bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of plasma circulating HER2/EFTUD2 ratio in predicting pathological complete response (pCR) after neoadjuvant dual anti-HER2 therapy in HER2-positive breast cancer (HER2+ BC).
Authors: Chan Jeffrey CH , Cho William CS , Chow James CH , Bao Kelvin K H , Leung Alex KC , Szeto Michelle OY , Ho Connie HM , Yiu Harry HY
Published: June 2023

e12592

Background: Achieving pCR following neoadjuvant chemo and anti-HER2 therapy is associated with a significantly better survival in HER2+ BC. There is currently a lack of a robust biomarker to predict pCR in HER2+ BC. Using EFTUD2 as chromosome 17 reference probe, circulating HER2/EFTUD2 plasma DNA copy number ratio (H-ratio) detected by droplet digital PCR (ddPCR) was shown to have high concordance with the tumor HER2 status. We aim to evaluate whether the change in H-ratio is associated with response to neoadjuvant dual anti-HER2 therapy. Methods: We prospectively recruited patients with HER2+ BC who received neoadjuvant taxane, trastuzumab and pertuzumab followed by radical surgery from May 2019 to April 2022. Serial plasma samples (n = 49) were collected at pre-treatment (Tpre), at 4th cycle (Tmid) and at completion of neoadjuvant treatment (Tpost). H-ratio was determined in each plasma sample using droplet ddPCR (QX200 ddPCR system, Bio-rad). H-ratio responders were defined as patients having a declining Tpost H-ratio, whereas patients having a rising or persistent Tpost H-ratio were defined as H-ratio non-responders. The relationship between pCR, H-ratio and various clinicopathological characteristics were evaluated by Spearman’s correlation, Fisher’s exact test and Wilcoxon signed-rank test. Results: Eighteen clinical stage II or III HER2+ BC patients with a median age of 56 years old (range 33 - 71) were included. The median H-ratio at Tpre, Tmid and Tpost were 1.27, 1.12 and 1.10, respectively. Higher Tpre H-ratio was significantly associated with larger tumor size (p = 0.004) and higher tumor grade (G1-2 vs G3; median H-ratio 1.15 vs 1.78; p = 0.024). Six patients (33.3%) were H-ratio responders. Ten (55.6%) of 18 patients achieved pCR after completion of neoadjuvant treatment. The pCR rate in H-ratio responders was significantly higher than the H-ratio non-responders (100% vs. 36.4%; p = 0.017). In predicting pCR, H-ratio response outperformed hormonal receptor (HR) negativity (HR- vs HR+; 72.7% vs 28.6%; p = 0.088) or high tumor grade (G1-2 vs G3; 66.7% vs 33.3%; p = 0.201). There was no association between pCR and Tpre/Tmid/Tpost H-ratio. With a median follow up of 22.8 months (range 8.2 - 41.8), there were no relapse or death. Conclusions: A high pre-treatment plasma circulating HER2/EFTUD2 ratio is associated with large tumor size and high tumor grade in HER2+ BC. The decline of HER2/EFTUD2 ratio after neoadjuvant dual anti-HER2 therapy predicts pCR, and may serve as a potential biomarker for treatment de-escalation.
Homologous recombination deficiency (HRD) status to predict the efficacy and prognosis of platinum-based neoadjuvant chemotherapy in patients with triple-negative breast cancer.
Authors: Jin Xuan , Chen Minyan , Chen Hanxi , Chen Lili , Lin Yuxiang , Wu Long , Tang Ganghuai , Li Weiwei , Huang Zhan , Li Qian , Zhu Changbin , Guo Wenhui , Fu Fangmeng , Wang Chuan
Published: June 2023

e12605

Background: Triple negative breast cancer (TNBC) is the most aggressive type of breast cancer, and the predictive role of homologous recombination deficiency (HRD) in TNBC treated with platinum-based neoadjuvant chemotherapy (NCT) is not well described. Here, we sought to assess the association of HRD with pathological complete response (pCR) and survival outcomes in TNBC patients treated with NCT. Methods: 123 patients with stage II to III TNBC received one type of NCT regimen, including paclitaxel followed by anthracycline and cyclophosphamide-based NCT, and platinum-based NCT were enrolled in this study. The optimal cutoff of HRD score was determined by the Youden’s index on the ROC curve. HRD status was defined by either HRD score ≥ threshold or BRCA1/2 [tumor BRCA (t BRCA) and/or germline BRCA (g BRCA)] mutation. Logistic regression analysis was used to analyze the relationship between HRD and pCR. The Kaplan-Meier method, log-rank test and Cox regression were used for survival analysis. Results: A total of 104 FFPE and paired blood samples were successfully profiled from the 123 patients. The optimal cutoff for the HRD score of 58 was calculated based on the maximum Youden index value (0.235). HRD-High (HRD-H) was defined by either HRD score ≥ 58 or BRCA1/2 mutation. Of the 104 patients, 11.54 % (12) demonstrated BRCA mutation (g BRCA1 = 4, g BRCA2 = 4, t BRCA1=2 and t BRCA2 = 2), and another 46.15% (48) demonstrated HRD-H. In univariate logistic regression analysis, HRD status was significantly associated with a better pCR (p = 0.025, OR = 3.071, 95% CI: 1.154-8.175). Patients with HRD-H (p = 0.0103) or BRCA1/2 mutation (p = 0.0199) were all associated with superior event-free survival (EFS). There was a trend toward improved distant disease-free survival (DDFS), breast cancer–specific survival (BCSS), and overall survival (OS) in patients with HRD-H or BRCA1/2 mutation compared with HRD-Low or BRCA1/2 wild-type, although the differences did not reach statistical significance. Homologous recombination repair (HRR)-related genes mutation status was only associated with EFS (p = 0.0458). In multivariate logistic regression, Stromal tumor-infiltrating lymphocytes (sTILs) (p = 0.033, OR = 3.134, 95% CI:1.096-8.963) and HRD status (p = 0.015, OR = 4.014, 95% CI: 1.306-12.332) were both significantly associated with pCR. Conclusions: TNBC patients with HRD-H or BRCA1/2 mutation were more likely to benefit from platinum-based standard NCT.
INSIGHT-HER2BC: Real-world evidence of TCHP regimen to describe the best patient profile and open up questions—The interim results.
Authors: Zhukova Lyudmila , Sorokina Irina , Danilova Anastasia , Yurchenkov Alexander , Pokataev Ilya , Alekseenko Irina , Stroyakovsky Daniil
Published: June 2023

