e13575 Background: Homologous recombination deficiency (HRD) can be resulted from dysfunction of BRCA and is associated with sensitivity to platinum, PARP inhibitor and other DNA-damaging drugs. The results from a neoadjuvant trial showed that pathological complete response (pCR) was not significantly higher with cisplatin than with doxorubicin-cyclophosphamide in BRCA1/2-mutated breast cancers (BC). It suggests that BC with HRD might benefit from anthracycline-containing regiment. There are many commercial HRD detection assays, including the FoundationFocus CDx BRCA LOH and myChoice CDx, but there is still no uniform standard in China. Methods: A total of 96 in-house BC samples and 6 HRD positive standard cells (Cat No. CBP90023) were analyzed by whole-genome sequencing (WGS). Besides, 122 BCs from the TCGA database were down-sampled to ̃1X WGS. We constructed a new algorithm for HRD score based on WGS at low coverage as input data to estimate large-scale copy number alteration (LCNA) events on the genome. The sensitivity and specificity were compared between our algorithm and the ShallowHRD. A clinical cohort of 50 BCs (15 cases carrying BRCA mutation) was used to assess the association between HRD status and anthracyclines-containing neoadjuvant treatment outcomes. Results: A 100kb-window was defined as the optimal size by using 41 in-house cases and the TCGA dataset. The threshold of HRD was determined as the number of 10 LCNAs by using 55 in-house BCs with BRCA mutation, with the goal of achieving 95% sensitivity. The sensitivity and specificity of our algorithm were both 100%, while those of the ShallowHRD were 40% and 100%, respectively, by testing standard samples with positive HRD. Meanwhile, similar results were also observed that the sensitivity of our algorithm was far superior to ShallowHRD (87% vs 13%) in the clinical cohort. The association between HRD status and BRCA mutations was compared between our algorithm and the ShallowHRD by 120 BC WGS samples (20 cases carrying BRCA mutation) from the TCGA database. The results showed that BRCA status was significantly associated with HRD status by our algorithm and ShallowHRD (P = 0.00838 and P = 0.00284, respectively). However, our algorithm had a higher positive concordance rate than the ShallowHRD algorithm (70% vs 60%). In the clinical cohort of neoadjuvant treatment, HRD group was more likely to respond to anthracycline-containing chemotherapy than non-HRD group, with outcomes of pCR (OR = 9.5, 95% CI: 1.11–81.5, p = 0.04) and residual cancer burden score of 0 or 1 (RCB0/1) (OR = 10.29, 95% CI: 2.02–52.36, p = 0.005). Among 35 patients lacking BRCA mutations, HRD group tended to have RCB0/1 responses compared to non-HRD group (OR = 6.0, 95% CI: 1.00–35.91, p = 0.05). Conclusions: Here, we developed a new stable algorithm for HRD score. It’s a promising assay for clinical application to predict sensitivity of DNA-damaging drugs.
e22525 Background: BARD1 (BRCA1-associated ring domain 1), nuclear partner of BRCA1, has been recognized as a breast cancer predisposition gene. Recently, two large-scale population-based case–control studies confirmed that germline loss-of-function mutations in BARD1 were associated with a risk of breast cancer. Since the germline mutation frequency of BARD1 is much less than that of BRCA1/2, the distinct mutation spectrum of BARD1 is still obscure, especially in Chinese breast cancer patients. To verify the utility of BARD1 genetic testing in Chinese population, we assessed the mutational frequency and spectrum of BARD1 in a sequential series of Chinese high-risk breast cancer patients. Methods: A cohort of high-risk breast cancer patients (n = 1449) were collected in Zhejiang Cancer Hospital from 2008 through 2020, including 608 familial breast cancer (BC) cases, 173 bilateral BC cases, 222 triple negative BC cases, 436 early-onset BC cases (≤40 years) and 10 male BC cases. The complete coding sequence and intron–exon boundaries of BARD1 were screened by a 98-gene panel sequencing assay. The SIFT, Polyphen2 and MutationTaster prediction programs were used for analyzing the effect of the variants of unknown significance (VUS) on the BARD1 protein function. Results: A total of three BARD1 pathogenic mutations (c.1348_1349delinsCAT, c.70_71insGT and c.373G > T) were identified, which had been all reported, and accounting for 0.2% (3/1449) in Chinese high-risk breast cancer patients. The frequencies were 0.33% (2/608) and 0.12% (1/841) in familial and non-familial breast cancer patients, respectively. In total, 19 VUSs including 17 missenses, one inframe deletion and one inframe insertion of BARD1 were identified in this study. Based on in silico analysis, nine BARD1 missense variants (c.76A > G, c.1912G > A, c.1693C > T, c.2191C > T, c.127C > A, c.1601C > T, c.443G > A, c.233G > A and c.1972C > T) were classified as potentially damaging. However, the two newly variants c.420_422del and c.68_69insTCCGGGAACGAGCCTCGTTCC still remain VUS, and the other eight variants were classified as benign. Conclusions: Our data presented the germline mutations of BARD1 in a large-scale Chinese high-risk breast cancer population, which accounted for 0.2% in our cohort. Moreover nine potential pathogenic variants were found based on in silico analysis. Clinically, these data may be helpful in genetic counseling of breast cancer patients with BARD1 germline mutation. While the further research on the VUS are needed.
