bluuebunny/crossref_metadata_2025 huggingface dataset:
Sentinel lymph node biopsy in Merkel cell carcinoma: A multi-institutional study from the Pan-Canadian Merkel Cell Collaborative.
Authors: Delisle Megan E , Dingley Brittany , Apte Sameer , Mallick Ranjeeta , Hamilton Trevor D , Stuart Heather , Francescutti Valerie , McKinnon Greg , Jost Evan , Easson Alexandra , Merchant Shaila J. , Hebbard Pamela , Wright Frances Catriona , Berger Richardson David , Younan Rami , Meguerditchian Ari , Mathieson Alex , Hetu Jessika , Johnson Stephanie , Nessim Carolyn ,   Pan-Canadian Merkel Cell Collaborative
Published: June 2022

9583

Background: There is controversy regarding sentinel lymph node biopsy (SLNB) in clinically node-negative Merkel Cell Carcinoma (MCC). We compared MCC recurrence and survival between patients who did versus did not undergo a SLNB. Methods: Patients with MCC across 13 Canadian centers were reviewed, from 2000-2018. Of a total cohort of 750 patients, 485 had clinically node-negative disease at presentation. A propensity score was created. The association between SLNB and local, regional and distant recurrence, and cancer-specific and overall survival were evaluated using competing risks and Cox proportional hazards regression. Results: 195 patients (40.2%) underwent a SLNB. SLNB was performed more commonly in younger, healthier patients with MCC located in the extremities or torso (Table). The results of 177 SLNBs were available; 60 (33.9%) were positive. SLNB-positive patients underwent completion dissection (n=15, 25%), completion dissection and nodal radiation (n=22, 36.7%), nodal radiation alone (n=18, 30%) or observation (n=5, 8.3%). Patients who did not undergo a SLNB underwent nodal radiation alone (n=40, 13.8%) or observation (n=250, 86.2%). The median follow-up was 2.7 years (range 0.2-14.4). The regional recurrence rate was 14.5% (n=17) among SLNB-negative versus 15% (n=9) among SLNB-positive patients. Among patients who did not undergo a SLNB, the regional recurrence rate was 25.2% (n=63) among those who underwent observation and 15% (n=6) among those who received nodal radiation alone. After propensity score matching, SLNB patients had a lower risk of regional recurrence (sHR 0.54 95% CI 0.34-0.86 p=0.01) and improved overall survival (HR 0.32 95% CI 0.23-0.45 p<0.01), but there was no difference in local recurrence (sHR 0.92 95% CI 0.50-1.69 p=0.79), distant recurrence (sHR 0.88 95% CI 0.52-1.49 p=0.63), or cancer-specific survival (HR 0.67 95% CI 0.31-1.45 p=0.31). Conclusions: SLNB is associated with a reduced risk of regional recurrence and improved overall survival. The role of SLNB in selecting patients for emerging therapies, such as immunotherapy, needs to be evaluated. [Table: see text]
Fertility preservation decisions and outcomes of young women with breast cancer.
Authors: Isseroff Devora , Thom Bridgette , Chang Cassandra , Abdo Nadia , Semler Rosemary , Gemignani Mary , Kelvin Joanne Frankel , Goldfarb Shari Beth
Published: June 2022

e12520

Background: As breast cancer (BC) survival improves, fertility preservation (FP) counselling prior to initiating gonadotoxic chemotherapy for women of child-bearing age becomes more important. This study explores the factors that influence the decisions to pursue FP before and after breast cancer treatment and the FP outcomes. Methods: An IRB approved web-based survey examining decisions about FP, factors influencing decisions, and post-decision regret was administered to English and Spanish speaking women (age 18-45) diagnosed with stage I-III BC. All women received education and counselling by a MSK Fertility Nurse Specialist prior to initiating cancer treatment at MSKCC in 2009-2017. Additional data was extracted from the medical record. Results: 211 women with BC (82% ER+, 19% HER-2+, 12% triple negative) with a mean age of 34 (age range 20-45) participated in this study. At the time of diagnosis 128 (61%) women were married/living with partner and 46 (22%) women had children. 151 (72%) wanted (additional) children, 48 (23%) were unsure if they wanted (additional) children and 12 (6%) did not want (additional) children. Of the 151 women who desired (additional) children, 94 underwent FP pre-treatment and 3 post-treatment. Of 48 unsure women, 14 underwent FP. A total of 115 women underwent FP before treatment: 73 froze eggs and 49 froze embryos. After treatment 28 (13%) women met with a reproductive endocrinologist and 13 underwent FP: 9 froze eggs and 4 froze embryo. The average number of eggs frozen was 14 pre-treatment and 18 post-treatment. The average number of embryos frozen was 7 both pre- and post-treatment. After completing primary breast cancer treatment, 61 women opted to try to build their family and 42 had children: 35 gave birth and 7 used a surrogate. In a multivariate analysis lower socioeconomic status and non-white race were predictive of discordance between desire for FP and completion of FP before treatment (p < 0.05). 65% of patients reported cost of freezing eggs/embryos was important in their decision. Insurance did not cover any FP treatment for 56/115 (49%) of women and 34% (39/115) of women paid $10,000 or more for their FP. Participants reported the ability to feel hopeful about their future (82%) and fear of regret (80%) were the most important factors when making their FP decision. 83% (176/211) of women believe they made the right FP decision and 80% would make the same decision again. Women had less regret if they underwent FP. Conclusions: Our study demonstrates the importance of discussing FP with women with BC of child-bearing age, regardless of race or economic status. Fertility preservation is often successful in women with BC. Regardless of pregnancy outcomes, women felt that having FP offered them a sense of control and hope for the future during a vulnerable time in their lives with low risk of regret.
Neuroendocrine differentiation in breast carcinoma-clinicopathological characteristics and prognostic significance.
Authors: Shafi Saba , Li Zaibo , Parwani Anil
Published: June 2022

