bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of tucatinib+trastuzumab+capecitabine (TTC) after trastuzumab-deruxtecan (T-DXd) exposure in Her2-positive metastatic breast cancer: A French multicentre retrospective study.
Authors: Frenel Jean-Sebastien , Zeghondy Jean , Guerin Catherine , Mailliez Audrey , Volant Elsa , Poumeaud Francois , Patsouris Anne , Arnedos Monica , Bailleux Caroline , Cabal Julie , Galland Loick , De nonneville Alexandre , Guiu Lahaye Severine , Dalenc Florence , Pistilli Barbara , Bachelot Thomas , Martin Pierre , Bocquet Francois , Larrouquere Louis , Loirat Delphine 
Published: June 2023

1014 Background: Recent guidelines have positioned T-DXd as a preferred treatment in the second line setting for HER2+ metastatic breast cancer (MBC). TTC is the preferred treatment in third line, however little is known on the efficacy of this combination after T-DXd exposure. Methods: We conducted a retrospective study in 12 French comprehensive cancer centers. All patients with HER2+ MBC treated with TTC after prior exposure to T-DXd were included. The primary end point was progression-free survival (PFS) in the whole population. Secondary end-points included overall survival (OS), PFS in subgroups and objective response rate. Results: Between 08/2020 and 12/2022, 101 patients were included. Median age was 56.4 y.o. (range 30.8 - 84.8). Median number of prior line of treatment for metastatic disease at TTC start was 4 (2 - 15). 82% and 95% of patients had received previous pertuzumab and T-DM1 respectively. The median duration of previous exposure to T-DXd was 8.9 months (1.4 - 31.4) and 82/101 (81%) patients had progressed under T-DXd while 19 had stopped T-DXd for toxicity or other reasons. TTC regimen was given as a 3rd line or 4th line for metastatic disease in 37/101 (37%) and beyond for the remaining patients. TTC was the immediate subsequent therapy to T-DXd for 86/101 pts (85%). With a median follow-up of 8.5 m (95%CI [7.7; 9.4]), 68/101pts (67%) have stopped TTC for progressive disease. Median PFS was 4.7 m (95%CI [3.8; 5.6]) and median OS not reached (95%CI [10.6; NA]) in the whole population. Patients treated with TTC as the immediate subsequent therapy to T-DXd, had a median PFS of 5.0 m (95%CI [4.0; 6.0]) and a median OS not reached (95%CI [11.9; NA]). Best response to TTC, evaluated by investigators in the 87/101 RECIST evaluable patients, was progressive disease, stable disease, partial response and complete response in 34%, 34%, 30% and 2% of patients respectively. At TTC initiation, 39 (39%) of patients had known brain metastases. Out of the 62 patients without known brain metastases at the initiation of TTC, 2 had brain metastases documented as a site of progression during TTC. Conclusions: In this large retrospective cohort, TTC shows significant efficacy for patients with HER2+ MBC previously exposed to T-DXd. Data and subgroup analyses will be updated for the meeting.
Trastuzumab deruxtecan (T-DXd) vs treatment of physician’s choice (TPC) in patients (pts) with HER2-low, hormone receptor-positive (HR+) unresectable and/or metastatic breast cancer (mBC): Exploratory biomarker analysis of DESTINY-Breast04.
Authors: Modi Shanu , Niikura Naoki , Yamashita Toshinari , Jacot William , Sohn Joohyuk , Tokunaga Eriko , Vidal Maria Jesus , Park Yeon Hee , Lee Keun Seok , Chae Yeesoo , Ueno Naoto T. , Prat Aleix , Suto Fumitaka , Kuwahara Yusuke , McEwen Robert , Feng Wenqin , Goto Hiroki , Orbegoso Cecilia , Cameron David A. , Tsurutani Junji 
Published: June 2023

1020 Background: DESTINY-Breast04 (NCT03734029) showed improved progression-free survival (PFS) and overall survival for T-DXd vs TPC in pts with HER2-low (IHC 1+ or 2+/ISH-negative) mBC. We present exploratory biomarker analysis in pts with HER2-low, HR+ mBC. Methods: Biopsy specimens collected from 326 pts after prior treatment were analyzed using RNA-sequencing and intrinsic subtypes estimated by PAM50 gene expression. ESR1 and PIK3CA mutations and known gene alterations associated with resistance to CDK4/6 inhibitors (CDK4/6i) were assessed in baseline (BL) circulating tumor DNA (ctDNA) samples from 414 pts by Guardant OMNI. Association with objective response rate (ORR) and PFS was evaluated. Results: Frequencies of BL intrinsic subtypes in the T-DXd and TPC arms were 41.3% and 46.6% for Luminal A, 48.0% and 37.9% for Luminal B, and 9.0% and 11.7% for HER2 enriched, respectively. According to ctDNA results in the T-DXd and TPC arms, respectively, ESR1 mutations were observed in 51.3% and 54.0% of pts, PIK3CA mutations in 36.1% and 41.6% of pts, and at least one CDK4/6i resistance marker (pts with prior CDK4/6i) was detected in 71.5% and 70.2% of pts. Improved T-DXd efficacy was seen regardless of intrinsic subtype (Luminal A, Luminal B, HER2-enriched), ESR1 mutation, PIK3CA mutation, or CDK4/6i resistance markers (Table). Conclusions: Greater clinical benefit was consistently observed with T-DXd vs TPC independent of intrinsic subtype, ESR1 mutation, PIK3CA mutation, or known CDK4/6i resistance marker status. Clinical trial information: NCT03734029 . [Table: see text]
Clinical features, genomic landscapes, and survival outcomes of HER2-low breast cancer.