e13576 Background: BRCA1/BRCA2, representing as an important genetic biomarker of breast cancer (BCA), can provide clinically significant implications for personalized risk assessment, effective treatment option, and prognostic prediction. Methods: We here proposed the BRCANet, a novel end-to-end convolutional neural network for noninvasively determining BRCA1/BRCA2 mutation by integrating clinical, radiomics and deep learning of dynamic contrast-enhanced (DCE) MRI. BRCANet accepts different forms of medical data including clinicopathologic identifications, high throughput radiomics and deep imaging features of breast MRI using a deep hybrid neural network for data/feature integration. Model training and cross-validation was performed in 132 case-controlled BCA patients from two in two tertiary care hospitals, in which clinicopathologic, genomic and image data of BCA lesions were available and center-standardized for study analysis. Results: Results show that a BRCANet-Plus model, embedded with clinicopathologic, radiomics and deep MRI features achieves an arear under curve of (0.783; 95% confidence intervals [CIs], 0.704 - 0.848) for predicting BRCA1/2 mutation, outperforming the compared state-of-the-art methods, i.e., BRCANet derived from image-only data (0.743; 95% CIs, 0.659 - 0.815; p = 0.037), and BRCARad derived from radiomics-only data (0.734; 95% CIs, 0.649-0.807; p = 0.031). After net benefit evaluation, the proposed BRCANet-Plus shows promise to improve diagnostic performance against conventional clinical or image approaches. Conclusions: Therefore, we concluded the presented deep hybrid approach by integrating multimodal clinical-imaging data, especially breast MRI, have a great potential to predict BRCA1/2 mutational status of BCA. This proof-of-concept strategy can be utilized for studying similar clinical questions.
Abstract Objective We aimed to investigate the pharmacokinetics, safety, efficacy, and immunogenicity of different dosing regimens (weekly and every three weeks) of inetetamab in combination with vinorelbine in human epidermal growth factor receptor 2 (HER2)+ patients with metastatic breast cancer who had received one or more chemotherapy regimens. Methods HER2+ patients with metastatic breast cancer who had received one or more chemotherapy regimens were included. Eligible patients received inetetamab administered weekly or every three weeks in combination with vinorelbine injection chemotherapy. Pharmacokinetics, safety, efficacy, and immunogenicity were compared between the groups. Results Sixty HER2+ patients were randomized into a single-week administration group ( n = 29) and a three-week administration group ( n = 31). After the final dose in the single-week administration group and the three-week administration group, the mean C max values were 79.773 μg/mL and 146.083 μg/mL; the mean C min values were 30.227 μg/mL and 11.926 μg/mL; the mean AUC tau values were 7328.443 μg·h/mL and 22647.101 μg·h/mL; and the mean C av values were 43.622 μg/ mL and 44.935 μg/mL, respectively. The best overall response (BOR) rates at 24 weeks and unconfirmed BOR rates at 24 weeks were both 40.7% in the single-week dosing group and 40.7% in the three-week dosing group, and the 24-week confirmed disease control rates (DCRs) were 88.9% and 81.5%, respectively. The incidence of adverse events (AEs) was generally consistent across all levels. Conclusion There were slight differences in the mean C max , C min , AUC tau and C av between the three-week dosing group and the single-week dosing group, and the mean steady-state concentrations of C av were comparable; however, there were no differences in efficacy, safety or immunogenicity between the two groups.
