bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of response-directed surgery and adjuvant therapy on long-term survival after neoadjuvant ipilimumab plus nivolumab in stage III melanoma: Three-year data of PRADO and OpACIN-neo.
Authors: Reijers Irene L.M. , Menzies Alexander M. , Versluis Judith M. , Saw Robyn P.M. , van Houdt Winan J. , Kapiteijn Ellen , Van Der Veldt Astrid Aplonia Maria , Suijkerbuijk Karijn , Eriksson Hanna , Hospers Geke , Klop Willem M.C. , Lopez-Yurda Marta I. , Grijpink-Ongering Lindsay G. , Gonzalez Maria , Spillane Andrew John , Scolyer Richard A. , van de Wiel Bart A. , Van Akkooi Alexander Christopher Jonathan , Long Georgina V. , Blank Christian U. 
Published: June 2023

101 Background: Neoadjuvant ipilimumab (IPI) + nivolumab (NIVO) has been shown to induce high pathologic response rates associated with an excellent relapse-free survival (RFS) in high-risk stage III melanoma. While OpACIN-neo tested different neoadjuvant IPI + NIVO regimens followed by therapeutic lymph node dissection (TLND) without adjuvant systemic therapy (ST), PRADO tested a personalized approach. In patients (pts) achieving a major pathologic response (MPR; ≤10% viable tumor), TLND and adjuvant ST were omitted, and pts with pathologic non-response (pNR; >50% viable tumor) were treated with adjuvant ST (BRAFi/MEKi or anti-PD1) ± radiotherapy after TLND. Here, we address 1) whether omitting TLND in MPR pts had an adverse effect on long-term survival and 2) whether adding adjuvant ST in pNR pts had a favorable effect on survival. Methods: The 3-year (3y) RFS and distant metastasis-free survival (DMFS) of pts with MPR and pNR from PRADO and OpACIN-neo were analyzed, comparing MPR pts with TLND versus without TLND and pNR pts with adjuvant ST versus without adjuvant ST. Survival rates were calculated and compared with Kaplan-Meier and log-rank methods. Associations between baseline characteristics and RFS or DMFS were examined by Cox regression analysis. Results: Median follow-up was 37.9 months in PRADO (cutoff Jan 8, 2023) and 46.8 months in OpACIN-neo (cutoff Feb 14, 2022). For MPR pts, TLND omission did not affect survival, with a 3y RFS of 93% versus 96% (p=0.47) and 3y DMFS 98% versus 98% (p=0.92) for pts without TLND (n=59) versus with TLND (n=53), respectively. In pNR pts, an indication for a RFS and DMFS benefit was seen favoring pts with adjuvant ST (n=17: n=10 BRAFi/MEKi and n=7 anti-PD1) over pts without adjuvant ST (n=23), with 3y RFS rates being 64% versus 35% (p=0.10) and 3y DMFS rates 70% versus 52% (p=0.24). Baseline clinical characteristics did not differ between PRADO and OpACIN-neo pts or were not associated with RFS and DMFS. Conclusions: Omitting TLND in MPR pts after neoadjuvant IPI + NIVO seems not to affect RFS/DMFS. Given the high survival rates, adjuvant ST is unlikely to give further benefit in these pts. In pts with pNR, addition of adjuvant ST with ongoing anti-PD1 or switch to BRAFi/MEKi appears to improve RFS and DMFS. Clinical trial information: NCT02977052 . [Table: see text]
HER2-low status discordance between primary and recurrent/metastatic breast cancer in a large-scale cohort.