e12540

Background: Invasive breast carcinoma with neuroendocrine (NE) differentiation has been controversial in terms of its definition and clinical outcome. The recent 5th WHO edition classifies breast carcinoma with NE differentiation into two categories: 1) invasive breast carcinoma, NST (no specific type) with NE features (IBC-NE) (≤90% NE histologic features); 2) NE neoplasm (NEN) (>90% NE features), which is further separated into NE tumor (NET) or NE carcinoma (NEC). However, very little is known about the difference in outcomes, if any, in these three groups of breast carcinomas with NE differentiation. In this study, we examined the clinicopathological characteristics of these three groups of breast cancers and their prognostic significance. Methods: 56 breast cancer patients from 2006 to 2021 were included in this study (IBC-NE: n=41; NET: n=5 and NEC: n=10). Cohort annotation was done by retrospective review of electronic medical records. Results: NEC was significantly associated with higher grade (grade 3 vs. grade1/2) than IDC-NE (90% vs. 26.9%, p=0.0002). IEC-NE showed a significantly greater expression of ER/PR than NET/NEC (ER=100% vs. 64.3%, p<.0001; PR=80.5% vs. 50%, p=0.02). Notably, there was no significant difference in the HER2 status, T stage or survival outcomes between the three groups. NET/NEC had a significantly higher incidence of distant metastases than IDC-NE (46.6% vs. 19.5%, p=0.04). Conclusions: Our data suggest NE neoplasms harbored some different clinicopathologic features from IBC with NE features. In addition, NE neoplasms showed more distant metastasis than IBC with NE features, although no significant difference was observed in overall survival, which may be caused by the small size of current cohort and short follow-up period. [Table: see text]
Predicting breast cancer in women using liquid biopsy-derived glycoproteomic markers.
Authors: Mitchell Alan , Srinivasan Apoorva , Xu Gege , Rice Rachel , Castellanos Alyn , Bhadra Ranjan , Serie Danie , Cong Xin , Lindpaintner Klaus
Published: June 2022

e12545

Background: Breast cancer is the most common cancer among women worldwide.Traditional methods of cancer detection such as tissue biopsy are invasive, costly, time consuming and not amenable for repetition. As a result, minimally invasive liquid biopsies, especially blood-based biomarkers show potential value for breast cancer risk prediction and early detection. In this study, we investigated the use of serum glycoproteins circulating in blood to identify a panel of potential prognostic markers that may aid in predicting breast cancer in women. Methods: We applied a novel platform for characterizing blood glycoproteomic biomarkers, combining liquid-chromatography/mass spectrometry (LC-MS) with artificial intelligence/neural networks (AI-NN) to analyze serum samples from 279 breast cancer patients (median age 56 years, with stage 0-4 N’s: 1 / 83 / 114 / 56 / 25) and 102 healthy control samples (median age 52 years). A panel of 596 serum glycosylated and non-glycosylated peptides, representing 71 serum proteins, were analyzed. Age-adjusted differential expression analysis for 596 normalized biomarkers were performed to evaluate statistically significant differential abundances using an FDR q-value of 0.05 as a cutoff. Using the top differentially expressed markers as input, a LASSO penalized logistic regression model with 5-fold repeated cross validation was applied to identify the top biomarkers contributing to the separation between healthy controls and breast cancer patients. Results: We identified 243 out of 596 markers that were differentially expressed (FDR <<0.05) between breast cancer samples and healthy controls. Out of those, 11 markers were obtained as the top predictors in classifying breast cancer patients and healthy controls. The classification algorithm yielded an accuracy of 94% (95.9% sensitivity, 88.7% specificity) and an AUC of 0.983 on the training set. This classifier was validated on an independent test set with 30% of the subjects, yielding an accuracy of 93% (96.4% sensitivity, 83.9% specificity) and an AUC of 0.974. Test sensitivity was high across stages, at 96% / 90% / 95% / 90% in stages 1-4, respectively. Conclusions: Based on the results, we conclude that circulating glycoproteins in serum may be useful in screening applications in breast cancer, and strongly demonstrates the utility of glycoprotein profiles as a powerful non-invasive diagnostic tool.
Circulating levels of PCSK9, ANGPTL3 and Lp(a) in stage III breast cancers.
Authors: Wong Chong Emilie , Joncas France-Hélène , Seidah Nabil Georges , Calon Frédéric , Diorio Caroline , Gangloff Anne
Published: June 2022

e12547

Background: Cholesterol plays an important role in sustaining tumor growth and metastasis in a large variety of cancers. New and powerful cholesterol-lowering drugs are being used in combination to treat cardiovascular diseases. As drugs directed against PCSK9 (evolocumab, alirocumab, inclisiran), ANGPTL3 (evinacumab) and Lp(a) (pelacarsen) are available, it becomes of interest to assess the circulating levels of these drug targets and their role in cancers. Our purpose here is to compare circulating levels of PCSK9, ANGPTL3, and Lp(a) in women with stage III breast cancer versus women with a premalignant or benign breast lesion. Methods: Twenty-three plasma samples from women diagnosed with a stage III breast cancer (ductal, lobular or mixed) were matched for age with twenty-three plasma samples from women bearing premalignant (stage 0, n=9) or benign (n= 14) breast lesions. Lipid profile (Apo B, total cholesterol, HDL and triglyceride levels) and Lp(a) were measured on a Roche Modular analytical platform. LDL levels were calculated with the Friedewald formula. ANGPTL3 and PCSK9 plasma levels were quantitated by ELISA. Difference between breast disease groups was deemed significant when group-comparison generated p-values < 0.05. Results: PCSK9 levels were significantly higher in women with stage III breast cancer compared to age-matched counterparts presenting a benign lesion (95.9 +/- 27.1 ng/mL vs. 78.5 +/- 19.3 ng/mL, p<0.05, n=14). Moreover, PCKS9 levels positively correlated with breast disease severity (benign, stage 0, stage III) (Rho=0.34, p<0.05, n=46). In contrast, ANGPTL3, Lp(a) or lipid plasma levels did not display any correlation with breast disease severity. Conclusions: In this cohort of 46 women, PCSK9 levels increased along with the severity of breast disease. Given that PCSK9 plays an important role in maintaining cholesterolemia and has been shown to degrade MHC-I on tumor cells, impeding immune T-cells response to tumors, confirmation of PCSK9 elevation in a larger cohort would pave the way for trials studying lipid-lowering drugs as adjuvant treatments in breast cancer.
Circulating tumor cells and vitamin D in primary breast cancer.
Authors: Mego Michal , Vlkova Barbora , Karaba Marian , Minarik Gabriel , Benca Juraj , Sedlackova Tatiana , Kalavska Katarina , Pindak Daniel , Mardiak Jozef , Celec Peter
Published: June 2022