Breast cancer,one of the common malignant tumors in women,has shown rising incidence in recent years,posing a serious threat to women's health.The advancement of molecular biology facilitates the revealing of the relationships between signaling pathways and breast cancer.Fibroblast growth factor receptor (FGFR) signaling pathway plays an important role in the proliferation,survival,differentiation,migration,and apoptosis of breast cancer cells.Strategies targeting the FGFR signaling pathway thus exhibit a promising prospect in breast cancer treatment.
Abstract Purpose Germline mutations in CDH1 are associated with hereditary diffuse gastric cancer (HDGC) and have been identified in multiple ethnicities. However, CDH1 germline mutations have seldom been documented in Chinese patients with HDGC, and their frequency remains unclear. Here, we aimed to examine the frequency of CDH1 germline mutations in Chinese patients with HDGC. In total, 285 patients who met the International Gastric Cancer Linkage Consortium 2015 testing criteria of HDGC for CDH1 germline mutations were recruited. Methods All 16 CDH1 exons, including neighboring intronic sequences, were amplified using polymerase chain reaction and screened using Sanger sequencing. Variants were analyzed using Mutation Surveyor V4.0, SIFT, and PolyPhen-2 software. Results Three nonsense and nine missense CDH1 germline mutations were identified in 21 of 285 index cases (7.4%). Two CDH1 germline mutations, N405Y (Asn405Tyr) and W409X (Trp409 Ter ) were identified as new variants. In addition, we found that up to 28.6% of CDH1 mutations in the 21 indicated patients identified as c.1775G > C (E551Q). The frequency of CDH1 mutations was 6.5% (7/108) in HDGC and 7.9% (14/177) in early onset diffuse gastric cancer (EODGC). The mutation detection rate of CDH1 in males and females was 6.7% (4/60) and 8.5% (10/117) in EODGC and 4.6% (3/65) and 9.3% (4/43) in HDGC, respectively. Conclusion These data reveal, for the first time, the type and frequency of CDH1 germline mutations in Chinese HDGC, and demonstrate that germline CDH1 mutations are a noteworthy contributor to the high frequency of HDGC in Chinese.
Abstract Background: Endocrine therapy resistance was classifed as primary and secondary, guiding the first-line (1L) treatment choices for hormone receptor positive, HER2-negative (HR+/Her2-) metastatic breast cancer (mBC). However, it is unknown whether it is primary ET resistance or not to the stage IV de novo patients. Therefore, We performed a retrospective study to predict primary resistance in advance in de novo patients and have a more appropriate treatment strategy. Methods: We identified newly diagnosed with stage IV de novo HR+/HER2- mBC patients received single-agent endocrine therapy (ET) or ET plus CDK4/6 inhibitors (CDK4/6i) in 1L setting from January 1, 2020 to Jun 30, 2022, using the National Cancer Information Database (NCID) in China. Primary ET resistance (PER) was defined as switching to second-line treatment within 6 months after receiving the 1L ET±CDK4/6i, whereas secondary ET resistance (SER) patients were those who received 1L ET±CDK4/6i treatment more than six months. The Chi-Square test was used to compare the baseline characteristics of PER and SER patients. Result: A total of 217 patients who met the inclusion criteria were included in the analysis, among which 161 patients received single-agent ET and 56 patients received ET plus CDK4/6i. 18.4% of the patients were classified as PER patients, whereas 81.6% showed SER patients. PER patients were younger (median age of 52 years vs. 58 years in SER patients, p=0.01). In terms of clinicopathological characteristics, patients with PER have a higher percentage of liver metastases (14/40 (35%) vs. 20/177 (11.3%) in SER, p< 0.01), distant lymph node metastases (19/40 (34%) vs. 45/177 (25.4%) in SER, p = 0.01), and bone metastases (30/40(75%) vs. 97/177(54.8%) in SER, p = 0.02). Furthermore, the PER rate was 21.7% (35/161) in patients received single-agent ET, compare with 8.9% (5/56) in ET plus CDK4/6i patients, p=0.04. Regarding the following treatment pattern in the PER patients, a high percentage of patients received chemotherapy, accounting for 50%, 30% still received another endocrine therapy, and the remaining 20% patients received CDK4/6i combined with endocrine therapy. Conclusions: There is still a significant proportion of de novo HR+/HER2- mBC patients with primary endocrine resistance, a relatively low proportion of PER in patients receiving endocrine in combination with CDK4/6i. Table. The proportion of primary endocrine resistance across treatment regimens in de novo HR+/HER2- metastatic breast Cancer Citation Format: Zhanhong Chen, Xiying Shao, Yabing Zheng, Wenming Cao, Junqing Chen, Weizhu Wu, Ting Wang, Xiaojia Wang. Primary endocrine therapy resistance in patients with de novo HR+/HER2- metastatic breast Cancer: a National Cancer Information Database Analysis in China [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-05-08.