e12607

Background: Neoadjuvant therapy (NAT) of TCHP regimen is approved for standard therapy for early and locally advanced HER2-positive breast cancer (eHER2+ BC) based on encourage TRYPHAENA and KRISTINE trials results. There are limited data regarding patients (pts) treatment outcomes after NAT TCHP in the routine clinical practice. Here we presented the 1st results of ambispective observational program to assess the efficacy and safety of cancer therapy in patients with solid tumors. Early HER2+ breast cancer group: INSIGHT-HER2BC. Methods: We ambispectively reviewed medical records of pts with eHER2+ BC who underwent NAT 6xTCHP (6 docetaxel/carboplatin + trastuzumab/pertuzumab) at three Moscow oncology centers since Jan’2017. This ongoing trial has launched in Feb’22. Here is presented descriptive analyses of pCR (ypT0/is, ypN0) rate for pts who completed NAT and 1-3 yrs. disease-free survival (DFS). Results: At the data cut-off (Jan’2023) 934 pts with HER2+ eBC underwent ≥ 1 cycle of NAТ. The median age is 54.3 y.o. (range: 22-78) where 36% pts were older 60 y.o.; 14% pts - younger than 40 y.o. 75% (571) pts had surgery results. pCR rate is related to KRISTINE trial: 58% (330) pts in the ITT (intention-to-treat) population vs 56% pts, respectively. pCR rate for pts with locally advanced BC is 55% vs 59% for operable BC (114/208 and 215/363 pts, respectively). There is difference in pCR rate achievement according to hormone status (HR+ vs HR-) and HER2 status (3+ vs 2+/ISH +). 1-yr. DFS for pCR group is 97% vs 94% for non-pCR; 2-yr. DFS is 83% vs 83%, respectively, and 3-yr. DFS 64% for pCR group vs 58% for non-pCR. In HR-HER2+ BC the biggest drop between pCR and non-pCR is registered at the 3-yr. DFS: 56% vs 22% while in HR+HER2+ there is almost equal decrease was observed every yr.: 97% vs 93% - 1st yr.; 90% vs 85% - 2nd yr.; 72% vs 68% - 3d yr. Conclusions: NAT TCHP is the effective regimen for HER2+ eBC in the real-world population. The efficiency is observed regardless of disease stage and age. However, there is clear unmet need to find new therapeutic options for HER2 (2+/ISH+) BC. Preliminary results of DFS is markedly lower than in TRYPHAENA and KRISTINE trials but in conjunction with another real-world evidence data. DFS in HR+HER2+ and HR-HER2+ pts likely reflects distinct tumor biology. The mature data for long-term outcomes are awaited. [Table: see text]
Retrospective analysis of Ki-67 as a predictive and prognostic marker for pathological complete response to neoadjuvant chemotherapy in breast cancer.
Authors: Randhawa Amritjot Singh , Roy Partha Sarathi , Hazarika Munlima , Ahmed Shiraj
Published: June 2023

e12610

Background: According to GLOBOCAN 2020, breast cancer with an estimated 2.3 million new cases (11.7%) is the world's most common cancer. Ki-67 has been established as a proliferation marker in breast cancer. However, there are still some conflicting results on the clinical significance of Ki-67 as predictive and prognostic marker for effectiveness of neoadjuvant chemotherapy. In this retrospective study, Ki-67 is evaluated as predictive and prognostic marker for effectiveness of neoadjuvant chemotherapy (NACT). Methods: Study design: A retrospective observational single institutional study. Place of study: Tata memorial Centre - BBCI, Guwahati. Study period and duration: November 2018 to October 2021 (3 years). Study population: All female patients with biopsy-proven breast cancer. Inclusion criteria: All female patients with the diagnosis of breast cancer, who received NACT. Exclusion criteria: Patients who did not receive NACT, patients who did not undergo surgery after NACT, patients who lost to follow-up after chemotherapy, and patients whose pre-chemo Ki- 67 was not available. Sample size: 2272 patients were reviewed, out of which 127 patients were included in this study. Assuming 30% of patients have a complete response, allowing an error of 8% on these, 127 samples were required for the study at a 95% confidence interval. ROC (receiver operating characteristic) curve analysis was done to know the optimal cut-off value for the Ki-67 labeling index (LI) to discriminate response to treatment. Chi-square test was applied to know the relation between receptor status (ER, PR, HER2neu) and pCR. The pathological response was assessed in reference to Miller-Payne score. Results: Age <40years (22.83%), >40years (77.17%); commonest histology, IDC (95.28%); grade 2 (59.84%), grade 3 (40.16%); ER negative with pCR, 88.2%, p < 0.05; PR negative with pCR, 88.2%, p < 0.05; HER2 positive (treated with trastuzumab) with pCR, 55.8%, p < 0.05; triple negative with pCR, 41.2%, p < 0.05; chemo regimen, 4AC->4T (37%), 4AC->4TH (32.3%); pCR, 26.77% (n=34/127); and Ki-67 LI of 27%, sensitivity 95.4%, specificity 21%. Conclusions: Neoadjuvant chemotherapy is more efficient in tumors presenting with at least 32% Ki-67 expression. A high sensitivity of 95.4% and low specificity of 21% indicate Ki-67 LI is not a reliable predictive and prognostic marker. Other markers like ER, PR, and HER-2 influenced the disease outcome significantly. In our study, ‘PR negative’, ‘ER negative’, ‘HER-2 positive treated with trastuzumab’ and ‘triple negative’ were significantly associated with pCR (p < 0.05). This indicates that pCR rate depends on ER/PR/Triple negativity rates or the rate of HER-2 positivity treated with trastuzumab. Ki67 by itself is poor marker. However, when combined with ER/PR/HER2, it can become predictive of responses at cut off 27% in our study to differentiate the subgroups.
Neoadjuvant PARP inhibitors in patients with early HER2-negative breast cancer harboring BRCA 1/2 germline mutations: A systematic review and meta-analysis.
Authors: Dacoregio Maria Inez , Vilbert Maysa , Stecca Carlos , Michelon Isabella , Castro Caio , Amir Eitan
Published: June 2023