e12558

Background: Circulating tumor cells (CTCs) contributing to the metastatic cascade and represent an independent survival predictor in breast cancer (BC) patients. Vitamin D has pleiotropic effects and its low concentrations are associated with infections, cancer, but also other pathologic conditions. The aim of this study was to assess plasma vitamin D level in primary BC patients in relation to CTCs. Methods: This study included 91 non-metastatic breast cancer patients (stage I-III) with plasma samples available in the biobank of the National Cancer Institute in Slovakia. Blood samples for the analyses were drawn at the time of surgery. Peripheral blood mononuclear cells (PBMCs) were depleted of hematopoetic cells using RossetteSepTM negative selection kit. RNA extracted from CD45-depleted PBMCs was analyzed for the expression of transcription factors (TWIST1, SNAIL1, SLUG, ZEB1) that induce epithelial-to-mesenchymal transcription (EMT-TF) and epithelial ( CK19) gene transcripts using qRT-PCR. Patient samples with higher epithelial and/or mesenchymal gene transcripts than those of healthy donors (n = 60) were considered CTCs positive. Total 25-OH vitamin D was measured in plasma using ELISA. Results: CTCs were detected in 30 (33%) patients, 14 (15.4%) patients had detectable CTCs with epithelial characteristics, 13 (14.3%) patients had CTCs with an EMT phenotype, while peripheral blood of 3 (3.3%) patients exhibit both CTCs subtypes. Patients with detectable CTCs in peripheral blood had significantly lower vitamin D concentrations in comparison to patients without detectable CTCs (mean ± SD) 8.50 ± 3.89 µg/L for CTCs positive vs. 9.69 ± 3.49 µg/L for CTCs negative patients respectively, P = 0.03). There was no association between plasma vitamin D and other patient/tumor characteristics. At a median follow-up of 96.5 months (range: 8.4 - 109.4 months), 28 patients (30.8%) had experienced a progression and 24 patients (26.4%) had died. Patients with vitamin D above median had better overall survival (HR = 0.36, 95%CI 0.16 – 0.80, P = 0.017) compared to patients below median vitamin D. Conclusions: According to our knowledge, this is the first report of an association between plasma vitamin D concentrations and CTCs in primary breast cancer patients. We suggest that vitamin D could play a direct role in tumor dissemination and its supplementation might affect metastatic cascade. Alternatively, decreased vitamin D could be a consequence and hence a biomarker of a more invasive disease. Animal experiments and interventional studies are needed to prove the causality of the observed association.
Serial genomic analysis of circulating tumor cells and circulating tumor DNA in triple-negative and HER2-positive advanced, metastatic breast cancer.
Authors: Lee Ji Eun , Shin Kabsoo , Joe Seung Yeon , Lee Hayoon , Park Junghoon , Jeon Byung Hee , Lee Ahwon
Published: June 2022

e12561

Background: Circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) have a promising role for detecting early response and progression in breast cancer. We performed serial genomic analysis of CTC and ctDNA in advanced, metastatic triple negative breast cancer (TNBC) and HER2 positive breast cancer (BC). Methods: Serial CTCs, ctDNA were prospectively collected in 9 early or advanced, and 10 metastatic BC patients periodically during systemic chemotherapy. CTC was isolated from whole blood through EpCAM positive bead selection, and ctDNA was isolated from plasma. For genomic profiling of CTC and ctDNA, Oncomine™ Comprehensive Assay Plus and Oncomine™ Pan-Cancer cfDNA assay (included BRCA1, BRCA2 and MYCN customized panel) was performed and analyzed, respectively. Results: TP63 was most commonly detected mutation (13 patients, 68.4%) at serial CTC analysis with median variant of allele frequency (VAF) of 18.6% (range 11.5̃25.2%), irrespective of tumor subtype and stage. In ctDNA analysis, 11 patients showed TP53 mutation with low VAF (median 1.4%, range 0.3̃12.3%). FGFR4 was equally detected, with median variant of allele frequency (VAF) of 57.2% (range 46.6-99.8) and there was no change of FGFR4 VAF irrespective of tumor response in CTC analysis. In three gBRCA1 mutated patients, BRCA1 was identically detected in 3 patients based on CTC analysis and in 2 patients based on ctDNA analysis with VAF of approximately 50%. There were no significant changes of VAF in target mutations of CTC irrespective of tumor response and subtype. In TNBC patients who received neoadjuvant chemotherapy, tumor mutation burden (TMB) showed gradual decrease during treatment. However, there were initial surge of TMB in HER2 positive BC patients who received neoadjuvant chemotherapy, irrespective of presence of pathologic complete response. Conclusions: Our study suggest that serial follow up CTC and ctDNA is feasible and reflect the general characteristics of baseline characteristics and dynamic molecular alteration of breast cancer. Further analysis with larger patient sample and correlation with tumor tissue is warranted in the future.
The relationship of oncotype Dx Recurrence Score (RS) with Ki 67 in early stage breast cancer patients in a community based cancer center in rural central Nebraska.
Authors: Copur Mehmet Sitki , Peterson Tonya , Tun Soe Min , Horn Adam , Wedel Whitney , Duckert Randall , Lintel Nicholas , Springer Carlene R. , Muske Chandra , Robbins Leslie , Arbogast Jessica , Fakkema Emily , Marshall Alison , Brunt Kathryn , Kelly Jacqueline
Published: June 2022