Abstract Background Homologous recombination deficiency (HRD) can result from BRCA dysfunction and is associated with platinum sensitivity, PARP inhibitor, and other DNA-damaging drugs. There are many commercial HRD detection assays, but there is still no uniform standard in China. This study aimed to develop and validate an HRD scoring algorithm. Methods Ninety-six in-house BC samples and 6 HRD positive standard cells were analyzed by whole-genome sequencing (WGS). Besides, 122 BCs from the TCGA database were down-sampled to ~ 1X WGS. We constructed a algorithm named AcornHRD for HRD score based on WGS at low coverage as input data to estimate large-scale copy number alteration (LCNA) events on the genome. The sensitivity and specificity were compared between our algorithm and the ShallowHRD. A clinical cohort of 50 BCs (15 cases carrying BRCA mutation) was used to assess the association between HRD status and anthracyclines-based neoadjuvant treatment outcomes. Results A 100kb-window was defined as the optimal size using 41 in-house cases and the TCGA dataset. HRD positive threshold was determined as HRD score ≥ 10 using 55 in-house BCs with BRCA mutation to achieve 95% sensitivity. The sensitivity and specificity of AcornHRD were both 100%, while those of the ShallowHRD were 40% and 100%, respectively. Meanwhile, AcornHRD sensitivity was superior to ShallowHRD (87% vs 13%) in the clinical cohort. BRCA status was significantly associated with HRD status by AcornHRD and ShallowHRD (P = 0.00838 and P = 0.00284, respectively). However, AcornHRD had a higher positive concordance rate than the ShallowHRD algorithm (70% vs 60%). In the clinical cohort of neoadjuvant treatment, the HRD positive group was more likely to respond to anthracycline-based chemotherapy than the HRD negative group, with outcomes of pCR (OR = 9.5, 95% CI: 1.11–81.5, p = 0.04) and residual cancer burden score of 0 or 1 (RCB0/1) (OR = 10.29, 95% CI: 2.02–52.36, p = 0.005). Among 35 patients lacking BRCA mutations, the HRD positive group tended to have RCB0/1 responses compared to the HRD negative group (OR = 6.0, 95% CI: 1.00–35.91, p = 0.05). Conclusion Here, we developed a stable algorithm for the HRD score. A promising assay for clinical application to predict the sensitivity of DNA-damaging drugs.
Abstract Background: Human epidermal growth factor receptor 2 (HER2) targeted therapy in combination with chemotherapy is the recommended first-line strategy for HER2-positive metastatic breast cancer. Pyrotinib is a small molecule tyrosine kinase inhibitor targeting HER1, HER2, and HER4. The phase 3 PHOEBE trial has proved its superiority over lapatinib when in combination with capecitabine in previously treated, HER2-positive metastatic breast cancer. This phase 2 trial aimed to investigate the activity of pyrotinib plus docetaxel as first-line treatment in HER2-positive metastatic breast cancer. Methods: Patients with measurable disease received oral pyrotinib 400 mg once daily until disease progression or intolerable toxicity. Intravenous docetaxel was given at 75 mg/m2 on day 1 for at least six 21-day cycles. The primary endpoint was investigator-assessed objective response rate (ORR) per RECIST 1.1. As per Simon’s optimal two-stage design, if 18 or more of 27 patients achieved complete response (CR) or partial response (PR) in the first stage, additional 40 patients would be enrolled. If 47 or more of 67 patients achieved CR or PR, the study was deemed successful. Considering a dropout rate of 15%, 79 patients were needed. The study is registered with ClinicalTrials.gov, NCT03876587. Results: Between June 2019 and June 2021, a total of 79 patients enrolled and received study treatment. As of June 18, 2021, 14 patients had not undergone response evaluation or had unconfirmed response, while 65 patients were included in the full analysis set. There were two patients meeting the exclusion criteria, leaving 63 patients in the per-protocol set. Of 65 patients, the median age was 52 years (range, 28-70). Most of them had Eastern Cooperative Oncology Group performance