Authors: Juan Jin , Li Bin , Wang Biyun , Tao Zhonghua , Hu Xichun 
Published: June 2023

1027 Background: Novel human epidermal growth factor receptor 2 (HER2)-directed antibody‒drug conjugates prompt the identification of the HER2-low subtype. To investigate whether HER2-low breast cancer can be defined as a distinct biological subtype, our study conducted a comprehensive analysis on the clinical and molecular features among patients with different HER2 statuses. Methods: Clinical and genomic data of 579 metastatic breast cancer patients were reviewed from our next-generation sequencing (NGS) database. Genomic data of breast tumor samples was generated by targeted NGS using a cancer-related gene panel. The cohort included 220 HER2-zero, 194 HER2-low and 165 HER2-positive patients according to the HER2 status from the most recent pathological results. Results: First, the clinicopathological characteristics of HER2-low patients were associated with hormone receptor (HR) status. Less lymph node invasion and higher bone metastasis in HER2-low patients were probably because of the higher percentage of HR-positive tumors in HER2-low patients than HER2-zero and HER2-positive patients (63.19%, 42.02% and 28.00%, respectively, p<0.0001). Second, HER2 status shifting from primary to recurrent breast cancer was common, with 38.1% and 48.4% of HER2-zero primary tumors converting to HER2-low tumors when they metastasized in the whole population and the HR-positive subgroup, respectively. Third, HER2-low patients had more brain and lung metastases and cases of de novo stage IV breast cancer than HER2-zero patients in the HR-positive subgroup. Fourth, germline BRCA2 mutations were observed only in HER2-low patients (11/139, 7.91%) and HER2-low tumors had more somatic PIK3CA mutations than HER2-zero tumors in the HR-negative subgroup. Fifth, HER2-low patients had a longer median overall survival (mOS) and median disease-free survival (mDFS) than HER2-zero patients (mOS:49.1 vs. 30.3 months, log rank P = 0.0005; mDFS: 28.17 vs. 20.27 months, log rank P =0.036), but difference was not evident when paired by HR status. Finally, three molecular subtypes based on genomic alterations in HER2-low breast cancer were identified, and Cluster 2, which enriched in TP53 mutations, was significantly associated with worse outcomes, which provided novel insights into heterogeneity in HER2-low breast cancer. Conclusions: The clinical and molecular significance of HER2-low status was influenced by HR expression, and HER2-low tumors had distinct features in subtype analyses based on HR status. Our elaboration of molecular subtypes in HER2-low tumors encourages clinicians to consider the heterogeneity in HER2-low breast cancer.
Concordance between liquid and tissue biopsy in participants with newly diagnosed recurrent breast cancer.
Authors: Lohmann Ana Elisa , Ennis Marguerite , Goodwin Pamela Jean , Veitch Zachary William Neil , Brezden Christine , Jerzak Katarzyna Joanna , Baer Kathie , Martel Samuel , Lemieux Julie , Guimaraes Jose Luiz Miranda , Cescon David W. , Thirlwell Michael P. , Slade Megan , Di Caro Giuseppe , Wenstrup Rick , Ethier Josee-Lyne , Soldera Sara V. 