e12566

Background: Oncotype Dx recurrence score (RS), is a prognostic and predictive test utilized for decision making in adjuvant therapy of 0-3 node/hormone receptor positive(HR+)/ HER-2-negative early breast cancer. Ki-67 is a marker of proliferating cells and is associated with prognosis and response. Immunohistological (IHC) assessment of Ki 67 expression is less expensive and with the approval of CDK inhibitors in the high risk adjuvant setting, it is increasingly being utilized in clinical decision making. A moderate to strong correlation between Ki67 and Oncotype Dx RS has been reported in the literature. We sought to examine the relationship of Ki 67 to Oncotype Dx RS in a community-based cancer center in rural central Nebraska. Methods: Forty-three consecutive postmenopausal breast cancer patients(pts) diagnosed and treated at our community based cancer center between 2020-2021 with T1–2 N0-1 M0, HR+, HER-2-negative disease were evaluated for histological type, tumor size, Nottingham grade, HR levels, Ki 67 expression (low < 10%, intermediate 10 ≥ Ki67 < 25 high ≥ 25), and Oncotype Dx RS(low <16,intermediate 16⩽RS<26), high ⩾26). Ki 67 and Oncotype Dx RS were treated as continuous variables to calculate a Pearson correlation coefficient. Results: Mean age at diagnosis was 59.4 years (range 48-89). Mean tumor diameter was 15.6 mm. 78.9% were intermediate histologic grade and 9.7% patients had lymph node involvement. Median expression of ER and PR were 90% (5-100) and 70% (0-100), respectively. The mean Ki 67 value was 17.5 (range 5-60 %), and mean Oncotype RS was 14.4 (range 4-34). There was a positive linear correlation between Ki 67 expression and Oncotype Dx RS (Pearson Correlation Coefficient=0.49, P-value <0.001). The vast majority of high Ki 67 pts (80%) had high/intermediate Oncotype RS. All pts with low Ki 67 (100%) had low/intermediate RS. Conclusions: Our community based rural cancer center data support a linear, statistically significant, positive correlation between Ki 67 and Oncotype Dx RS in early stage 0-3 node/HR+ positive breast cancer pts. Increasing use of Ki 67 testing in different clinical settings will generate more data to better define this correlation.[Table: see text]
A prospective decision impact study to evaluate the utility of the Oncotype DX Breast DCIS score assay in selecting patients with ductal carcinoma in situ (DCIS) following breast conservation surgery (BCS) for radiotherapy.
Authors: Barry Mitchel , Walsh Siun , Kelly Sinead , Stokes Maurice , Gribbin Anne , Maher Michael A. , Kell Malcolm R.
Published: June 2022

e12571

Background: There is increasing reliance on data provided by genomic risk assessment assays to guide therapeutic decisions. The objective of this prospective study was to assess the impact of the Oncotype DX Breast DCIS Score assay on radiation treatment recommendations in patients with DCIS undergoing BCS. Methods: This decision impact study is a prospectively enrolled observational study of newly diagnosed patients (n = 135) following BCS for removal of DCIS of all grades 30mm or less with clear margins (i.e. 2 mm or normal re-excised margins). Only patients who were candidates to receive radiation therapy were considered. Fifteen patients withdrew from the study or had insufficient volume of DCIS for assay analysis. Radiation Oncologists were blinded to the Oncotype DX Breast DCIS Score assay prior to recording their recommendation for radiotherapy or not. IRB approval was granted following review of study protocol and informed consent was obtained from all patients. Results: Among 120 patients tested, the Oncotype DX Breast DCIS Score assay determined that 58/120 (48.3%) of patients had a low score (LS) (0-38), 30/120 (25%) had an intermediate score (IS) (39-54) and 32/120 (26.7%) had a high score (HS) (>55). The Oncotype DX Breast DCIS Score assay concurred with the Radiation Oncologists recommendation to proceed with radiation treatment in 96.7% of patients (i.e. 60/62 patients with an IS or HS). The Oncotype DX Breast DCIS Score assay altered treatment decisions in 12.5% (4/32) of patients with a HS and in 7.1% (2/28) patient with an IS. In patients where the Oncotype DX Breast DCIS Score assay altered treatment recommendation all had a low volume (i.e. less than 10mm) of high/intermediate grade DCIS with an IS or HS. Conclusions: This study demonstrates that Oncotype DX Breast DCIS Score assay accurately supports the selection of patients with DCIS for radiation treatment and equally can be helpful in selecting a subgroup of patients with small volumes of intermediate/high grade DCIS who can potentially avoid radiotherapy.
The effect of tumor size on nodal disease burden in clinically node negative breast cancer.
Authors: Lee Minna K. , Rubenstein Robyn , Sevilimedu Varadan , Montagna Giacomo , Shamsunder Meghana , Nelson Jonas A. , Le Tiana , Garcia Paula , Morrow Monica , Tadros Audree
Published: June 2022