status of 1 (69.2%), visceral metastases (56.9%), hormone receptor-positive disease (55.4%), and prior (neo)adjuvant therapy with (27.7%) or without trastuzumab (32.3%). In the first stage, 24 of 27 patients achieved confirmed objective response (one CR and 23 PR), and the study proceeded to the second stage. The confirmed ORR in 65 patients was 78.5% (95% CI, 66.5%-87.7%); two patients achieved CR and 49 achieved PR. The confirmed ORR in the per-protocol set (n=63) was 81.0% (95% CI, 69.1%-89.8%). Progression-free survival was immature. Of 65 patients, the most common grade ≥3 treatment-emergent. adverse events included decreased neutrophil count (30.8%), decreased white blood cell count (26.2%), diarrhea (20.0%), and hypokalemia (6.2%). Grade ≥3 diarrhea was less common in patients with loperamide prophylaxis (5.3%; 2/38) than in those without loperamide prophylaxis (40.7%; 11/27). Conclusions: Pyrotinib in combination with docetaxel exhibits promising antitumor activity and acceptable safety profile among patients with HER2-positive metastatic breast cancer in the first-line setting. Loperamide prophylaxis is an effective approach for the prevention of diarrhea. Citation Format: Xiaojia Wang, Jian Huang, Yabing Zheng, Xiying Shao, Wenming Cao, Zhanhong Chen, Yanxia Shi, Li Cai, Wenyan Chen, Zhen Guo, Jian Liu, Peng Shen, Yiding Chen, Xian Wang, Huiping Li, Man Li. Pyrotinib in combination with docetaxel as first-line treatment for HER2-positive metastatic breast cancer (PANDORA): A single-arm, multicenter phase 2 trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-31.
1072 Background: Apatinib is an oral, highly potent tyrosine-kinase inhibitor targeting VEGFR2. A series of clinical studies have shown that anti-angiogenic drugs combined with chemotherapy enable to improve the efficacy of HER2-negative advanced/metastatic breast cancer(MBC). Methods: Patients with HER2-negative MBC with less than two lines of systemic therapy were enrolled in this open-label, controlled, phase II trial. Patients with measurable disease were randomly assigned, in a 1:1 ratio, to receive oral apatinib (250 mg once daily) combined with chemotherapy(A+CT) or chemotherapy(CT) alone (the physician’s choice) until disease progression or intolerable toxicity. The primary end point was progression-free survival(PFS), which was assessed by investigator and was analyzed on an intention-to-treat basis. Results: Between August 2017 and January 2021, of the 80 patients who underwent randomization, 40 were assigned to receive apatinib plus chemotherapy(A+CT) and 40 were assigned to receive standard therapy(CT). As of January 2022, 10 patient had not undergone response evaluation or dropout, 70 patients(36 patients in A+CT, 34 patients in CT were finally included with PFS events and 72 patients were included in safety set. Median PFS was significantly longer in A+CT than in CT (182 days vs 63 days; P = 0.043);The median PFS of TNBC subgroup (11 in A+CT group, 14 in CT) was longer in the aptinib group than in CT group (167 days vs 63 days; P = 0.637);The median PFS of HR+ subgroup(25 in apatinib group, 20 in chemotherapy group) was longer in the aptinib group than in CT group (259 days vs 56 days; P = 0.054);The median PFS of patients with liver metastases(19 in apatinib group, 17 in chemotherapy group) was longer in the aptinib group than in the CT group (151 days vs 54 days; P = 0.191); The severe adverse reactions (grade 3/4) were neutropenia(22.2% vs 13.9%), hypertension(11.1% vs 0.0%), leukopenia(8.3% vs 8,3%), hypokalemia(8.3% vs 2.8%), anemia(5.6% vs 11.1%), ALT(2.8% vs 8.3%), AST(0.0% vs 5.6%) in the apatinib group and the CT, respectively. Proteinuria did not occur in both groups. Treatment delay or dose reduction owing to adverse event was 16.7% and 11.1%, respectively. Treatment discontinuation owing to adverse event was 23.5% and 8.8%, respectively. Conclusions: Apatinib combined with chemotherapy showed a significant improvements in PFS and a manageable safety profile in HER2 negative MBC.
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