Published: June 2023

1028 Background: Tissue biopsy is recommended to confirm breast cancer (BC) recurrence. Liquid biopsy [including circulating tumour cells (CTCs) and circulating tumour DNA (ctDNA)] is a non-invasive approach for detecting cancer that may provide information to identify treatment choices and replace invasive biopsies. This ongoing study aims to assess the concordance between tissue and liquid biopsy testing in subjects presenting with suspicion of distant recurrence from BC. Methods: Patients with suspected metastatic BC were enrolled; tumour characteristics and treatment were recorded. Blood samples were collected within 30 days before tissue biopsy, or within 7-28 days after tissue biopsy and before any systemic or radiation treatment. Samples were shipped to EPIC Sciences and processed within 96 hours; after plasma isolation, nucleated cells were plated; slides and plasma were banked. CTCs were identified using Epic Sciences digital imaging and machine learning algorithms. Single-cell isolation for genomic ctDNA analysis was performed. Cell free DNA was analyzed using a validated NGS panel to detect ctDNA alterations. The presence of metastases was classified as suspicious, highly suspicious, definitely metastatic BC or other by the treating oncologist based on the patient's clinical presentation and biopsy pathology results. Epic Sciences classified samples into similar categories based on CTC and ctDNA assay results. These classifications were performed independently. Sensitivity of the Epic Sciences methodology to detect metastatic BC (as determined by the treating oncologist), and its false positive rate were calculated. Results: 100 patients were enrolled from June 2020 to October 2022; shipping delays precluded EPIC assays in six patients; 94 patients were analyzed. Of 83 cases deemed suspicious, highly suspicious, or definitely metastatic BC by the treating oncologist, 61 were also deemed so by Epic Sciences (sensitivity of 73.5%, 95% confidence interval, CI 63.1% - 81.9%). Of 66 cases assigned as suspicious, highly suspicious, or definitely metastatic BC by the Epic Sciences, 4 had new primary cancers (3 lung cancer, 1 hepatocarcinoma), for a false positive rate of 6.1% (95% CI 1.9% - 15.0%). One additional case was classified as un-specified adenocarcinoma (possibly breast) by the treating oncologist; resolution awaits further follow-up. Conclusions: Preliminary results show that 73.5% of distant BC recurrences were correctly identified by liquid biopsy. A small number of false positive results occurred in patients with other new primary cancers. Additional analyses with CTC characterization are ongoing. [Table: see text]
Metastatic patterns and outcomes by HER2 and hormone receptor (HR) status in patients (pts) with metastatic breast cancer (mBC).
Authors: Yuan Qianyu , Castellanos Emily , Fidyk Erin , Schwed Karen , Estevez Melissa , Nemeth Sheila , Linzmayer Robin , Cohen Aaron B. 
Published: June 2023

1031 Background: HER2-low status in mBC is predictive of benefit to trastuzumab deruxutan, but whether it is biologically distinct from HER2-neg disease is unclear. To better understand the prognostic significance of HER2-low status, we assessed patterns of metastases and real world overall survival (rwOS) by HER2 and HR status. Methods: Pts with mBC diagnosis from 1/1/2011 to 5/31/2022 were selected from the nationwide deidentified Flatiron Health electronic health record (EHR)-derived database. HER2 and HR status was derived from human abstraction (IHC 0-1+/2+/3+, FISH pos/neg, ER/PR) and machine learning-extraction (to classify IHC 0/1+). HER2 and HR tests prior and up to 60 days after metastatic diagnosis date (met Dx date) were included, results closest to met Dx date were used. Sites of metastasis (SOM) were grouped into mutually exclusive groups: brain, non-visceral (bone, skin, lymph node) and visceral (liver, lung, etc). Metastatic patterns stratified by HR/HER2 status were compared using chi-square tests. The association between HER2 status and rwOS, stratified by HR status, was evaluated using Cox models adjusted for age, race/ethnicity, practice, SOM, SES, and stage. rwOS stratified by HR/HER2 status and SOM were estimated via KM analysis. Results: Among 22,932 pts with mBC, HER2-low prevalence was 49%. HER2-low mBC was more likely to be HR+ than HER2-neg or HER2+ (84%, vs 70% and 65%; p<0.01). Pts with HER2-low and HER2-neg mBC had similar SOM overall, distinct from HER2+. For example, among HR+ pts, HER2-low and HER2-neg pts were less likely than HER2+ pts to have brain (4% and 4% vs 10%; p<0.01) or visceral metastases (51%, 50% vs 58%; p<0.01) but more likely to have non-visceral metastases (45% and 46% vs 32%; p<0.01). Compared to HER2-low pts, HER2-neg pts had similar rwOS if HR+ (hazard ratio 1.02, 95% CI 0.98-1.08) and slightly worse if HR-neg (hazard ratio 1.18, 95% CI 1.03-1.21). rwOS varied by HR/HER2 status and SOM. Conclusions: Our findings indicate that HER2-low mBC has biologic similarities to HER2-neg mBC. While slight differences were observed between HER2-neg and HER2-low pts in the HR-neg subgroup, overall rwOS differences were associated more strongly with HER2+ status, HR+ status, and metastatic pattern, indicating that HER2-low status may be more informative as a predictive rather than a prognostic biomarker. [Table: see text]
Genomic characterization of the GATA3 mutational landscape in breast cancer.
