR 0%, SD 22%, PD 78%, and CBR 0%. PFS for the standard treatment was 1.6 months, whereas PFS for the intervention treatment was 1.3 months. In the standard treatment, febrile neutropenia was observed in two patients. No increases in adverse events were observed with the intervention treatment. Conclusions: No clinical benefit was demonstrated with the intervention treatment in the present study. Top-up with P after standard treatment with T and chemotherapy post-PD was deemed ineffective. Clinical trial information: UMIN000020837.
Monitoring treatment efficacy and resistance in breast cancer patients via circulating tumor DNA genomic profiling.
Authors: Jia Wang Xiao , Chen Zhan-Hong , Sun Tian , Yang Zi Yan , Zheng Yabing , Yu Ruoying , Wu Xue , Yan Junrong , Shao Yang , Shao Xiying , Huang Jian , Wenming Cao
Published: May 2019

e12502

Background: Circulating tumor DNA (ctDNA) from liquid biopsy provides a valuable assessment of invasive breast cancer (BC). We evaluated the utility of ctDNA to reflect the efficacy of HER2-targeted trastuzumab in treating HER2+ BC patients, as well as chemotherapy in treating HER2- BC patients, to monitor trastuzumab and chemotherapy resistance mechanisms. Methods: Targeted next-generation sequencing (NGS) of 416 cancer-relevant genes was performed in 41 plasma biopsy samples from 19 HER2+ and 12 HER2- BC patients in a retrospective study. We compared ctDNA somatic mutations and germline mutations for analyzing acquired and innate resistance, respectively. Results: ERBB2 somatic copy number of HER2+ BC patients who developed progressed diseases to HER2-target therapy was significantly higher than those benefited from HER2-target therapy. HER2+ BC patients who developed acquired resistance to trastuzumab showed frequent genomic alterations on ERBB2, TP53, EGFR, NF1 and SETD2 genes. Specifically, in longitudinal analyses, somatic mutations found in the original breast tumor can be detected in the liver metastasis and plasma ctDNA with increased allele frequencies. Newly emerged deleterious mutations occurred when the patient was benefiting from trastuzumab, predicting the poor prognosis. From these newly emerged somatic mutations, EBBB2L869R was further investigated in vitro and contributed to trastuzumab resistance. In the HER2- BC patients with chemotherapy resistance, frequently genetic alterations on TP53, PIK3CA and DNA damage repair genes were observed in ctDNA mutation profiling. Conclusions: liquid biopsy ctDNA, particularly longitudinal analyses, provides insights into targeted therapy efficacy and gene alterations underlying trastuzumab resistance and chemotherapy resistance in HER2+ and HER2- BC patients, respectively.
Changing trends in HER-2 neu positive breast cancers in women: A study by a medical student and his preceptor.
Authors: Monga Aaron , Prasad Chaya , Prasad Rama , Alcantara Rita
Published: May 2019