e12575

Background: Randomized trials have shown no difference in outcomes for cT1-2N0 breast cancer patients with 1-2+ sentinel lymph nodes (SLNs) undergoing sentinel lymph node biopsy (SLNB) alone compared to axillary dissection (ALND). No studies have yet evaluated whether these results can be applied to cT3N0 patients. Our objective was to evaluate nodal burden in cT3N0 compared to cT1-2N0 patients. Methods: Patients with cT1-3N0 breast cancer undergoing upfront surgery were identified from the National Cancer Database (NCDB) from 2012 through 2017. Analysis was limited to those with ≥ 3 lymph nodes (LNs) retrieved. Clinical and pathologic characteristics were examined using Wilcoxon Rank sum tests, Chi square, or Fisher’s exact tests. Univariate and multivariable logistic regression analyses were performed to examine characteristics associated with increased nodal burden (≥ 3 +LNs). Results: During the study period, we identified 198,137 cN0 patients with ≥ 3 LNs retrieved, of which 191,672 (97%) were cT1-2 and 6,465 (3%) were cT3. Most patients had ductal histology (83%) and ER+/HER2- subtype (83%). Of cT1-2 patients, 7% (13,902/191,672) had ≥ 3 +LNs compared to 28% (1,791/6,465) of cT3 patients. Among patients with ≥ 3 +LNs, the majority (91%) underwent ALND with a median of 14 (interquartile range [IQR] 9,19) LNs retrieved. Of these patients, cT3 disease was associated with an increased number of +LNs compared to cT1-2 disease (median [IQR], 6 [4,10] vs. 4 [3,7], p<0.01). On multivariable analysis, invasive lobular carcinoma (ILC) (OR 2.11, 95% CI 1.34-3.30), lymphovascular invasion (LVI) (OR 5.22, 95% CI 4.43-6.16), and pathological tumor size > 8 cm (OR 2.76, 95% CI 2.16-3.53) were independently associated with ≥ 3 +LNs in cT3 patients. Triple-negative breast cancer (TNBC) was associated with lower odds of ≥ 3 +LNs (OR 0.50, 95% CI 0.36-0.68). In those with tumors 5-8 cm in size, 364 (27%) of 1,363 patients with IDC had ≥ 3 +LNs, compared to 152 (48%) of 315 patients with ILC. Conclusions: cT3N0 patients have increased nodal burden compared to cT1-2N0 patients. Caution should be used in extrapolating guidelines for cT1-2N0 patients to high-risk cT3N0 patients with large tumors, LVI, and lobular histology.[Table: see text]
Real-life analysis of pathologic complete response with neoadjuvant trastuzumab plus taxane with or without pertuzumab therapy in HER2 positive locally-advanced breast cancer (HER2PATH Study).
Authors: Bilici Ahmet , Olmez Omer Fatih , Sezer Ahmet , Oksuzoglu Berna , Kaplan Muhammet Ali , Karadurmus Nuri , Cubukcu Erdem , Sendur Mehmet A.N. , Aksoy Sercan , Erdem Dilek , Basaran Gul , Cakar Burcu , Seker Mesut , Arslan Cagatay , Sezgin Goksu Sema , Cicin Irfan , Gumus Mahmut , Selcukbiricik Fatih , Harputluoglu Hakan , Helvaci Kaan
Published: June 2022

e12610

Background: Studies in HER2+ locally-advanced breast cancer (LABC) patients with neoadjuvant dual HER2 blockage therapy demonstrated high rates of pathologic complete response (pCR). This study evaluates neoadjuvant chemotherapy (NCT) plus trastuzumab (H) with or without pertuzumab (P) therapy with a nation-wide real world setting. Methods: In this study, 1528 female HER2+ LABC patients’ data received NCT plus H with or without P were collected retrospectively from 21 centers. Ethics committee approved the study (NCT04765124). Primary end point was pCR rate (ypT0/Tis ypN0 in the current AJCC staging system). Results: Of the 1528, 951 (62.2%) were received NCT-H, 577 (37.8%) were received NCT-HP, follow-up durations were 30 months and 15 months, median ages were similar between 2 groups (47 years, range: 20-81 and 47 years, range 22-88, respectively). According to the menopausal and hormone receptor status 60% and 53.7% of patients were classified as premenopausal, 56% and 57.8% as estrogen receptor positive and 46.2% and 47.2% as progesterone receptor positive respectively at NCT-HP and NCT-H groups. Despite the patients at NCT-HP group mostly received docetaxel (75%), NCT-H group received weekly paclitaxel (59.4%) as taxane (p<0.001). pCR rate for patients treated with NCT-HP was significantly better than that for patients received NCT-H (66.4% vs. 56.8%, respectively, p<0.001) and there were not any statistical difference according to hormone receptor status. Two-years event-free survival (EFS) rates were 93.5% and 93.2% for NCT-HP and NCT-H groups, respectively (p=0.655), however, two years EFS rate was statistically significant in patients who achieved pCR compared to those who did not achieve pCR (95.1% vs. %90.6, p<0.001). There was not any toxicity leading to death. Conclusions: Our analysis of this real world data shows higher rates of pCR than in clinical trials, also adding pertuzumab to NCT-H demonstrates higher pCR rates and EFS rates compared with NCT-H in patients with HER2+ LABC.
HDAC inhibitor Tucidinostat plus exemestane as neoadjuvant therapy in patients with hormone receptor positive, HER2 negative breast cancer.
Authors: Wang Xin ,   Tianjin Medical University Cancer Institute and Hospital
Published: June 2022

e12623

Background: Tucidinostat (formerly known as chidamide) is an oral subtype-selective histone deacetylase (HDAC) inhibitor with demonstrated efficacy and safety in combination with exemestane in postmenopausal patients with advanced, hormone receptor-positive breast cancer. The aim of this study was to evaluate the efficacy of tucidinostat combined with exemestane as neoadjuvant strategy in hormone receptor-positive early breast cancer patients. Methods: The study (ChiCTR2100046678) is a single-center, prospective, open-labeled, single-arm phase II study. Patients with HR-positive, HER2-negative, and node-positive, stage II–III breast cancer were enrolled at Tianjin Medical University Cancer Institute and Hospital. Eligible patients received 30 mg oral tucidinostat twice weekly in combination with 25 mg oral exemestane daily for up to a total of 24 weeks. The primary endpoint was to determine percent of pts who achieve a PEPI score of 0. The secondary endpoints were to analyze the the pathological complete remission (pCR) rate, complete cell cycle arrest (CCCA, defined as Ki67<2.7%), objective response rate (ORR), disease control rate (DCR) and event free survival (EFS), and overall survival (OS) as well as the safety and tolerability. Results: Patient enrollment initiated in Jan. 2021 and ended in Nov. 2021. Of the 20 pts enrolled, 20 were treated and radiologically evaluable for response. The ORR was 40% with CR 5% (n=1) and PR 35% (n=7). The DCR was 100%. Four patients were still on wait lists for surgery. Of the 16 pts with surgery, one case achieved pCR. The follow-up remains ongoing and updated results will be presented thereafter. Most adverse events (AEs) were grade 1 or 2. Grade 3 AEs included neutropenia (11.8%), thrombocytopenia (5.9%) and lung infection (5.9%), respectively. Conclusions: The combination of Tucidinostat and exemestane was well tolerated with encouraging clinical responses in early hormone receptor positive, HER2 negative breast cancer. Further investigation is warranted. Clinical trial information: ChiCTR2100046678.
Neoadjuvant therapy with concurrent anthracyclines and taxanes in Her2-negative breast cancer (HNBC): TAC legacy.
Authors: García Samblás Victoria , David Morales Pancorbo , Aragon Manrique Isabel , Bayo Juan L.
Published: June 2022