e12611

Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) are approved for the treatment of germline BRCA mutated (gBRCAm) breast cancer (BC) patients in the adjuvant and metastatic settings. Several studies have explored the role of PARPi in the neoadjuvant setting both with and without chemotherapy. Here, we explore the efficacy and safety of neoadjuvant PARPi in early HER2-negative BC patients. Methods: We searched PubMed, Scopus, and the Cochrane Library databases for randomized (RCT) and non-randomized clinical trials (non-RCT) that reported the proportion of patients with pathological complete response (pCR) after neoadjuvant PARPi and safety. Statistical analysis was performed using R software. Data were pooled using the random effects model. Results: Analysis included 3 RCTs and 4 non-RCTs, with 942 HER-2 negative breast cancer patients, 293 harboring a gBRCA 1/2 mutation. In a pooled analysis, gBRCAm carriers achieved a significantly higher rate of pCR than BRCA wild-type patients (56% versus 37%, p=0.04) with neoadjuvant PARPi. There was no difference in pCR when PARPi were combined with carboplatin (+/- chemotherapy) (40% versus 44%, p=0.69). Among RCTs (n=457) patients received PARPi in combination with either Paclitaxel plus Carboplatin (PCb) (85%) or with Paclitaxel alone (P) (15%). PARPi were associated with a higher pCR which approached, but did not meet statistical significance (51% vs 41%; Odds Ratio [OR]: 1.30, 95%CI 0.97 to 1.74, p=0.08). gBRCAm was associated with higher pCR compared to wild type in RCTs analysis (60% versus 48%; OR: 1.64, 95%CI 1.01 to 2.68, p=0.05). The most common adverse events (AEs) were cytopenias, nausea, fatigue, alopecia, and dizziness. Hematological toxicities were the most frequent serious AEs, including anemia (15%), neutropenia (22%), and thrombocytopenia (3%). The combination of PARPi and carboplatin was associated with higher hematological AEs (78% versus 46%; P=0.002). Conclusions: The addition of PARPi in the neoadjuvant setting improves pCR in early-stage HER2-negative breast cancer and germline BRCA 1/2 mutations, but not for unselected patients. Combination of PARPi with carboplatin does not improve pCR and leads to substantially worse toxicity. Further studies are warranted to identify the best neoadjuvant PARPi schema.[Table: see text]
DCE-MRI-derived microvasculature mapping and outcome prediction in patients with breast cancer.
Authors: Stefka Andrew T. , Feiger Bradley , Pfeiffer John R. , Pandey Tushar , Peterson Joseph R. , Antony Anuja K.
Published: June 2023

e12614

Background: Tumor response to neoadjuvant therapy (NAT) in patients with breast cancer is related to perfusion in the tumor microenvironment and surrounding tissue. Direct and indirect measures of microvascular (MV) permeability could improve the ability to predict short- and long-term patient outcomes. Detection and quantification of circulating tumor DNA (ctDNA) is one such measurement that depends on microvasculature and has been shown to strongly correlate with both response to therapy and overall prognosis in a wide range of cancers. We hypothesized that a combination of ctDNA and numerical computations of MV permeability using pretreatment dynamic contrast-enhanced (DCE) MRI images (MV maps) can predict patient response to NAT and long-term survival outcomes. Here, we show how MV maps — computed from standard-of-care (SOC) imaging — improve upon ctDNA measurements in predicting pathologic complete response (pCR) following NAT as well as distant recurrence free survival (DRFS). Methods: DCE-MRIs were obtained for a sub-sample of I-SPY2 patients (n = 81) whose ctDNA levels were previously reported (Magbanua et al 2021). Tumors were segmented from pretreatment images by a convolutional neural network with manual verification. MV maps were computed using a Tofts-like model to describe the transfer kinetics between microvasculature and extracellular extravascular space. Microvasculature parameters (MVPs), such as median and skewness, were extracted from MV maps to describe the distribution of kinetic parameters in the intra- and peritumoral regions. Logistic regression was used to predict pCR with leave-one-out cross validation. Univariate Cox models were used to stratify DRFS. Results: MVPs exhibited a moderate correlation with pretreatment ctDNA levels (Spearman rho = -0.26; p = 0.018) and with pCR status in this cohort (rho = 0.25; p = 0.026). In a series of logistic regression models, a combination of SOC clinical features and ctDNA levels correctly classified 23% of true pCRs, with an F1 score of 0.58. This predictive power increased when informed by MV maps; 45% of true pCRs were identified after the addition of MVPs, and the F1 score increased to 0.68. In univariate Cox models, 24 MVPs significantly stratified DRFS (p < 0.05) when uncorrected for multiple hypothesis testing bias. The top MVP carried a hazard ratio 3.8 (95%CI 1.6 - 9.0) compared to 11.9 (95%CI 2.7 - 53.6) for ctDNA levels. Conclusions: DCE-MRI-derived kinetic features are calculated from SOC images with no additional clinical intervention. We found that MVPs substantially improve pCR prediction when added to models trained on ctDNA levels and clinical features. ctDNA levels and MVPs were predictive of DRFS to differing degrees of confidence. Although further validation in larger datasets is needed, this exploratory analysis uncovered a promising role for MV maps in predicting response to NAT as well as patient outcomes.
Tumor-infiltrating lymphocytes (TILs) for prediction of response to platinum-based neoadjuvant chemotherapy (NACT) in triple-negative breast cancer (TNBC).
Authors: Abdullaeva Sheyda , Semiglazova Tatiana , Artemyeva Anna , Semiglazov Vladislav , Krivorotko Petr , Semiglazov Vladimir ,   N.N. Petrov National Research Oncology Institute, Saint-Petersburg, Russian Federation
Published: June 2023