e12509

Background: Breast cancer affects 3.5 million women in the United States with 155, 000 women living with metastatic breast cancer in the US with 40,290 deaths every year. In particular, HER-2 NEU positive lesions are aggressively malignant, with increased recurrence and decreased survival but good response to Herceptin. This study reviews trends of breast cancers and looks in depth into prognostic indicators, in HER-2 NEU positive breast cancers. Methods: Anonymized medical data including demographics and tumor characteristics from San Antonio Regional Hospital’s (SARH) tumor registry database were collected from 2015-2017. Inclusion criteria included female patients with a diagnosis of invasive breast cancers. Data was stratified according to age at diagnosis, race of the patient, histologic grade, size of the tumor, lymph node status, HER-2 NEU status and stage (pathologic and clinical). Results: From 2015 to 2017 we identified 371 patients with invasive breast cancers. The percentages of HER-2 NEU positive patients in these years was 15.7%, 16.0%, and 9.4% in 2015, 2016 and 2017 respectively. This represented a 6.6% drop in HER-2 NEU positive patients from 2016 to 2017. We then looked at all HER-2 NEU positive breast cancers. In 2017, 71% of patients with HER-2 NEU positive tumors presented with a low pathologic size compared to 36% in 2016 and 44% in 2015, and 29% presented with low histologic grade compared to 14% in 2016 and 12% in 2015, and 0% of patients presented with lymph node metastases compared to 18% in 2016 and 20% in 2015. Overall 100% of patients with HER-2 NEU positive tumors presented at a low stage compared to 73% in 2016 and 52% in 2015. Conclusions: Our data shows a decrease in HER-2 NEU positive cancers from 2015 to 2017. It is important to note that these HER-2 NEU lesions were associated with, smaller pathologic size, lower histologic grade, lower incidence of lymph node involvement and lower clinical stage. The identification of this subset of low grade, low stage HER-2 NEU positive tumors may be attributed to newer imaging modalities such as digital tomosynthesis and more aggressive preventive screening measures. These sensitive screening techniques may ensure a good clinical outcome.
Selected reaction monitoring mass spectrometry (SRM-MS) evaluation of HER2 equivocal breast cancer.
Authors: Edenfield William Jeffery , Merchant Krupa , Martin Julie C. , Drusbosky Leylah , Elliott Mary Helen , Reddy Sandeep K. , Szeto Christopher , Cecchi Fabiola , Schammel Christine , Schammel David P , Grinstead Rhett M , Chung Ki Y.
Published: May 2019

e12510

Background: Human epidermal growth factor receptor type 2 (HER2) is a significant driver of breast oncogenesis and has been found to be amplified in one-fifth of all breast cancers. Identification of cell surface over-expression of HER2 can be completed using immunohistochemistry (IHC), while amplification of the gene can be detected using fluorescence in situ hybridization (FISH) or differential polymerase chain reaction (PCR). Definitive diagnostic standards for each detection method are established, however approximately 5-10% of breast cancer patients have a HER2 status of “double equivocal,” offering little guidance to directing therapy. Previously, selected reaction monitoring mass spectrometry (SRM-MS) illustrated the dynamic range of HER2 positive protein expression by IHC or amplified FISH to have a threshold determination of 740amol.We hypothesized that this method could delineate which ‘double equivocal’ patients may indeed express enough HER2 to be candidates for targeted therapy. Methods: Overall, 76 invasive breast cancer samples identified as equivocal by IHC and FISH between 1/1/2010 and 12/31/2017 were evaluated. Typical demographic and clinicopathologic data were collected to include age, race, histology, size, hormone receptor status, treatments and outcomes. HER2 levels in each equivocal sample were quantitated using SRM-MS. Data were analyzed using Fisher’s t-tests, chi-square and ANOVA (p < 0.05). Results: Using the 740 amol/ng as the SRM-MS cut-off for HER2 positivity, the group was divided into two cohorts. No significant differences were found for demographic or pathologic variables. While identified HER2 levels were between 209.1-1286.6amol, 18 patients had SRM-MS results above the threshold but outcomes were not correlated with treatment received. Conclusions: We report the largest series of doubly equivocal HER2 patients evaluated with SRM-MS. For patients with invasive ductal carcinoma, SRM-MS was not able to identify patients for whom HER2 directed therapy would be a benefit. Future plans include an assessment of this cohort with an RNA seq algorithm given the high degree of accuracy we have shown with known HER2 positives and negatives.
Novel tetravalent bispecific T-cell engaging antibodies for cancer immunotherapy.
Authors: Lakshmikanthan Sribalaji , Wyant Timothy , Pandian Swarna , Murphy Shaun , Chen Yangde
Published: May 2019

