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Abstract The remarkable advances in next-generation sequencing technology have enabled the wide usage of sequencing as a clinical tool. To promote the advance of precision oncology for breast cancer in China, here we report a large-scale prospective clinical sequencing program using the Fudan-BC panel, and comprehensively analyze the clinical and genomic characteristics of Chinese breast cancer. The mutational landscape of 1,134 breast cancers reveals that the most significant differences between Chinese and Western patients occurred in the hormone receptor positive, human epidermal growth factor receptor 2 negative breast cancer subtype. Mutations in p53 and Hippo signaling pathways are more prevalent, and 2 mutually exclusive and 9 co-occurring patterns exist among 9 oncogenic pathways in our cohort. Further preclinical investigation partially suggests that NF2 loss-of-function mutations can be sensitive to a Hippo-targeted strategy. We establish a public database (Fudan Portal) and a precision medicine knowledge base for data exchange and interpretation. Collectively, our study presents a leading approach to Chinese precision oncology treatment and reveals potentially actionable mutations in breast cancer.
Salvage mastectomy is traditionally recommended for patients who developed ipsilateral breast tumor recurrence (IBTR) in light of previous breast irradiation. However, it remains controversial whether surgical axillary staging (SAS) is necessary for IBTR patients with negative nodes. This study aimed to evaluate the oncologic safety of omitting SAS for IBTR.We retrospectively identified patients who developed invasive IBTR with negative nodes after undergoing breast-conserving surgery (BCS) from 2010 to 2018. Patterns of care in nodal staging were analyzed based on prior axillary staging status. Clinicopathologic characteristics and adjuvant treatment of the initial tumor, as well as the IBTR, were compared between the SAS and no SAS groups. Kaplan-Meier method and Cox regression model were utilized to compare the locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), and overall survival (OS) rates after IBTR removal between the two groups.A total of 154 IBTR patients were eligible for final analysis. Compared to the no SAS group, SAS group was less likely to undergo ALND (15.1 vs 73.3%, p < 0.001) at initial BCS, had a longer recurrence interval (2.8 vs 2.1 years, p = 0.03), and were more likely to have discordant molecular subtype (35.8 vs 12.9%, p = 0.001) and different quadrant location (37.7 vs 19.8%, p = 0.02) with primary tumor. However, the extent of axillary staging did not affect systemic or radiation recommendations. In the subgroup of patients without previous ALND, the clinicopathologic characteristics were roughly comparable. No significant differences were observed in LRRFS, DMFS or OS between the two groups.For node-negative IBTR patients, we observed selection bias on the basis of prior ALND, shorter recurrence interval, and concordant molecular subtype favoring no SAS but comparable LRRFS, DMFS, and OS. These results support a wider consideration of sparing SAS in the management of IBTR, especially in patients without previous ALND.
Abstract Background: Some special consensus recommended the duration of perioperative antibiotic prophylaxis was within 24 hours postoperatively in breast cancer undergoing postmastectomy implant breast reconstruction. However, surgeons in practice favored to prolong the duration. The aim of this study was to estimate the effects of duration of antibiotics on major adverse outcomes in real clinical practice setting with diverse population using overlap weighting model. Methods: In this retrospective study, patients with breast cancer undergoing breast implant reconstructions were collected in Fudan University Shanghai Cancer Center from 1 January 2008 to 31 December 2021. Cases were divided into two groups according to the duration of perioperative antibiotic prophylaxis: short-term group (≤ 24 hours) and long-term group (>24 and≤48 hours). The primary outcomes were unplanned reoperations and complication-related unplanned reoperations. Unplanned reoperation was defined as debridement, expander removal without prosthesis implantation, expander removal and expander implantation, prosthesis removal and prosthesis implantation, prosthesis removal, prosthesis removal and expander implantation. By reviewing the patients’ detailed medical history, all unplanned reoperations were divided into non-complication-related unplanned reoperations and complication-related unplanned reoperations. Non-complication-related unplanned reoperations included: patients voluntarily gave up continuing reconstruction, suspected recurrence of cancer, changed reconstruction methods, unsatisfactory appearance, and unknown reasons. Complication-related unplanned reoperations included: infection, exposure of prosthesis or expander, poor wound healing, rupture of expander, necrosis of skin flap, bleeding. The secondary outcomes were infections that required intervention. It was defined as both met with white blood cells elevation and physician antibiotic prescription during outpatient follow-up. To adjust confounders, propensity score overlap weighting was used, and subgroup analysis and sensitive test were conducted to demonstrate the robustness of results. A P value less than 0.05 was considered statistically significant. Results: In 4367 cases of unilateral implant reconstructions, 4128 (95%) were included in this study. Among them, 1689 were expander implantation, 1124 were prosthesis implantation and 1315 were expander removal and prosthetic implantation. At inclusion, only 283 cases (6.9%) received antibiotics prophylaxis ≤24 hours, 3090 cases (74.9%) with duration >24 and≤48 hours, and 755 cases (18.3%) with duration >48 hours. Of them, 230 cases (5.6%) underwent unplanned reoperation, including 131 (3.2%) complication-related unplanned reoperations, and 99 (2.4%) non-complication-related unplanned reoperations. And there were 110 cases (2.7%) with infections that required intervention. In unweighted or weighted data set, short-term antibiotic use did not significantly increase the risk of adverse outcomes, including unplanned reoperation, complication-related unplanned reoperation, and infection required intervention, compared with long-term antibiotic use with or without patients with duration more than 48 hours. Most subgroup analysis showed no evidence of heterogeneity of the effects of duration of antibiotic use on adverse outcomes. Conclusion: In clinical setting with diverse population, prolong antibiotic prophylaxis with more than 24 hours is not necessary to reduce major adverse outcomes, even in some critical conditions. Appropriating and accessible prophylactic initiatives should be developed and implemented with shorten the duration of antibiotic prophylaxis and minimized adverse outcomes. Key words: perioperative antibiotic prophylaxis, breast cancer, postmastectomy implant reconstruction, unplanned reoperation Citation Format: Zeqing Li, Jiajian Chen, Shuang Hao, A-Yong Cao, Xiaoyan Huang, Zhiming Shao, Jiong Wu. Effects of different duration of prophylactic antibiotic use on unplanned reoperation in breast cancer patients undergoing implant-based breast reconstruction: A retrospective study with overlap weighting analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-07-02.