e12620

Background: According to several previous trials the rate of pathological complete response (pCR) for patients with TNBC is increased when carboplatin is added to NACT. However, it is largely unknown which group of patients would truly benefit from platinum-based NACT and for whom chemotherapy could be de-escalated. Several clinical trials have evaluated the stromal TILs as an important prognostic and predictive biomarker in breast cancer. We assessed the pCR rates and the outcomes in patients with TNBC randomized to receive NACT ± Carboplatin regarding TILs status. Methods: The clinical data were obtained from 132 patients diagnosed with TNBC (ER&PgR < 10%) and treated with either anthracycline-taxane NACT (n = 68) or сarboplatin-based chemotherapy (n = 64) from 2017 to 2022 at N.N. Petrov National Medicine Research Center of Oncology. TILs were evaluated in 132 formalin-fixed paraffin-embedded tumor tissue samples stained with H&E at baseline biopsies according to guidelines from the International TILs Working Group. Classification of TILs into low ( < 10%), intermediate (≤10% to < 40%) and high (≥ 40%) levels was performed. Data are presented using the methods of descriptive statistics. The differences between groups were assessed using the Сhi-square test. P-values below 0.05 were considered statistically significant. Results: The proportion of patients who achieved a pCR was higher in the carboplatin group 66% than in patients without carboplatin 35% (OR 3,5; 95% CI 1,71-7,17; p = 0,0006). There were 25 (18.9%), 77 (58.3%) and 30 (22.7%) patients with low ( < 10%), intermediate (≤10% to < 40%) and high (≥ 40%) levels of TILs, respectively. In total, the tumors with high TILs had a pCR rate of 63.3%, compared with 46.1% for low TILs (OR 2,0; 95% CI 0,87-4,67; p = 0,097). No significant statistical difference in pCR rates was shown between carboplatin-based and standard NACT groups with high TILs - 71% and 54%, respectively (OR 2,06; 95% CI 0,45-9,30; p = 0,346). When analyzing a group with low TILs infiltration, the pCR was more frequent in the platinum-based 64% compared to 31% in the standard NACT group (OR 3,9; 95% CI 1,72-9,00; p = 0,0011). Conclusions: These data may support the de-escalation of carboplatin-based NACT in patients diagnosed with TNBC with high TILs infiltration. Further investigations are warranted to explore the predictive value of TILs in platinum-based NACT. [Table: see text]
Identifying determinants of pathologic complete response in patients with breast cancer after receiving neoadjuvant systemic therapy.
Authors: Chan Abigail Sy , Bhargava Anika , Chandler Natasha , Tavcar Michelle , Gunaratnam Bakeerathan , Dong Brian
Published: June 2023

e12622

Background: In locally advanced breast cancer, neoadjuvant systemic therapy aims to downstage the disease, clear micrometastasis, assess chemosensitivity, and allow for breast conserving surgery. The attainment of a Pathologic Complete Response (pCR) has been associated with improved event free survival (EFS) and improved overall survival (OS) among various studies. We aim to identify clinicopathological factors which may influence pCR. Methods: This is a single center retrospective study of patients diagnosed with locally advanced breast cancer from 2017-2022 who received neoadjuvant therapy and investigating predictors of pCR in this subset of patients. Descriptive statistics were used to summarize the baseline characteristic variables. Variables relating to pCR were analyzed by binary logistic regression and chi-square test. A p-value of < 0.05 was considered statistically significant. Results: Of the 165 patients included, all were female, with a mean age of 50 and majority (97%) with invasive ductal carcinoma (IDC) histology. Baseline characteristics are summarized. 52 had hormone (HR)pos/Her2neg, 51 with triple negative, 47 had HR pos/Her2pos, and 15 had HR neg/Her2pos disease. pCR was seen in 36% of patients. A normal BMI of < 25 (p=0.03), nonsmoker (p=0.01), grade III (p=0.01), HR pos/Her2pos (p=0.02), and HR neg/Her2pos (p=0.0001), were associated with pCR. In patients with triple negative breast cancer, the use of immunotherapy did not influence pCR (p = 0.0565). There were no differences based on age, race, menopausal status, stage, size, presence of LVI or DCIS or multifocal disease. In the 157 patients where Ki-67 was known, tumors with higher Ki-67 values of 30-49% and > 50% achieved pCR compared to those with lower Ki-67 (p = 0.002). Conclusions: Those with normal BMI, non-smokers, and aggressive clinicopathological factors such as Her2 positive, higher Ki67 (30% and above), and grade III disease were more likely to achieve pCR after neoadjuvant systemic therapy. These findings further identify tumor characteristics most likely to respond to neoadjuvant chemotherapy. [Table: see text]
Neoadjuvant endocrine therapy for early-stage breast cancer: An institutional experience during the COVID19 pandemic.
Authors: Buteau Anne Christine , Chamberlin Mary D. , Tau Steven , Miller Todd W.
Published: June 2023