Authors: Lin Mingxi , Luo Ting , Zhang Hui , Hu Xichun , Yang Wentao , Zhang Jian 
Published: June 2023

1021 Background: Trastuzumab deruxtecan (T-DXd) was recently approved to treat unresectable/metastatic HER2-low breast cancer. However, patients whose primary tumor is HER2-0 but recurrent/metastatic lesion is HER2-low will lose therapeutic opportunities for T-DXd if a rebiopsy is not performed. In this study, with the largest sample size to date, we aimed to investigate the prevalence of HER2 status conversion. Moreover, it remains debated whether HER2-0 and HER2-low tumors have different prognoses, probably because previous studies did not assess HER2 status entirely based on recurrent/metastatic lesions. Our study aimed to fill this gap. Methods: We included 1299 patients with available HER2 status on both primary tumors and recurrent/metastatic lesions at Fudan University Shanghai Cancer Center and West China Hospital. Results: A total of 370 (28.5%) patients experienced HER2 status conversion throughout disease recurrence. 144 (31.7%) HER2-0 tumors converted to HER2-low. Inter-metastases heterogeneity of HER2 status was also observed. Compared to HER2-low tumors, HER2-0 tumors showed a higher TP53 mutation rate in the ER-positive subgroup, and a lower PIK3CA mutation rate in the ER-negative subgroup. Patients with tumors converting from HER2-0 to HER2-low had a longer overall survival (HR = 0.59, adjusted P = 0.033) than those with consistent HER2-0 status in the ER-negative subgroup. By combining four risk factors (ER status, Ki67 index, biopsy site, and disease-free interval), we established the first prediction tool to estimate the probability of HER2 status conversion from HER2-0 to HER2-low/positive. Conclusions: HER2 status was unstable during the disease course. Our prediction tool could help to screen out patients with a high probability of HER2 status conversion. Our results support that HER2-0 and HER2-low recurrent/metastatic tumors have different genomic features and prognoses.
Negative estrogen receptor expression assessed by 18F-FES PET in metastatic breast cancer with ER-positive primary tumor.
Authors: Wang Biyun , You Shuhui , Xie Yizhao , Ji Mengjing , Yang Zhongyi 
Published: June 2023

1034 Background: The 18F-fluoroestradiol positron emission tomography/computed tomography (18F-FES PET/CT) technique provides a convenient method to evaluate the overall estrogen receptor (ER) expression in metastatic breast cancer (MBC) patients. There are long debates on the characteristics and treatment strategy of patients with positive primary ER lesion but negative ER expression in metastatic disease. 18F-FES PET offers an opportunity to answer this question. Methods: This study enrolled MBC patients with ER-positive primary tumor who received 18F-FES PET/CT in our center. Descriptive statistics were used in clinicopathologic characteristics and compared with Chi square test or t test. Progression‐free survival (PFS) was estimated by Kaplan-Meier method and compared by log-rank test. Results: 16.46% (52/314) patients with an ER-positive primary tumor had negative ER expression assessed by 18F-FES for MBC prior to receiving first-line systemic therapy. The rate of ER-negativity tested by 18F-FES was negatively co-related with levels of ER expression in early stage, with a positive to negative conversion in 2 of 3 (46.3%) ER-low (ie, ER 1%-9%) tumors, 7 of 10 (70.0%) ER-moderate (ie, ER 10%-49%) tumors, 16 of 114 (14.0%) ER-high (ie, ER 50%-95%) tumors, and 1 of 8 (12.5%) ER-very high (ie, ER > 95%) tumors (p < 0.001). Chemotherapy (83.33%, 40/48) was the most common treatment strategy afterward, among which capecitabine monotherapy (64.29%, 27/42) was a dominant alternative. PFS was significantly prolonged with capecitabine alone versus other chemotherapy (median PFS: 13.14 vs 6.21 months, p = 0.035). Conclusions: 18F-FES could identify negative conversion of ER in MBC which occurred frequently. Patients with lower ER expression in the primary lesion were more likely to have negative ER expression in the metastasis. In real-world clinical practice, chemotherapy was the primary choice by most physicians and capecitabine monotherapy had shown good efficacy.
Cardiac function of long-responders to dual anti-HER2 antibodies amongst patients with HER2 positive advanced breast cancer.