Authors: Mouabbi Jason A , Meric-Bernstam Funda , Turova Polina , Chernyshov Konstantin , Kushnarev Vladimir , Kotlov Nikita , Brown Jessica H. , Clayton Patrick , Nomie Krystle , Fowler Nathan , Tripathy Debu , Damodaran Senthil 
Published: June 2023

1039 Background: GATA3 expression is broadly used as a biomarker for diagnosing cancer of breast origin and its expression is strongly associated with estrogen receptor (ER)-positive luminal phenotype. Although GATA3 mutations are observed in 12-18% of breast cancers (BC), they are poorly characterized. Recently, the pharmacological inhibition of MDM2 has been shown to significantly impair tumor growth in GATA3-deficient models in vitro, in vivo, and patient-derived xenograft harboring GATA3 somatic mutations. Therefore, given the potential targetability of GATA3-mutated BC cells, it is important to better understand and characterize the mutational landscape of GATA3 to help guide future prospective clinical studies. Methods: We accessed a cohort of BC samples profiled genomically and transcriptomically from two open-source datasets: TCGA (n=961) and METABRIC (n=1866). We used the chi-squared test to analyze the frequency of GATA3 mutations across PAM50 subtypes (Basal, HER2, Luminal A, Luminal B, Normal-like) and histological BC subtypes (invasive ductal carcinoma [IDC] and invasive lobular carcinoma [ILC]). Mutations affecting other genes in the GATA3-mutated samples and the GATA3 wild-type (WT) samples were compared using the chi-squared test. We analyzed the mutational landscape of the GATA3 gene and correlated different sites of mutations with GATA3 expression, MDM2 amplification, other co-occurring mutations, and clinical behavior. GATA3 expression levels were compared using the Mann-Whitney test. Results: Of the analyzed 2,827 BC samples, GATA3 mutations were unevenly distributed in the five PAM50 subtypes, as Luminal A and B subtypes had the highest frequency (16% and 17%, respectively) and the basal subtype had no observed GATA3 mutations (p <0.0001). Further analysis showed that GATA3 mutations were more common in luminal IDC than ILC (17% vs 8.7%; p <0.0001). While mutations in CBFB, AKT1, TBX3 and ARID1A were more frequently co-occurring with GATA3 mutations, mutations in TP53, CDH1 and PIK3CA were mutually exclusive with GATA3 mutations (adjusted p <0.0001 for all genes). Analysis of the GATA3 mutational landscape identified two types of mutations in GATA3: a group of truncating mutations occurring at the end of the GATA3 gene (after the 307 position including the splice site at 308) and a group occurring before the 307 position. The first group was associated with increased GATA3 expression, MDM2 amplification, and was mutually exclusive with TP53 mutations. The second group had little to no effect on GATA3 expression and behaved similarly to GATA3 WT. Conclusions: A subtype of GATA3 mutations are mutually exclusive with TP53 mutations and are associated with increased MDM2 amplification, making them an ideal target for clinical trials involving MDM2 inhibitors.
Updated results from a phase 2 study on dalpiciclib and pyrotinib, a dual-oral chemotherapy-free regimen in HER2-positive advanced breast cancer (DAP-HER-01).