e12629

Background: Adyuvant therapy with Concurrent docetaxel-adriamycin-cyclophosphamide (TAC) increases overall survival in positive node breast cancer. However it is associated with an increased risk of infection and cardiotoxicity. Switching to epirubicin (TEC) and adding Filgrastim prophylaxis (GCSF) could be an useful and safe option in the neoadjuvant setting. Methods: We reviewed the efficacy and safety of neoadjuvant regimen TEC x 6 cycles(c) and GCSF in HNBC. Kaplan–Meier, Cox regression and binary logistic regression were performed to analyze survival prognostic factors, pathological complete response rate (pCR) and serious adverse events. Results: From 2015 to 2021, 204 patients (pt) and 1125 cycles were registered. Median follow-up of 39.4 months. Median age 48 years (SD 8.3), stage II to IIIC (35% IIB), 64% were positive node and 25% Triple Negative(TN) tumors. A median dose of 90% (87.9-93.4) was administered, 93% with a cumulative dose higher than 66% (equivalent to 4 c). Radiologic response in 75% pt. 16.3% pt achieved pCR (3.2% in LumA, 15% in LumB and 35% in TN tumors). OR 4.98 (2.18-11.35) for TN and OR 0.94 (0.89-0.99) for older p<0.05. No relapses were detected in TN patients with PCR. PCR was non-inferior in pt who received 66% of planned dose (OR 1.3, p=0.76) and was higher in LumB than LumA, OR 5.2 (1.13- 24.61), p <0.05. Lymphadenectomy was avoided in 29.2% of patients with affected node at baseline. 3 years (y) relapse free (F) survival (S) of 86.1% (91-80%), better prognosis in stage II HR 0.29 (0.14-0.58) and older HR 0.93 (0.89-0.98), p< 0.005. 3y overall FS of 89% (93-84%), worse prognosis in TN with HR 3.48 (1.37-8.84). Lower risk in stage II with HR 0.31 (0.13-0.75) and in Pegfilgastrim with HR 0.14 (0.03-0.67), p<0.05. Hospital admissions in 24% for any cause. Older age (OR 1.05, p=0.01). 21% neutropenia G3/4. Infections in 17.2% of pt. Febril neutropenia in 18.1%, no related to age (p=0.5) or pegfilgrastim Vs filgrastim (p=0.99). Asthenia 17%, colitis 6% and thrombosis in 2%. No cardiacs events were reported. Conclusions: TEC is effective in the neoadjuvant setting of HNBC. It has similar pCR and survivall to those reported in meta-analysis. GCSF facilitates treatment compliance but the risk of neutropenia and admissions are still present. A lower cumulative dose could be enough to achieve the same results. Stage III and TN have shown a worse prognosis.
The decline of circulating tumor cell clusters count for predicting the treatment response in breast cancer patients.
Authors: Chou Hsu-Huan , Che Ting-Fang , Chen Shin-Cheh , Tsai Chi-neu , Chang Ying , Chen Fang Ming
Published: June 2022

e13009

Background: Circulating tumor cells (CTCs) are the precursors of metastatic cancer because they originate from primary tumor sites into the vascular system. The prognostic information of CTCs was well established in breast cancer treatment while the predictive value was still unclear. The aim of this study was to analyze the predictive value of CTCs count during treatment. Materials and Methods: A prospective study was conducted from 2019 to 2021, and 31 female breast cancer patients were enrolled, and 54 blood samples were collected at Linkou Chang Gung Memorial Hospital. The median age was 47 years old. We used LIPO platform for CTC isolation with anti-EpCAM antibody. To achieve maximum cellular viability, the LIPO platform was further optimized by using liposomes-lipid bilayers instead of lipid bilayers as the underneath surface coating to facilitate the detachment of bound cells from the surface and maintain cellular viability. Results: Fourteen patients were Stage II or stage III (non-metastasis) and 17 metastatic patients were included. Eleven patients (35.5%) were ER-positive HER2-negative while 10 patients (32.6%) were ER-positive HER2-positive. Three patients (9.7%) were HER2 enriched subtypes, and 7 patients (22.6%) were triple negative breast cancer. Blood samples from a total of 28 patients can be analyzed. At least one CTC was detected in 44/49 (89.8%) blood samples, CTC can’t be identified in 2/5 (40%) post-treatment with good response. The average single CTC count per 2 ml was 34.40 in non-metastatic patients versus 110.43 in metastatic patients (p = 0.3895). The average clustered CTC count per 2 ml was 13.44 in non-metastatic patients versus 40.16 in metastatic patients (p = 0.424). The total single and clustered CTC count per 2 ml was 47.84 non-metastatic patients versus 150.59 in metastatic patients (p = 0.3977). In 10 patients with clinically partial response, the average single CTC count per 2 ml was 61.9 before treatment and 11.81 after treatment (p = 0.0716), and the average clustered CTC per 2 ml was 15.83 before treatment and 5.28 after treatment (p = 0.8806). In 4 patients with clinical progression, the average single CTC count per 2 ml was 22.694 before treatment and 26.125 after treatment (p = 0.0257), and the average clustered CTC per 2 ml was 7.69 before treatment and 16.61 after treatment (p = 0.3798). Conclusions: Our findings concluded that the decline of circulating tumor cell clusters count can predict the treatment response in breast cancer patients.
Effectiveness and safety of eribulin as a front-line treatment in advanced breast cancer patients in China: A prospective real-world study.
Authors: Zhao Jian-Li , Dinglin Xiao-Xiao , Yang Ya-Ping , Luo Si-Min , Cai Yang-Yang , Chai Jie , Liu Dong-Geng , Wang Ying , Yao He-Rui
Published: June 2022