Authors: Bao Kelvin K H , Chan Jeffrey CH , Sutanto Leone , Chan Jocelyn G , Cheung Ka Man , Yiu Harry HY 
Published: June 2023

1043 Background: Dual anti-HER2 antibodies pertuzumab (P) and trastuzumab (T) in combination with taxane (D), followed by PT maintenance, is the standard first line treatment for HER2 positive advanced breast cancer (HER2+ ABC). Treatment associated cardiotoxicity necessitates regular cardiac function surveillance, which is a burden particularly for treatment long-responders. Data for cardiac safety of prolonged P+T exposure is scarce. We investigate the real-world impact on cardiac function in long-responders to treatment with dual anti-HER2 antibodies. Methods: We identified consecutive patients with HER2+ ABC who received the CLEOPATRA regimen (PT-D) between Jan 2014 and Dec 2020 from an institutional cancer registry. All patients had pre-treatment multiple-gated acquisition (MUGA) scan or echocardiogram, and subsequently at 3-monthly intervals until end of treatment to monitor left ventricular ejection fraction (LVEF). Patients on treatment for ≥36 months were considered long-responders. The Wilcoxon signed-rank test was used to assess any significant difference in LVEF at various landmark time-points in comparison to their pretreatment baseline. Results: 101 women with HER2+ ABC were eligible for analysis. Median age at treatment was 62 (IQR, 56.0-69.0). The median duration of treatment was 17.3 months (IQR, 9.0-31.3). 22.8% of patients were long-responders, who received a median of 67 cycles of treatment (IQR, 58-88). Compared to baseline, median LVEF was significantly decreased at 6m (median, 66% vs 69%, p=0.02), however there were no significant differences for any of the subsequent time-points up to 84 m. All of the larger LVEF drop (≥10% from baseline) occurred by the first 24 months, representing 4.7% of the overall measurements. Risk factors present for patients experienced treatment suspension (n=3) included previous exposures to anthracycline and left sided radiotherapy. Conclusions: In patients with HER2+ ABC who were long-responders to first-line PT-D, prolonged exposure to dual anti-HER2 antibodies was not associated with significant cardiotoxicity. It is safe to de-escalate the cardiac surveillance for this population. [Table: see text]
Zanidatamab (zani), a HER2-targeted bispecific antibody, in combination with docetaxel as first-line therapy (1L) for patients (pts) with advanced HER2-positive breast cancer (BC): Updated results from a phase 1b/2 study.
Authors: Wang Xiaojia , Lee Keun Seok , Zeng Xiaohua , Sun Tao , Im Young-Hyuck , Li Huiping , Wang Kun , Li Huiyan , Zhou Ping , Bao Yuanyuan , Jiang Zefei 
Published: June 2023

1044 Background: Despite HER2-targeted agents improving outcomes in HER2-positive (+) BC, some pts develop resistance, relapse, or do not respond to current 1L therapies. Zani, also known as ZW25, is a novel HER2-targeted bispecific antibody that binds to two distinct extracellular domains of HER2. Preliminary results from this phase 1b/2 trial (NCT04276493) showed that zani plus docetaxel had a manageable safety profile and demonstrated promising antitumor activity in pts with advanced HER2+ BC; here we present the updated data following enrollment completion. Methods: Cohort 1 of this open-label study is evaluating zani in combination with docetaxel as a 1L therapy in adult females with advanced HER2+ BC who may have received prior neoadjuvant/adjuvant therapy. Cohort 1a pts received zani 30 mg/kg intravenously (IV), Cohort 1b pts received zani 1800 mg IV, both with docetaxel 75 mg/m2 IV every 3 weeks. The primary endpoints were safety and investigator (INV)-assessed objective response rate (ORR) per RECIST v1.1. Secondary endpoints included INV-assessed duration of response (DoR) and disease control rate (DCR). Results: As of Nov 22, 2022, 37 pts (median age 55.0 years [range: 33-80]) were assigned to Cohort 1a (n=10) or 1b (n=27). Median study follow-up was 15.5 months (range: 1.1-29.3); patients received a median of 13 treatment cycles (range 1-37) and 18 (48.6%) pts remained on treatment. Of the 33 efficacy evaluable (EE) pts, confirmed ORR was 90.9% (95% confidence interval [CI]: 75.7, 98.1). Efficacy data are summarized in Table. In total, 36 (97.3%) pts experienced ≥1 treatment-related adverse event (TRAE); 25 (67.6%) pts experienced ≥grade 3 TRAEs. The most common ≥grade 3 TRAEs were decreased neutrophil count, experienced by 18 (48.6%) pts, and decreased white blood cell count, experienced by 7 (18.9%) pts. Serious TRAEs occurred in 6 (16.2%) pts; no TRAEs led to death. Conclusions: Zani combined with docetaxel demonstrated promising antitumor activity as 1L therapy for advanced HER2+ BC, with a manageable safety profile. Clinical trial information: NCT04276493 . [Table: see text]
PLEASURABLE: Results and biomarkers analysis from the phase II study of dalpiciclib combined with pyrotinib and endocrine therapy (ET) in women with dual-receptor positive (ER+/HER2+) metastatic breast cancer (MBC).