e12513

Background: Current immunotherapy involves redirection of T cells against tumor either by chimeric antigen receptors (CAR-T) or bispecific T-cell engagers (BiTEs). These T cell-engaging technologies have been enabled by engineering single-chain variable fragment (scFv). Most BiTEs are designed as heterodimers, with monovalent binding to tumor cell surface antigens and to CD3+ T cells. Here, we describe a novel tetravalent bispecific (TetraBi) platform: a tumor associated antigen specific, T-cell engaging antibody that provides significant advantages over traditional BiTEs. Specifically, we showcase three unique TetraBi antibodies targeted for various cancers. Methods: ABP-100 was engineered by fusing CD3-binding scFv to the c-terminus of anti-HER2 IgG1 light chain, resulting in two binding sites each for HER2 and CD3. In preclinical studies, ABP-100 was compared with a clinical-stage heterodimeric antibody that is monovalent for HER2 and CD3. We also built TetraBi for anti-Glypican 3 (GPC3, ABP-110) and Claudin 18.2 (CLDN18.2, ABP-150) for gastric cancer therapy. Results: We observed bivalent binding to the tumor antigens (HER2, GPC3, CLDN18.2) on tumor cells like the monoclonal antibodies do. Interestingly, the CD3-binding domains in our TetraBi format showed functionally monovalent binding to CD3. ABP-100 displayed comparable cytokine release to the heterodimer molecule both in vitro and in vivo. In HER2+ cancer models, ABP-100 showed highly potent antitumor activity, resulting in complete responses in tumor bearing mice at doses as low as 0.1 mg/kg with no evidence of tumor relapse. ABP110 and ABP-150 also demonstrated potent cancer cell killing in vitro. Conclusions: This novel TetraBi antibody format enables concurrent bivalent and monovalent co-engagement of distinct target antigens in tumor microenvironment with promising therapeutic implications. Furthermore, it provides a potentially larger therapeutic index than more traditional bispecific formats that feature monovalent recognition of tumor antigens.
Risk stratification based on a prognostic factor index among patients with HR+, HER2- MBC.
Authors: Vidal Gregory A. , Cuyun Carter Gebra , Gilligan Adrienne , Saverno Kim , Zhu Yajun Emily , Price Gregory L , Deluca Angelo , Nash Smyth Emily Nash , Koustenis Andrew G. , Huang Yujing , Schwartzberg Lee S.
Published: May 2019

e12516

Background: Patient and tumor characteristics, such as tumor grade (TG), site of metastases, hormone receptor status, and endocrine resistance, affect the prognosis for patients (pts) with HR+, HER2- metastatic breast cancer (MBC). This study explored the impact of multiple clinical prognostic factors on pt overall survival (OS) and real-world progression-free survival (rwPFS). Methods: This retrospective study used electronic health record (EHR) data of US pts from a network of community oncology practices maintained in the Vector Oncology Data Warehouse from 1/1/2008 to 4/30/2017. Eligibility included HR+, HER2- MBC diagnosis in 2008 or later and prior systemic therapy for MBC. An index variable was created to assess the effect of multiple clinical prognostic factors collectively, including liver metastases (LM), primary endocrine resistance (PER) (Cardoso F et al. 2018), negative progesterone receptor (PR-) status, and high TG. Pts were grouped based on the number of prognostic factors present at MBC diagnosis: 0, 1, and 2+. Differences in rwPFS and OS from start of first line therapy were evaluated by Kaplan-Meier method and multivariable Cox proportional hazards regression. Results: Eligible pts (n=378) had a mean age of 60.3 years. Among these 57.1% were white, 36.5% were de novo metastatic, 22% had LM, 27.2% had high TG, and 27.1% were PR- at baseline. Among all pts, 170 (45%) had received endocrine therapy as first-line treatment, followed by chemotherapy (28%), CDK4 & 6 inhibitor (17%), or other anti-cancer treatment (9%). After adjustment, rwPFS and OS were significantly (p<.05) shorter in pts with 1 and 2+ clinical prognostic factors compared to pts with none (Table). Conclusions: Among pts with HR+, HER2- MBC, these data demonstrate the heterogeneity in pt survival outcomes depending on the presence and number of prognostic factors. Further research should explore the collective importance of these prognostic factors in treatment decisions. [Table: see text]
Acquired NF2 mutations confer resistance to HER2 targeted therapy in HER2-mutant breast cancer.
Authors: Li Xuelu , Ma Jing , Pan Bo , Zhao Zuowei , Li Man
Published: May 2019