e13015

Background: Eribulin is a non-taxane microtubule inhibitor, which was approved for the third-line treatment of advanced breast cancer (ABC) in China in 2019. However, the efficacy and safety data of eribulin for the ABC in Chinese patients is lacking, whether as first, second, or third-line regimens. This study aimed to evaluate the clinical effectiveness, safety, and treatment pattern of eribulin in first to third-line settings in Chinese ABC patients. Methods: Patients with histologically confirmed advanced breast cancer, who previously received ≤2 lines of treatment for metastatic disease were enrolled. In HR+/HER2- ABC, eribulin monotherapy was used; in HER2+ ABC, eribulin plus anti-HER2 targeted therapy were used; in metastasis triple-negative breast cancer (mTNBC), eribulin plus immunotherapy/chemotherapy were used. Primary outcome was progression-free survival (PFS). Secondary outcomes included disease control rate (DCR) and safety. This study was approved by the SYSMH and SYSUCC Ethics Committee (approval No. 2020-KY-064). Results: Forty-seven patients were enrolled from 2021.1.1 to 2021.10.20, including 41 metastatic and 6 de novo ABC patients. Eribulin was used as first-line therapy in 12 (25.5%) patients, second-line therapy in 24 patients (51.1%), and third-line therapy in 11 (23.1%) patients. More than 90% of the patients did not receive gemcitabine or vinorelbine, and 30.0% of them did not receive anthracycline or taxane previously. DCR was 70.2%, as 24 cases (51.1%) had stable disease and 9 cases (19.1%) had complete or partial remission. In subgroup analysis, median PFSs of 9.6 (95% CI: 6.5-12.7), 7.1 (95%CI: 4.4-9.8), and 5.6 (95%CI: 3.8-7.5) months were observed in patients receiving eribulin as first-, second-, and third-line therapy, respectively. In addition, median PFSs were 7.1 (95% CI: 5.1-9.3), 9.6 (95%CI: 3.6-15.7), 4.6 (95%CI: 4.6-4.6) and 5.8 (95%CI: 4.4-7.3) months for HR+/HER2-, HR+/HER2+, HR-/HER2+, and mTNBC patients, respectively. Other results from the subgroups analysis were shown in table. Common treatment-related toxicity was hematological toxicities including leukopenia (23%), neutropenia (17%), and thrombocytopenia (10%). There was no ≥grade 3 adverse events and no adverse event-related treatment discontinuation. Conclusions: Eribulin monotherapy or combined with targeted therapy was effective and well-tolerated as the first to third lines of treatment in ABC. This promising therapeutic outcome might warrant further studies in early eribulin administration in ABC patients. Clinical trial information: NCT04683445. [Table: see text]
28-gene classifier model for prediction of local recurrence and distant metastasis risk in HER-2 positive operable breast cancer.
Authors: Kang Yikun , Wang Huimin , Ding Ran , Xu Binghe , Yuan Peng
Published: June 2022

e13018

Background: Accurate prediction of postoperative recurrence risk is very important for the formulation of appropriate treatment for breast cancer patients. However, traditional clinicopathological indicators cannot accurately assess the recurrence risk of patients. We aimed to build a novel gene-clinical variable model, which included 28 genetic profiles and clinical variable information, to assess the risk of recurrence in a more individualized and accurate manner. Methods: We retrospectively included a cohort of operable HER-2 positive breast cancer patients treated in Cancer Hospital of the Chinese Academy of Medical Sciences from 2010 to 2016. The genetic and clinical data were used to train and validate the 28-gene classifier model in predicting local recurrence and distant metastasis risk. Results: A total of 260 HER-2 positive breast cancer patients were Included in the study. All patients received standard adjuvant chemotherapy and routine targeted therapy after mastectomy. All patients were followed up for a median of 60.4 months for disease recurrence. Among them, 21 patients had distant metastasis events and 18 patients had local recurrence events. We used the 28 gene-clinical variable model to classify 260 patients into high- and low-risk groups. Kaplan-Meyer survival curves were used to compare the prognostic difference of DFS into high- and low- risk groups. Conclusions: 28 gene-clinical variable model may be a reliable toll to predict local recurrence and distant metastasis risk in HER-2 positive operable breast cancer.
Association of intrathecal trastuzumab to standard therapy in patients with leptomeningeal metastasis in HER2 positive breast cancer.
Authors: Trifanescu Oana Gabriela , Gales Laurentia Minea , Ciornei Ana , Mitrea Dan , Anghel Rodica Maricela
Published: June 2022

e13021

Background: Leptomeningeal metastases are rare but fatal manifestation of metastatic breast cancer, especially in HER2 positive sub-type, with limited treatment options and median overall survival in the range of only 4-6 weeks in untreated patients. Methods: Our prospective study included 9 patients with HER2 positive breast cancer with leptomeningeal metastases that received intrathecal treatment with Trastuzumab along with systemic therapy. Data was compared with a control lot of 9 patients with leptomeningeal metastasis that did not receive intrathecal treatment. Radiotherapy was administered in all patients. The patients included in the study received cures of 150 mg of Trastuzumab injected intrathecal every 3 weeks. Results: Median age of the patients at the time of diagnosis was 53 years. Median time from diagnosis of BC until diagnosis of leptomeningeal carcinomatosis was 3.4 years. Median progression free survival for patients receiving trastuzumab intrathecal was 11.1 months compare with 6.4 months in patients receiving standard treatment, p < 0.019. In our lot of patients, response rate was 66.6%. A clinical benefit with symptoms relief was observed in 77.7% of patients. Mean number of administrations was 12. Two patients presented pain and in two instance the administration was not possible. Concurrent systemic treatment consisted in lapatinib and capecitabine (22.2%), trastuzumab emtansine (44.5%), tucatinib combination (22.2%), vinorelbine (11.1%) and no unexpected toxicity to systemic treatment was noticed. Conclusions: Intrathecal administration of trastuzumab along with systemic treatment and radiotherapy, might improve or stabilise the consequences of leptomeningeal involvement by HER2-positive breast cancer with manageable toxicity.
The CDK4/6 inhibitor FCN-437c plus letrozole for the treatment of HR+/HER2– advanced breast cancer: Updated results from a phase 1b study.
Authors: Zhang Jian , Wang Xiaojia , Wang Xian , Li Wei , Cheng Ying , Huang Tao , Wang Ying , Hui Ai-Min , Wu Zhuli , Tian Ling , Zhao Han , Yang Yuchen , Zhang Wenjing , Zhang Yushun , Hu Xichun
Published: June 2022