Authors: Zhang Jian , Meng Yanchun , Wang Biyun , Wu Xinhong , Zheng Hongmei , Cai Li , Chen Wenyan , Wang Leiping , Cao Jun , Tao Zhonghua , Li Ting , Sujie Ni , Yu Zhengyan , Chen XueSong , Peng Qiang , Hu Xin , Yao Wenqing , Hu Xichun 
Published: June 2023

1046 Background: In the front-line setting, our previous work demonstrated an impressive median progression-free survival (PFS) of 11.3 months with 66.7% response rate, and concluded a recommended phase 2 dose of pyrotinib 320mg/d, dalpiciclib (SHR6390, a novel CDK4/6i) 125mg/d, and letrozole 2.5mg/d for HR+/HER2+ MBC patients (pts) (Xichun Hu, FRONT ONCOL 2022). Results and biomarkers analysis from phase II dose expansion study are presented. Methods: ER+/HER2+ MBC Pts eligible for first- or second-line treatment were enrolled to receive dalpiciclib combined with pyrotinib and ET (letrozole or fulvestrant determined by physician’s choice). The primary endpoint was objective response rate (ORR). For biomarkers analysis, 68Ga-HER2 affibody, pre-treatment tissue-derived DNA and circulating tumor DNA (ctDNA) were assessed by PET/CT, and next-generation sequencing (NGS), respectively. Results: As of January 19, 2023, 48 pts were enrolled. 17 pts (35.4%) were treatment naïve, and 31 pts (64.6%) had received prior trastuzumab. The ORR was 68.1% (32/47) and disease control rate was 100% (47/47). In trastuzumab-naïve and trastuzumab-pretreated patients, ORR was 81.3% (13/16) and 61.3% (19/31), respectively. PFS and OS data were not mature by cut-off date. No new safety signals were observed. The most frequent treatment-related adverse events were neutropenia (95.8%; G3:60.4%, G4:6.3%), leukopenia (91.7%; G3:45.8%), diarrhea (87.5%; G3:2.1%), anemia (79.2%; G3:4.2%), oral mucositis (68.8%, G3:2.1%) and platelet count decreased (41.7%; G3:2.1%, G4:2.1%). The heterogeneity of 68Ga-HER2 affibody uptake was observed among patients, both at baseline (N=16，median SUV max 7.5, range, 2.3-34.9) and after 2 cycles of therapy (N=12，median SUV max 4.0, range, 0-14.9). All patients with a decline in 68Ga-HER2 affibody uptake (N=8) achieved partial response, while the uptake in non-responders was elevated (N=2). NGS was conducted to detect somatic and germline mutations in baseline tissue (n=10) and ctDNA (n=10) samples. Two patients with BRCA mutation (one had somatic BRCA1/ 2 mutation and another with germline BRCA2 mutation) had no tumor response. Conclusions: The chemotherapy-sparing regimens showed significant anti-tumor activity for ER+/HER2+ MBC pts in the front-line setting. The 68Ga-HER2 affibody PET/CT may be a potential predictive biomarker of therapy response. Additional analysis including correlation of biomarkers with long-term outcomes is underway. Clinical trial information: NCT03772353 .
Real-world treatment patterns in patients with HER2+ unresectable or metastatic breast cancer: Interim results from HER2 REAL Asia cohort.