e12518

Background: Preclinical studies suggest that HER2 mutations lead to constitutive HER2 activation, but knowledge about effective treatment options and clinical resistance mechanisms remain uncharacterized. Methods: We performed dynamic monitoring of >300 serial plasma samples collected from 49 metastatic breast cancer patients used targeted sequencing of 425 clinically relevant genes, to detect HER2 mutations and track resistance to HER2-targeted treatments in HER2-mutant breast cancer. Results: We identified activating HER2 mutations (S310F、D769Y、V777L、778insGSP) in ctDNA and paired tissue samples from four patients with ER positive/HER2-amplification negative metastatic breast cancer, who had developed resistance to multi-line (>3) endocrine therapy. Two patients achieved a durable partial response (approximately 1 years) to trastuzumab combined with everolimus. Intriguingly however, analysis of ctDNA revealed that the NF2 mutation was acquired from a patient with HER2S310F/V777L who had developed resistance to HER2-targeted treatments. We showed that HER2S310F/D769Y/V777L/778insGSP mutations were constitutively active, and T47D and MCF7 overexpressing HER2S310F/V777L/778insGSP were sensitive to HER2 targeted therapies combined with everolimus. Consistent with our clinical findings, NF2 knockdown in HER2 S310F/V777L/778insGSP overexpressing T47D and MCF7 contributed to HER2-targeted therapy resistance. Furthermore, MEK inhibitor remarkably sensitized NF2 knockdown and HER2 mutations co-expressing T47D and MCF7 cells to trastuzumab. Conclusions: Dynamic monitoring of ctDNA could provide the candidate resistance genes for metastatic HER2-mutant breast cancer. Our findings validated NF2 mutations as a potential mechanism of resistance to HER2-targeted therapy, and the combined use of HER2 and ERK inhibitors may overcome resistance to HER2 targeted therapy in HER2-mutant breast cancer.
Fulvestrant in hormone receptor-positive advanced breast cancer: A UK retrospective multicenter study.
Authors: Keshwani Karim , lerner anna , Sanderson Benjamin , Board Ruth E. , Flynn Michael , Sharkey Elizabeth , Okines Alicia Frances Clare , Konstantis Apostolos , Roylance Rebecca , Hanna Daire , King Judy , Murphy Ravindhi , Rehman Farah , Guppy Amy Elizabeth , Westbury Charlotte , Takeuchi Elena , Spurrell Emma , Raja Fharat
Published: May 2019

e12525

Background: Fulvestrant is a selective oestrogen receptor (ER) down regulator used to treat hormone receptor-positive advanced breast cancer in postmenopausal women. It is used at various time points in treatment. However, variations in funding across the UK limit universal patient access to fulvestrant. We sought to investigate its use and efficacy in UK clinical practice. Methods: Medical records of 458 patients with ER positive advanced breast cancer treated with fulvestrant between August 2011 and November 2018 at ten UK centres were reviewed. Demographics and treatment responses were recorded. Efficacy was analysed by progression free survival (PFS), clinical benefit rate (CBR) and overall survival (OS) with alive patients censored to December 2018. Results: Of the 445 patients with analysable data, median age was 70 (range 21-95). ECOG performance status was 0-1 in 70% (n = 285). Bone was most commonly involved (73%, n = 323), 307 (69%) had visceral involvement and 228 (51%) had nodal metastases. Both locally advanced and metastatic patients had received a median 2 (range 0 – 5 for all patients) prior endocrine therapy lines and 0 (range 0 – 6) prior chemotherapy lines. Fulvestrant was the first line treatment in 49 (11%). Median duration of fulvestrant use was 5 months (range 1-88). Overall, median PFS was 6 months. This increased to 7 months in absence of visceral disease, in whom 22% of patients achieved a prolonged PFS extending to 30 months. Fulvestrant produced a CBR of 41% in 355 patients assessed, of which 16% partially responded. First radiological assessment occurred at median 3 months (range 1-37). Progressive disease accounted for 82% of discontinuation compared to 4% owing solely to adverse events in 341 assessed patients. Median OS for the whole cohort was 23 months. Conclusions: This is one of the largest studied patient cohorts treated with fulvestrant. This heavily pre-treated population reflects real life fulvestrant use. Reassuringly the results confirm its clinical benefit in maintaining disease response. Given its potential synergistic action with other systemic agents, fair access to this highly active drug for all patients is as important now as ever before.