e12625

Background: Neoadjuvant Endocrine therapy (NET) is under-utilized for locally advanced hormone receptor + breast cancer (BC) despite literature to date concluding that chemotherapy and NET have comparable response rates but with lower toxicity for the latter. The COVID19 pandemic presented a unique occasion to extend the use of NET for localized BC. Many surgical procedures across the country, including at Dartmouth-Hitchcock Medical Center (DHMC) were postponed in order to redirect resources. The American Society of Breast Surgeons released guidelines to manage patients in which surgery was delayed. For Estrogen Receptor + (ER+), HER2- early-stage tumors, the guidelines recommended NET as first-line treatment. Herein we review the rate of adoption of NET and patient/tumor characteristics associated with NET adoption at DHMC during the lockdown. Methods: A Retrospective analysis of patients diagnosed with early-stage ER+, HER2- BC between December 2019 and June 2020. Inclusion criteria included patients with non-metastatic hormone receptor + BC. Data extracted from chart review included age, menopausal status, tumor stage/grade, body mass index (BMI). A delay in surgery was defined as days between surgical consult and surgery over 14 days. Descriptive statistics will be applied to data collected on patient/tumor characteristics, and the number of patients accepting or declining NET. Results: 109 cases were identified within the study period with 42 cases designated as experiencing delays in surgery. The median age of the group (n = 42) was 62 and the majority was post-menopausal. 36 patients received NET with most started on an aromatase inhibitor. Median BMI was 28.5. Median duration of treatment was 39.5 days. Tumor response to NET was not clearly described in the pathology reports. Three cases were noted to have some decrease in cellularity for pathologic partial response and four had no definite response. Imaging modalities were compared to pathology size and MRI was found to be a fair predictor of size obtained from pathology specimens with a correlation metric of 0.78 indicating that it may serve as the best proxy for pre-treatment size. Pre-surgical MRIs were obtained in 51.3% of cases. The majority of patients on NET had no change in the grade of their pathology. During the course of the pandemic long-term adherence of adjuvant endocrine therapy decreased from 78% for those diagnosed in early 2020 to 56% for those diagnosed in late 2020. Conclusions: The COVID19 crisis was an unprecedented challenge to healthcare systems. Delays in surgery resulted in increased use of NET in early-stage BC. We plan to integrate other data including impact of NET on long-term adherence to endocrine therapy. Change in clinical vs pathologic stage will be reported for those with or without NET. This experience may help guide care during healthcare crises or in resources limited settings.
Pathologic complete response in germline mutation carriers by mutation type and biomarkers in a safety-net population.
Authors: Shah Sidrah , Bulsara Shaun , Hilsenbeck Susan G. , Sullivan Cathy , Garza Georgiann , Tran Tiffaney , Brown Ria , Fang Mary , Osborne C. Kent , Rimawi Mothaffar F. , Higashiyama Nicole , Nangia Julie R.
Published: June 2023

e12628

Background: Pathologic complete response (pCR) after neoadjuvant chemotherapy in early to locally advanced breast cancer has important prognostic implications with high cure rates. Understanding its associations with hereditary breast cancer mutations, specifically by mutation type and biomarkers, adds additional prognostic value. In this retrospective chart review, we investigated pCR rates among patients who have undergone genetic testing in a safety-net hospital comprised primarily of racial minorities. Methods: All patients at Smith Clinic (affiliated with the Harris County’s safety-net hospital system) with a diagnosis of stage I-III breast cancer who agreed to undergo genetic testing, were found to have a genetic mutation from October 1, 2009 to September 30, 2019, and received neoadjuvant chemotherapy followed by lumpectomy or mastectomy were included. Demographic and clinical characteristics as well as post-operative pathologic data were collected. Results: 71 patients qualified for the analysis. 50 (70%) were Hispanic, and the median age was 42. 41 (58%) were BRCA1+, 13 (18.3%) were BRCA2+, and 12 (16.9%) were PALB2+. They ranged from stage I-III, with 49% falling in stage III. In terms of biomarker status, triple negative breast cancer (TNBC) comprised 35 (49%) patients, HER2+ 8 (11%), and ER+ and/or PR+ (HER2-) 28 (39%). 36 (51%) were treated with both neoadjuvant anthracycline and taxanes. pCR rates were highest among triple negative cancers (17, 48%). 16 (39%) of patients with a BRCA1 mutation achieved pCR, 5 (38.5%) of BRCA2 patients and 3 (25%) of PALB2 patients. RCB class by mutation type and biomarker status will be reported as well as a more detailed analysis of pCR by mutation status and biomarkers. Conclusions: In our population of primarily Hispanic patients, those with BRCA1, BRCA2, and PALB2 had the highest pCR rates. As expected, patients with TNBC had the highest pCR rates. More data in patients with germline mutations may help us determine prognosis and how to best treat these patients. [Table: see text]
D-dimer as a predictive biomarker of response to chemotherapy in patients with metastatic breast cancer.
Authors: Alkhoder Lubana , Alwassouf Sulaf , Salamoon Maher , Saifo Maher
Published: June 2023