Authors: Lee Soo-Chin , Chung Wei-Pang , Ngan Roger Kai-Cheong , Im Seock-Ah , Hui Rina , Barrios Carlos , Tung Teresa 
Published: June 2023

1047 Background: HER2 REAL (NCT04857619) is the first multi-country, retrospective study exploring the treatment practices and outcomes in patients (pts) with HER2+ locally advanced, unresectable (u)/metastatic (m) breast cancer (BC) from routine clinical care in the APAC and LATAM. Methods: Adult HER2+ u/mBC pts diagnosed since reimbursement or wider access of trastuzumab emtansine (T-DM1) or 01 Jan 2017, whichever was earlier with ≥12 months (mo) of follow-up data from index date (u/mBC diagnosis) and treated with ≥1-line of therapy (LOT) were enrolled per medical chart review from 6 countries. Here we present interim descriptive analyses (cut-off 30 June 2022) on demographics, clinical characteristics, and treatment patterns. Results: Of the 763 enrolled pts, 370 with median (range) age of 55 (20–81) yrs from Hong Kong, Korea, Singapore, and Taiwan were eligible for interim analyses; 368 (99.5%) were female with 210 (57.1%) postmenopausal. A total of 210 (57.1%) pts with reported data had a median time of 2 (0–18) yrs from initial BC diagnosis to u/mBC relapse. At index date, majority had ductal carcinoma (227/254 [89.4%]), visceral (255/355 [71.8%]), and non-visceral (258/355 [72.3%]) metastases; 80/355 (22.5%) had CNS metastases. Family history of BC was reported by 45/370 (12.2%) pts completing the questionnaire; 209/370 (56.5%) had hormone receptor-positive BC. Treatments reported in the first to fifth line were quite variable. HER2-directed therapy was received by 323/367 (88.0%) in LOT1 (mainly trastuzumab [TRA] and pertuzumab [PTZ]-based) and 298/343 (86.9%) in LOT2 (mainly T-DM1). Median duration of LOT1 and LOT2 were 7.8 (0–130) and 5.0 (0–100) mo, respectively, that decreased to 2.3 (0–30) mo in LOT5. The prime reason for treatment discontinuation was disease progression (LOT1: 294 [80.1%]; LOT2: 273 [79.6%]; LOT3: 187 [68.5%]). Serious adverse effects from treatments were rare (LOT1: 7 [1.9%]; LOT2: 10 [2.9%]; LOT3: 5 [1.8%]). Conclusions: The interim analyses show heterogeneous treatment patterns in real-world among pts with HER2+ u/mBC progressing on HER2-directed therapies possibly due to access disparity in these 4 Asian countries. Clinical trial information: NCT04857619 . [Table: see text]
Pyrotinib plus capecitabine for patients with HER2-positive metastatic breast cancer and brain metastases: 3-year follow-up results from the phase 2 PERMEATE trial.