e13025

Background: FCN-437c is an oral potent and highly selective CDK4/6 inhibitor without the inhibition of CDK1, CDK2, or CDK5. In the phase 1a dose-escalation part of this study (NCT04488107), the safety profile of FCN-437c was acceptable in patients with ABC, and the maximum tolerated dose was determined to be 300 mg QD when used as monotherapy (presented at AACR 2021). Phase 1b aimed to explore the RP2D and to evaluate the tolerability and antitumor activity of FCN-437c combined with letrozole in patients with previously untreated HR+/HER2– ABC. Methods: Adult, post-menopausal female patients diagnosed with treatment-naive ER+/HER2– ABC were eligible for this expansion stage. Patients received FCN-437c once daily at 200 mg or 300 mg on a 21-day-on and 7-day-off schedule in combination with letrozole 2.5 mg once daily in 28-day cycles. The primary endpoints were safety and RP2D. Results: As of November 26, 2021, 29 patients were enrolled and had a median follow-up of 10.4 months. Of these patients, 25 (86.2%) were endocrine-sensitive and 4 (13.8%) were endocrine-resistant. Visceral disease was present in 21 patients (72.4%), and 1 (3.4%) patient had bone-only disease. DLTs of grade 4 neutropenia occurred in 2 patients (40.0%) in 300 mg dose group; they were considered intolerable. One out of the first 6 patients experienced DLTs in 200 mg dose group (grade 4 neutropenia, leukopenia, and thrombocytopenia); these were also considered to be FCN-437c-related SAEs. FCN-437c-related grade ≥3 TEAEs were observed in 26 (89.7%) patients, with neutropenia (n=24, 82.8%) and leukopenia (n=14, 48.3%) being most common. Among the 28 measurable patients, 16 patients had a PR, the ORR was 57.1% (95% CI 37.2–75.5); the CBR was 82.1% (95% CI 63.1–93.9) (Table). Median PFS, DOR, and OS were not reached. At 6 and 12 months, PFS rates were 92.3% and 83.5%, and DOR rates were 100% and 90%, respectively. A RP2D of 200 mg was suggested per safety considerations and preliminary antitumor activity. Conclusions: FCN-437c plus letrozole was well tolerated and demonstrated antitumor activity in patients with previously untreated HR+/HER2– ABC. FCN-437c in combination with NSAI as the first-line treatment for HR+/HER2– ABC will be further investigated in a phase 3 trial. Clinical trial information: NCT04488107. [Table: see text]
Single center experience with alpelisib-fulvestrant in heavily pretreated women with HR(+), HER-2 (−) metastatic breast cancer.
Authors: Tryfonopoulos Dimitrios , Tzouda Vasiliki , Zouki Dionysia , Kyriakidou Athina , Sarris Evangelos , Grivas Anastasios , Gouveris Panagiotis , Papaxoinis George , Demiri Stamatina G
Published: June 2022

e13034

Background: HR-positive, Her2-negative metastatic breast cancer patients harboring PIK3CA mutations are associated with resistance to endocrine therapy and worse prognosis. Results from the phase III SOLAR-1 trial demonstrate improved PFS for patients treated with Alpelisib-Fulvestrant after failure on first or second line treatment with aromatase inhibitor. Methods: Within an early access program for Alpelisib in a single oncology center, patients diagnosed with metastatic HR-positive, Her2 -negative breast cancer were screened for PIK3CA mutations. New generation sequencing (NGS) was the preferred technique to identify carriers with PIK3CA mutations on soft tissue or liquid biopsy. Patients who progressed and carried PIK3CA mutations received Alpelisib and fulvestrant as subsequent line of therapy. Results: Among 32 patients (pts) screened, 13 (40,6%) had a PIK3CA mutation. In total, 11 pts received alpelisib. Median age at diagnosis was 57.5 years (range, 39-69). Eight pts (72.7%) had been operated for early-stage breast cancer, 6 (54.5%) had received adjuvant chemotherapy and 5 (45.5%) had received adjuvant radiotherapy. Of 11 pts with evaluable histology, 3 pts (27.3%) had high grade tumors at diagnosis. Ten pts (90.9%) had PR positive tumors. Median Ki67 was 20% (range, 2-80). Eight pts (72.7%) had PIK3CA exon 20 and 3 (27.3%) had exon 9 mutations. Six pts (54.5%) had received prior chemotherapy in the metastatic setting and 10 (90.9%) prior CDK4/6 inhibitor. Three pts (27.3%) received Alpelisib as 2nd line and all remaining patients received alpelisib beyond 3rd line treatment. All pts (100%) had metastasis to the bones, 8 pts (72.7%) to the liver, 6 pts (54.5%) to the lungs and 2 pts (18.2%) to the brain. Until the date of last assessment, Alpelisib was administered for a median of 5.1 months (range, 0.4-21.3). Ten pts were evaluable for response to treatment with Alpelisib. One (10%) had CR, 5 (50%) SD and 4 (40%) PD as best response. Median duration of disease control was not reached. Baseline characteristics were not associated with disease control. Adverse events noticed were thrombocytopenia grade II (1/11), diarrhea grade II (2/11), skin rash grade I &II (4/11), weakness grade III (1/11) and hyperglycemia (3/11). Conclusions: Prevalence of PIK3CA mutations is consistent with published data. Furthermore, combination of Alpelisib-Fulvestrant is a highly active line of therapy even in heavily pretreated patients.