// Min He 1,4 , Xin Hu 1 , Li Chen 1,4 , A-Yong Cao 1 , Ke-Da Yu 1 , Ting-Yan Shi 2 , Xia-Ying Kuang 1,4 , Wen-Biao Shi 1 , Hong Ling 1 , Shan Li 1 , Feng Qiao 1 , Ling Yao 1 , Qingyi Wei 3,5 , Gen-Hong Di 1,4 and Zhi-Ming Shao 1,3,4 1 Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, China 2 Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China 3 Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China 4 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China 5 Duke Cancer Institute, Duke University Medical Center, Durham, NC, United States of America Correspondence: Zhi-Ming Shao, email: // Xin Hu, email: // Keywords : XRCC4, homozygous variant, nuclear localization, susceptibility, breast cancer Received : September 07, 2014 Accepted : October 22, 2014 Published : October 22, 2014 Abstract XRCC4 plays a crucial role in the non-homologous end joining pathway that maintains genome stability. In this two-stage case-control study with 1,764 non- BRCA1/2 breast cancer patients and 1,623 cancer-free controls, we investigated the contribution of genetic variants of XRCC4 to breast cancer susceptibility in Chinese women. We identified a recessive missense variant, rs3734091 (c.739G>T, p.Ala247Ser), of XRCC4 that was significantly associated with an increased risk of breast cancer (odds ratio [OR] = 3.92, P = 0.007), particularly with the risk of developing triple-negative breast cancer (OR = 18.65, P < 0.0001). This p.Ala247Ser variant disturbed the nuclear localization of XRCC4 in cells homozygous for the rs3734091-T allele but not in heterozygous cells at both the cellular and tissue levels. In heterozygous cells, wild-type XRCC4 facilitated the nuclear localization of the XRCC4 A247S mutant, thus compensating for the impaired localization of XRCC4 A247S . This provided a biological mechanism by which rs3734091 conferred an increased susceptibility to non- BRCA1/2 breast cancer exclusively under a recessive model. Further functional analyses revealed that p.Ala247Ser impaired the DNA damage repair capacity and ultimately perturbed genomic stability. Taken together, our findings document the role of XRCC4 in non- BRCA1/2 breast cancer predisposition and reveal its underlying biological mechanism of action.
To develop and validate a dual-energy CT (DECT)-based model for noninvasively differentiating between benign and malignant breast lesions detected on DECT.
Supplementary Figure from Famitinib with Camrelizumab and Nab-Paclitaxel for Advanced Immunomodulatory Triple-Negative Breast Cancer (FUTURE-C-Plus): An Open-Label, Single-Arm, Phase II Trial
We conducted this study to investigate the prevalence of potential chemo-response-related gene mutations in triple-negative breast cancer (TNBC) patients and to evaluate the potential relationship between these gene mutations and neoadjuvant chemotherapy response in TNBC patients.One hundred sixty-two TNBC patients in Fudan University Shanghai Cancer Center who received NAC with 4 cycles of paclitaxel and carboplatin were enrolled in this study. Fifty-six pathological complete response (pCR) patients and 56 non-pCR patients were enrolled in this retrospective study for the training set. Clinical assessments of postoperative residual tumors were performed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Forty chemo-response-related genes were screened in each tumor specimen by second-generation sequencing analysis. Fifty TNBC patients who received neoadjuvant chemotherapy with paclitaxel and carboplatin were enrolled in the validation group.Fifty-seven of 112 (50.9%) TNBCs contained at least one detected somatic mutation. As expected, TP53 mutation was the most common alteration, which was observed in 21.4% of patients. BRCA1, BRCA2, RET, PI3KCA, and PTEN mutations were each observed in 11.6%, 4.5%, 5.4%, 2.7% and 3.6% of all cases, respectively. No significant differences in any gene mutation frequency between pCR and non-pCR groups were identified. We found that the mutation status of 10 DNA repair genes involved in homologous recombination (HR) pathway successfully discriminated between responding and nonresponding tumors in the training group. Up to 18 patients who were mutation-positive experienced pCR compared to only 6 in the non-pCR group (P=0.006), and 75% the HR related gene mutation patients achieved pCR. In the validation group, TNBC patients with DNA repair gene mutations achieved 77.8% pCR.A subset of TNBC patients carry deleterious somatic mutations in 10 HR-related genes. The mutation status of this expanded gene panel is likely to effectively predict respond rate to neoadjuvant chemotherapy based on paclitaxel and carboplatin. Our findings need to be validated through follow-up studies in this and additional cohorts.
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