Authors: Yan Min , Ouyang Quchang , Sun Tao , Niu Limin , Yang Jin , Li Li , Song Yuhua , Hao Chunfang , Chen Zhanhong 
Published: June 2023

1048 Background: HER2-positive metastatic breast cancer has a high risk of brain metastases, leading to poor survival. Our phase 2 PERMEATE trial (NCT03691051) has shown the promising efficacy of pyrotinib (an irreversible pan-HER receptor tyrosine kinase inhibitor) plus capecitabine in patients with HER2-positive metastatic breast cancer and brain metastases, with an intracranial objective response rate of 74.6% (44/59) and 42.1% (8/19) in patients with radiotherapy-naïve (cohort A) and radiotherapy-treated (cohort B) brain metastases, respectively. Here we updated 3-year follow-up results from this trial. Methods: Patients received 21-day cycles of pyrotinib (400 mg orally once daily) and capecitabine (1000 mg/m2 orally twice daily on days 1-14) until disease progression or intolerable toxicity. Patients with progression isolated to the brain lesions would be withdrawn from the study, but could resume on the study treatment after local surgery or radiotherapy until the second progression at any site or death, at the discretion of the investigator. Intracranial and extracranial responses were assessed according to the Response Evaluation Criteria In Solid Tumors, version 1.1. Progression-free survival (PFS; time from the initiation of the study treatment to progression at any site or any-cause death), overall survival (OS), and second PFS (PFS2; time from progression isolated to the brain lesions to the second progression at any site) were reported. Results: By the data cutoff date on February 8, 2023, the median follow-up duration was 40.5 months (95% CI: 39.0-43.0). Cohort A showed a median PFS of 10.7 months (95% CI: 7.6-14.9) and a median OS of 35.9 months (95% CI: 25.1-not reached). The 1-year and 3-year OS rates were 84.6% (95% CI: 76.0-94.4) and 49.8% (95% CI: 38.0-64.6), respectively. Fifteen patients with progression isolated to the brain lesions in cohort A resumed on the study treatment after local treatment, with a median PFS2 of 10.4 months (95% CI: 6.5-19.7). Cohort B showed a median PFS of 5.6 months (95% CI: 5.4-11.9) and a median OS of 31.4 months (95% CI: 22.0-not reached). The 1-year and 3-year OS rates were 78.9% (95% CI: 64.0-99.6) and 29.1% (95% CI: 13.0-60.4), respectively. Conclusions: These findings suggest the long-term survival benefit provided by pyrotinib plus capecitabine in patients with HER2-positive metastatic breast cancer and brain metastases, especially in the radiotherapy-naive cohort. Clinical trial information: NCT03691051 .
POT1 germline pathogenic variants and evolving understanding of tumor spectrum: Evidence for lung cancer predisposition.
Authors: Walsh Michael Francis , Mukherjee Semanti , Gao Ming , Fiala Elise , Mauguen Audrey , Kemel Yelena , Bandlamudi Chaitanya , Mehine Miika , Carlo Maria Isabel , Murciano-Goroff Yonina R. , Vijai Joseph , Birsoy Ozge , Mandelker Diana , Berger Michael F. , Jones David Randolph , Rudin Charles M. , Ladanyi Marc , Stadler Zsofia Kinga , Offit Kenneth 
Published: June 2023

10511 Background: As a critical component of the shelterin complex, the protection of telomeres 1 protein (POT1) plays important roles in telomere length regulation and tumorigenesis. POT1 germline pathogenic/likely pathogenic variants (PVs) have been primarily linked to the development of melanoma, chronic lymphocytic leukemia, and glioma. Recent studies report POT1 PVs also predispose to other tumors such as certain sarcomas and thyroid cancer. Methods: To better understand the role of POT1 in the development of solid tumors, we explored the spectrum of POT1 germline variants in 6644 patients with POT1 sequencing performed utilizing the MSK-IMPACT assay. Results: In total, 91 POT1 germline rare variants (population frequency < 0.01%) were identified in our cohort in 90 patients across 47 cancer types. We found 16 POT1 PVs including frameshift variants (p.Ile49fs, p.Gln358fs, p.Asp617fs), a nonsense variant (p.Arg363Ter), a missense variant (p.Asp224Asn), and splice site variants (c.10-2A > C, c.1369+1G > T). One cutaneous melanoma patient, one uveal melanoma patient, and one glioma patient were identified to have POT1 PVs. Interestingly, 8 patients with germline POT1 PVs were diagnosed with lung cancer (7 with lung adenocarcinoma and one with small cell lung cancer). Three of these 7 patients with lung adenocarcinoma had biallelic inactivation of POT1 in their tumor. The proportions of POT1 PVs in MSK lung adenocarcinoma compared to the gnomAD non-cancer control cohort were statistically significantly different (odds ratio = 16.28, 95%CI = 6.52-33.54, P = 2.87e-06). Moreover, of the 90 patients with rare germline POT1 variants, 22 had POT1 biallelic inactivation, and 9 of these 22 were diagnosed with lung adenocarcinoma. Conclusions: Taken together, our study refines the role of POT1 germline variants in solid tumors and highlights an apparent association of POT1 PVs with lung adenocarcinoma development.