e13000

Background: Tumor-induced coagulation is considerably observed in cancer patients. Moreover, it is associated with tumorigenesis, tumor progression, and metastasis, by creating a proliferative and proangiogenic microenvironment. Therefore, D-dimer, a fibrin degradation product, correlates with tumor prognosis in several cancer types. This study aims to investigate whether D-dimer levels can be a predictive and monitoring indicator for chemotherapy response in metastatic breast cancer (MBC) patients. Methods: This study included two groups, 76 patients diagnosed with metastatic breast carcinoma, and 25 with early breast carcinoma as a control group. Plasma D-dimer levels were measured prospectively before chemotherapy initiation, and after the fourth treatment cycle in MBC patients. The levels of D-dimer before chemotherapy (D0) were analyzed using receiver operating characteristic (ROC) curves to determine the optimal cutoff baseline values of D0, and to evaluate their discriminatory abilities in predicting response to chemotherapy. Results: In the preliminary response evaluation, the mean level of D-dimer significantly decreased by 2.74 μg/ml in patients with partial response, and by 2.17 μg/ml in patients with stable disease. In the progression disease group, a considerable increase was seen in D-dimer levels by 2.16 μg/ml. Analysis of ROC curves showed that D-dimer levels at D0 could discriminate the response to chemotherapy, whereas the progressive disease rate correlated with higher levels of D-dimer (>1.055 μg/ml; P= 0.000). Conclusions: D-dimer level in plasma is a useful predictive and monitoring marker of response to chemotherapy in metastatic breast cancer.
Prevalence of BRCA1 and BRCA2 mutations in an unselected cohort of Indian women with breast cancer.
Authors: Gogia Ajay , S G Nithin , Pramanik Raja , Gupta Ritu , Deo S.V.S. , Mathur Sandeep , Sharma Dayanand , Batra Atul , Prasad Chandra Prakash , Sagiraju Hari Krishna Raju
Published: June 2023

e13004

Background: Familial breast cancer accounts for 10-15% of breast cancer cases. The prevalence of germline pathogenic mutations in breast cancer susceptibility genes 1 and 2 ( BRCA1/2) among female breast cancer patients remained variable across studies depending on the population/settings studied. The estimate varied between 8-10% of the unselected female breast cancer population. There is a lack of data regarding the prevalence of BRCA1/2 among female breast cancer patients in India. Methods: This prospective observational study included consecutive patients with breast cancer in females, registered at All India Institute of Medical Sciences (AIIMS), New Delhi, India between the period of 1st September 2022 to 25th January 2023(5 months duration). The staging description was done as per anatomic TNM staging according to AJCC 7th edition. Mutation testing was performed in all patients by a standard next-generation sequencing (NGS) assay covering the BRCA1/2 gene. The reflex multiplex ligation by probe amplification method was performed in all cases that were negative by NGS. For patients with detected germline mutations in BRCA1/2, post-test counseling was done, and family screening was also advised. Results: A total of 210 female patients with breast cancer were sequentially included in the study. Young breast cancer (less than 35 years of age) constituted 40 (19.04%) cases. Thirty-eight patients (18.09%) women had a positive significant family history. The median age of the cohort was 46 years (range 18-85 years). Synchronous breast cancer was present in 7 (3.3%) cases. The stage distribution was stage I, 11(5.23%); stage II, 73 (34.76%); stage III, 83 (39.52%); and stage IV, 43 (20.47) %. One hundred and ten patients (52.38%) were hormone-receptor-positive, whereas 66 (31.42%) patients were HER2/neu positive. Triple-negative breast cancer (TNBC) was found in 65 (30.95%) cases. Overall, the prevalence of germline BRCA1/2 mutations was 35/210 (16.6%), which included BRCA 1 and 2 mutations in 22 (10.47%) and 12 (5.71) cases respectively. One case had mutations in both BRCA 1 and BRCA2. Young ( < 35) TNBCs (22 cases/210, 10.47%) have a high propensity for detecting pathogenic BRCA1 mutation (8/22, 36.36%). Conclusions: The prevalence of pathogenic BRCA1/2 in 16.6% of our cohort of unselected consecutive breast cancer patients. It is higher than that reported in the Western population likely due to the younger population and more proportion of triple-negative breast cancer patients in our cohort.
Body composition measures as predictors of toxicity in patients with metastatic breast cancer receiving PARP inhibitors.
Authors: Etan Tal , Kessner Rivka , Peleg Hasson Shira , Raphael Ari , Sonnenblick Amir , Zlothover Noa , Epstein Jessica , Shachar Shlomit Strulov
Published: June 2023

e13010

Background: Poor body composition metrics (BCM), such as high adiposity or low muscle mass, are associated with inferior cancer outcomes. Poly ADP-ribose polymerase inhibitors (PARPi) revolutionized the treatment of metastatic breast cancer (MBC) with germline BRCA mutation but can cause substantial toxicity. The recommended dose of PARPi is fixed and neither weight nor BCM are taken into consideration during initial prescription or during dose reductions. We aimed to investigate the association between BCM and toxicity and tolerability to PARPi in MBC patients. Methods: We identified all MBC patients treated with PARPi between 2015-2022 at Tel Aviv Sourasky Medical Center. Using computerized tomography (CT) images taken for the evaluation of disease burden, BCM such as: skeletal muscle area (SMA) and subcutaneous adipose tissue area (SAT), were measured at the level of the third lumbar (L3) vertebrae. Low SMA was defined as < 107.2 cm2 and low SAT was defined as < 190 cm2. Receiver operating characteristic (ROC) curves were used to define these thresholds. Sarcopenia was defined as skeletal muscle index (SMI = SMA/height2) < 41 based on literature. Fisher exact tests and Mann-Whitney U tests were used for statistical analyses. Results: We identified 30 patients with MBC who were treated with PARPi and met the study requirements at a median age of 54 (range 29-87). Median duration of PARPi treatment was 214 days (range 35-921). Among them, 19 (63%) were sarcopenic, 22 (73%) had low SMA, 10 (33%) had low SAT and 17 (57%) suffered from Grade 2-4 adverse events (AE). Patients with sarcopenia had non-significantly more Grade 3-4 AE (42% vs. 18%) and more dose reduction or dose delay events (42% vs. 27%) compared to non-sarcopenic patients. Patients with low SMA had borderline significantly more Grade 3-4 AE, dose reduction or dose delay events (55% vs. 13%, p = 0.065), compared to patients with high SMA. Patients with low SAT had significantly more Grade 3-4 AE (60% vs 20%, P = 0.036), compared to patients with high SAT. Moreover, patients with Grade 2-4 AE had significantly lower SAT compared with patient with < Grade 2 AE (median 183 vs. 298 cm2, p = 0.008). Conclusions: Our study implies an association between BCM and PARPi toxicity and tolerability. Skeletal muscle mass and adipose tissue may be taken into consideration in PARPi treatment and dosing decisions. A larger study is needed to further examine this hypothesis.
Characterization of patients with recurrent breast cancer submitted to neoadjuvant therapy in a Brazilian cancer center.
Authors: Rossato de Almeida Guilherme , Tavares Monique Celeste , Sanches Solange Moraes , Cesca Marcelle Goldner , Leite Luciana de Moura , Lima Vladmir Cordeiro , Campos Fernando Augusto Batista
Published: June 2023