Authors: Yan Min , Niu Limin , Lv Huimin , Zhang Mengwei , Liu Zhenzhen , Chen Xiuchun , Lu Zhenduo , Zhang Chongjian , Zeng Huiai , Zhao Shengnan , Feng Yajing , Wang Jing , Sun Huihui , Li Huajun 
Published: June 2023

1045 Background: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have shown synergistic effect with anti-HER2 therapy on hormone receptor (HR)-positive and HER2-positive breast cancer from preclinical models and several clinical studies, while data of this combination in HR-negative and HER2-positive diseases are limited so far. DAP-HER-01 (NCT04293276) was aimed at evaluate the efficacy and safety of the novel dual-oral, chemotherapy-free regimen of CDK4/6 inhibitor dalpiciclib and pan-HER tyrosine kinase inhibitor pyrotinib in HER2-positive advanced breast cancer (ABC) regardless of HR status, and reported to meet the primary endpoints previously (overall ORR 70%), in which HR-negative patients achieved a higher ORR (81.8%, vs 55.6% in HR-positive patients; Min Yan, et al. ESMO 2021, Poster 276P). Here we reported the updated results of this trial. Methods: DAP-HER-01 was a single-arm, phase 2 study conducted in HER2-positive ABC patients with no more than one prior systemic treatment at advanced setting. Enrolled patients received dalpiciclib and pyrotinib until progression, unaccepted toxicity, or no further benefit. The primary endpoint was ORR as per RECIST 1.1, and secondary endpoints included progression-free survival (PFS), overall survival and safety. Results: Between April 9, 2020, and May 19, 2021, 41 patients were enrolled and received study treatment, and 40 of them were assessable for efficacy. With a median follow-up of 19.2 months, the median progression-free survival (PFS) was 11.0 months (95% CI 7.3-19.3). Considering HR status, the PFS in HR-negative patients was not matured (estimated median: 16.6 months; 95% CI: 7.3- NA), but still showed a tendency to be longer than that in HR-positive patients (median: 9.1 months; 95% CI: 5.4-11.0). Patients with brain metastases at baseline could also benefit from this treatment (median PFS: 11.0; 95% CI: 5.4-NA). Consistent with the safety data reported before, the most common grade 3 or 4 treatment-related adverse events were leukopenia (68.3%), neutropenia (65.9%) and diarrhea (19.5%). Most adverse events were tolerable, and no study-related death reported. Conclusions: Combined with previous reports, our findings suggest dalpiciclib combined with pyrotinib achieved promising efficacy and manageable toxicity in the treatment of HER2-positive ABC, including patients with HR-negative disease or brain metastases. This combination could be considered as a completely oral, chemo-free regimen for patients with HER2-positive ABC and is worthy of further study. Clinical trial information: NCT04293276 .
Secondary primary malignancy risk by ER, PR, and HER-2 status in post-menopausal women with breast cancer: A population-based analysis.
Authors: Khan Muhammad Hammad , Fatima Maurish , Akbar Usman Ali , Rehman Mohammad Ebad Ur , Basit Jawad , Aman Aleena , Taj Sobaan , Ali Fatima , Vikash Sindhu , Yousuf Saira , Khaliq Waseem , Ahmad Nabeel 
Published: June 2023

1050 Background: Breast cancer is the most commonly diagnosed cancer and second leading cause of death due to cancer in women in the United States. We aimed to determine site specific incidence of SPMs in post-menopausal women with primary BC using data from the US Surveillance, Epidemiology, and End Results (SEER-17) cancer registries. Methods: We retrospectively analyzed post-menopausal women aged 45 or older with a first primary breast cancer diagnosis between 2000 and 2019, excluding those aged 45 or younger or with non-breast cancers as their first malignancy. We defined SPMs as second malignancies occurring at least 6 months after the initial breast cancer diagnosis and calculated standardized incidence ratios (SIRs) and absolute excess risk (AER) using SEER*Stat. Statistical significance was determined using p-values <0.05 and a 95% CI assuming a Poisson distribution of SPM incidence. Results: Among 774,965 post-menopausal women ≥45 years old with primary breast cancer, 10.8% developed SPMs, with significantly increased risk compared to the general population (SIR=1.14, 95% CI=1.13-1.15, p<0.05), particularly for solid tumors (SIR=1.16, 95% CI=1.15-1.16, p<0.05) and certain malignancies including salivary gland (SIR=1.77), thyroid (SIR=1.56), endocrine system (SIR=1.56), and hematological malignancies such as ALL, ANLL, and AML (SIR>1.70). Women aged 45-59 and Black women had the highest risk for all malignancies. PR receptor-positive women had higher risk for thyroid SPMs, while PR-negative women had higher risk for SPMs in female genitalia, bones and joints, and hematological malignancies. HER-positive and triple-positive (HER ER PR) women had higher risk for thyroid and hematological SPMs, while triple-negative women had higher risk for ALL, ANLL, and AML. Conclusions: This study found that 11% of post-menopausal women with primary BC develop SPMs, with thyroid cancer being the most common. Black and older women (45-59 years) had a higher risk of developing SPMs. [Table: see text]