e13013

Background: Breast cancer patients submitted to neoadjuvant therapy have clinical-pathological factors that can correlate with favorable outcomes, such as pathologic complete response (pCR). However, patients who achieve pCR may develop recurrence due to other identifiable risk factors, and some molecular subtypes lack a prognostic marker such as pCR, depending on other factors to determine the risk of recurrence. Objective: Analyse clinical-pathological data from patients with recurrent breast cancer who received neoadjuvant therapy, and identify possible risk factors in this population. Methods: This is an observational, descriptive, retrospective study of patients with recurrent breast cancer, submitted to neoadjuvant therapy between January 2007 and December 2018, at the AC Camargo Cancer Center; São Paulo, Brazil. Of the 1145 patients treated with neoadjuvant therapy, we evaluated 304 who recurred, and crossed data with 841 patients that didn't present recurrence. Results: We analysed 304 patients (26.6%), 60.1% pre-menopause, 6.5% with BRCA1/2 gene mutation, 85.9% had invasive ductal carcinoma (IDC), 53.8% were histologic grade (HG) III, and 84.2% had KI67 >20%. Clinical stage was 44.7% cT4, 28.3% cT3, 25.7% cT2 and 1.3% cT1, while 13.3% were cN3, 21.1% cN2, 43.8% cN1 and 21.7% cN0. Grouped clinical stage was 74.4% III, 25% II and 0.7% I. Molecular subtypes were 52.4% hormone receptor positive/HER2 negative (HR+/HER2-), 12.2% HR+/HER2+, 6.9% HR-/HER2+ and 28.6% HR-/HER2-. Regarding neoadjuvant chemotherapy, 92% received anthracycline and taxane, 23% dose-dense, 17.4% received trastuzumab with or without pertuzumab, and 20% of ER-/HER2- received carboplatin. Chemotherapy interruption occurred in 13.2% of patients, and 31.1% interrupted anti-HER2 therapy. Surgery was 82.9% mastectomy, 77% axillary dissection and 16.4% breast-conserving surgery. Residual Cancer Burden (RCB) score was 13.1% RCB 0, 5.8% RCB I, 35.3% RCBII and 45.8% RCB III. Ninety percent received adjuvant radiotherapy, 9.2% adjuvant capecitabine and 45% of HR+ adjuvant tamoxifen. We observed recurrence association with HG III ( p = 0,001), Ki67 >20% ( p = 0,001), clinical stage III ( p < 0,001), cT4 and cN2/3 ( p < 0,001), RBC > II/III ( p = 0,001), molecular subtypes HR+/HER2- and HR-/HER2- ( p = 0,042), interruption of neoadjuvant therapy ( p = 0,002) and anti-HER2 therapy ( p = 0,012), and use of adjuvant tamoxifen ( p < 0,001). Adjuvant capecitabin and radiotherapy had no correlation with the outcome. Conclusions: Recurrence was associated with intrinsic factors, such as HG III, Ki67>20%, cT4, cN3/4 and molecular subtype, as well as RCB > II/III, treatment interruption and choice of adjuvant hormonal therapy, pointing out possible risk factors in our population.
The mechanism of exosome delivered circ-PDE7B promoting liver metastasis of breast cancer.
Authors: Dandan Wang , Tang Jinhai
Published: June 2023

e13016

Background: According to “seed and soil” hypothesis, tumor microenvironments have major effects on the survival and metastasis of cancers, including breast cancer. Importantly, exosomes are believed to partake in cellular communications through delivering oncogenic ncRNAs (including circRNAs) to the recipient cells and tumor microenvironment, which resulting in distant metastasis. Unfortunately, exosomes delivering circRNAs from breast cancer cells still remained many potential functions that are not completely understood in the progression of liver metastasis of breast cancer. This study aims to provide a theoretical basis to use stable exosomal circRNAs as new biomarkers and target spot for the liver metastasis of breast cancer. Methods: A strategy combining RNA-sequencing technique, RT-qPCR and bioinformatic analysis were used to determine the level of differential expressed circRNAs in tissue exosomes (n=5) and serum exosomes samples (n=5) from liver metastatic breast cancer patients compared with healthy person. The expression of circPDE7B was also detected in tumor tissues (n=10) from liver metastatic patients compared with healthy person, breast cancer cell lines (MDA-MB-231), high-liver metastatic cell lines (LM-MDA-MB-231), exosome from MDA-MB-231 (231/exo) and from LM-MDA-MB-231 (LM-231/exo) by RT-qPCR. In animal experiments, exosomes (enriched in circPDE7B) were injected from tail vein for 24h, follow up with injection with LM-MDA-MB-231 cells, then, fluorescence imaging and pathology showed the metastasis in liver. Results: Isolated serum exosomes were characterization by transmission electron microscope (TEM) and Nanosight 300 (NTA 300) system. We profiled the circRNAs in the tissue and serum exosomes samples from liver metastatic patients and healthy person by RNA sequencing and detected 332 significantly differentially-expressed circRNAs. After bioinformatic analysis with GEO database, circPDE7B was chose to further study. RT-qPCR results showed that higher expression of circPDE7B in liver metastatic tissue and LM-MDA-MB-231, also in LM-231/exo. Moreover, overexpressed circPDE7B in exosomes from breast cancer changes premetastatic microenvironment of the liver microenvironment, which can promote the occurrence of breast cancer liver metastasis. Conclusions: The expression of circPDE7B was found significantly upregulated in tissue and serum exosomes from liver metastatic breast cancer patients. Moreover, circPDE7B could promote liver metastasis of breast cancer. Therefore, this study provides a fresh perspective on novel therapeutic targets and potential biomarkers for liver metastasis from exosomal circRNAs.
The role of ct-DNA in breast cancer surveillance assessing treatment response and recurrence: A community center experience.
Authors: Khalid Farhan , Tayyeb Muhammad , sirpal vishakha , Kashyap Richi , Al-alwan Ahmad , Gupta Rajshree , Singh Vinit , Meghal Trishala
Published: June 2023

e13021

Background: Breast cancer is a heterogeneous disease and primarily classified on immunohistochemistry. Currently treatment is based on biopsy but studies have showed changes in subtype and acquired resistance in the original subtype due to cancer therapies. While biopsy is gold standard, recently liquid biopsy from serum containing circulating tumor DNA (ct-DNA) has emerged as a noninvasive technique of tumor surveillance. Methods: This is a retrospective study approved by the IRB at Monmouth Medical Center. Objectives were to identify use of ct-DNA level and highlight the trends over course of treatment. Subjects were identified by reviewing patient’s charts and included on criteria of age > 18 years and in whom ct-DNA level was followed up. 27 patients were identified and results were obtained by categorizing the patients and calculating the proportions. Results: A total of 27 patients were included. The mean age at diagnosis of cancer was 56.29 years (95% CI 51.19-61.39). Among 27 patients, 11 had left sided and 16 had right sided tumor. The pathology identified was Invasive ductal in 18, adenocarcinoma in 2, lobular in 4, poorly differentiated in 2 and mesenchymal in 1 of the patients. Hormonal subtypes identified were triple negative in 11, ER/PR+ve/Her 2-ve in 8, triple positive in 2, ER/PR-ve/Her 2+ve in 1 and ER+ve in 5 of the patients. Among 27, 8 of the patients had stage I, 15 had stage II, 3 had stage III and 1 had stage IV disease. During the course of treatment, 7 of patients had left, 10 had right and 7 had bilateral mastectomy due to BRCA mutation identified on genetic testing. 3 of the patients did not undergo surgery. ct-DNA levels were elevated 8.05 and 1.31 MTM/ml in 2 patients and subsequently became undetectable and decrease in tumor size was noticed from 6.1 cm to 1.1 cm and 1.8 cm to 9mm. ct-DNA levels remained undetectable the rest of 25 patients and patient’s remained gross tumor free on interval MRI imaging of the breasts. Conclusions: The ct-DNA levels have a great utility in establishing the correlation of treatment effect on tumor volume. All this information is vital for clinical decision making and appropriate management. Therefore, the application of liquid biopsy and ct-DNA analysis in breast cancer opens a window of opportunity that encompasses all possible disease situations: from early diagnosis, through the detection of minimal residual disease, the early detection of relapse, and the monitoring and treatment planning for advanced disease. A limitation of study was low sample size. [Table: see text]
Identifying the optimal therapeutics for patients with hormone receptor-positive, HER2-positive advanced breast cancer: A systematic review and network meta-analysis.
Authors: Wang Yan , Xu Hangcheng , Han Yiqun , Wu Yun , Sa Qiang , Xu Binghe , Wang Jiayu
Published: June 2023

e13023

Background: Hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-positive breast cancer is a distinct subtype with different prognosis and response to treatment. HER2-targeted therapy is currently recommended for patients with HR+/HER2+ advanced breast cancer. However, there is debate over which drugs to add on the basis of HER2 blockade yields the optimal efficacy. Moreover, the research on replacing chemotherapy with endocrine therapy in the regimens are under way. This systematic review and network meta-analysis was conducted to find the optimal treatment for this subtype. Methods: Eligible randomized controlled trials (RCTs) comparing different interventions in metastatic HR+/HER2+ breast cancer were included by comprehensively searching PubMed, Embase, the Cochrane Library, ClinicalTrials.gov, and abstracts of oncology conferences before September 5th, 2022. The outcomes of interest included progression free survival (PFS), overall survival (OS) and treatment-related adverse events (TRAEs). Pooled hazard ratios (HRs) or odds ratios (ORs) with credible intervals (CrIs) were calculated to estimate the predefined outcomes based on the data type. The optimal therapeutics were identified by utilizing the cumulative ranking curves (SUCRA). Results: In total, 23 pieces of literature of 20 RCTs were included. Regarding PFS, significant differences were detected between dual HER2 blockade plus endocrine therapy versus endocrine therapy alone (HR 0.45, 95% CrI 0.25-0.83; HR 0.47, 95% CrI 0.27-0.87), and trastuzumab, pertuzumab plus chemotherapy versus trastuzumab plus chemotherapy (HR 0.69, 95% CrI 0.47-0.96). The SUCRA values suggested the relatively better efficacy of dual HER2-targeted therapy plus endocrine therapy (86% to 91%) or chemotherapy (62% to 81%) in prolonging PFS and OS. The HER2 blockade-containing regimens showed similar safety profiles in eight documented TRAEs. Conclusions: Prominent status of dual-targeted therapy for patients with HR+/HER2+ metastatic breast cancer was revealed. Compared with chemotherapy-containing regimens, the endocrine therapy-containing regimens showed better efficacy and similar safety profile, which could be recommended in practice.