bluuebunny/crossref_metadata_2025 huggingface dataset:
Outcomes among survivors of childhood cancer in low- and middle-income countries: A systematic review.
Authors: Denburg Avram , Wong Kevin Alexander , Moskalewicz Alexandra , Gupta Sumit
Published: June 2023

10057

Background: Low- and middle-income countries (LMICs) account for most of the global childhood cancer burden. Though cure rates lag behind those in high-income countries (HICs), a substantial proportion of LMIC children do survive. Long-term side effects of cancer or cancer therapy (late effects) are well-documented among childhood cancer survivors (CCS) in HICs, but whether prevalence and risk factors of late effects are comparable in LMICs is unclear. We thus conducted a systematic review to assess LMIC CCS outcomes. Methods: Five major health sciences databases were searched from inception to November 2022 in all languages. We included observational studies conducted in LMICs (World Bank 2021 classification) that evaluated outcomes in CCSs diagnosed with any malignancy. Mean or median length of follow-up must have been ≥ 5 years from original cancer diagnosis. Meta-analyses were precluded by cohort and outcome heterogeneity. Results: Of 1,994 studies identified, 113 underwent full-text review and 21 met inclusion criteria (16 full articles and 5 conference abstracts). Studies were conducted in lower-middle income (N = 12, 57%) or upper-middle income (N = 9, 43%) countries; no low-income country data were found. Study regions were mainly South and East Asia (N = 10, 48%) and the Americas (N = 8, 38%). Almost half (N = 9, 43%) of studies were conducted in India and only one African study from Cameroon was identified. Over half (N = 12, 57%) of studies were cross-sectional in design. Only five (24%) cohorts were comprised entirely of 5-year survivors. CCS of all childhood cancer types were evaluated in 12 (57%) cohorts, and 9 (43%) were specific to one cancer type. Ten (48%) studies were conducted in a survivorship clinic. Second cancers, followed by endocrine, reproductive, and cardiovascular late effects were most frequently assessed. Second cancers were reported in 1%–11% of CCS cohorts (N = 10 studies). The prevalence of hypothyroidism and metabolic syndrome ranged from 2%-49% (N = 6 studies) and 4%-17% (N = 5 studies), respectively. Gonadal dysfunction ranged from 2%-82% (N = 6 studies). Cardiac dysfunction and hypertension ranged from 1%-16% (N = 3 studies) and 5-19% (N = 3 studies), respectively. Late effects of the musculoskeletal (N = 4 studies) and urinary (N = 4 studies) systems were least investigated. Conclusions: Substantial knowledge gaps exist in LMIC childhood cancer survivorship. Few LMIC-based studies were identified, with no low-income country data available. In middle-income countries, variability existed in how late effects were defined and assessed; data was also limited by selection bias and small sample sizes. Additional systematically collected data on LMIC CCS cohorts are urgently needed.
Influence of genetic predisposition and lifestyle on modifiable cardiovascular risk factors among survivors of childhood cancer.
Authors: Wilson Carmen L , Dhaduk Rikeenkumar , Zhou Xin , Matt Gavriel , Yasui Yutaka , Im Cindy , Armstrong Gregory T. , Dixon Stephanie B , Sapkota Yadav , Wang Zhaoming , Hudson Melissa M. , Robison Leslie L. , Ness Kirsten K.
Published: June 2023

10061

Background: We aimed to evaluate associations between polygenic risk score (PRS), and lifestyle with cardiovascular risk factors (CVRFs) assessed as continuous phenotypes (LDL, HDL, triglycerides, fasting glucose [FG], systolic [SBP] and diastolic blood pressure [DBP]) among childhood cancer survivors. Methods: Participants included 2,347 White survivors (mean age=35.5 (±9.3) years) enrolled in the St. Jude Lifetime Cohort. Phenotype-specific PRS (derived from general population) were divided into tertiles and survivors classified as being at low-, intermediate-, or high-genetic risk. Lifestyle, classified as good, intermediate, or poor, was assessed based on four factors (smoking [yes/no], physical activity [meeting CDC guidelines for physical activity], diet quality [Healthy Eating Index score >59], and obesity [BMI≥30kg/m2]). A general linear model was created for each CVRF in which the effect of lifestyle (good, intermediate, poor) was examined within genetic risk group (low, intermediate, high), adjusting for sex, age, cancer therapies and current medication use. Results: The table shows worsening CVRF profiles associated with declining lifestyle and with increasing genetic risk. For example, among survivors with poor lifestyle-high genetic risk, SBP and DBP were higher on average by 14 (95% CI = 9-18) and 9 (95% CI = 6-12) mmHg respectively, compared to survivors with good lifestyle-low genetic risk. In analyses restricted to survivors with high genetic risk, mean SBP (7, 95% CI=2-12) mmHg, DBP (4, 95% CI=1-7) mmHg, triglyceride (61, 95% CI=5-117) mg/dL, and FG (7, 95% CI=4-10) mg/dL values were higher among survivors with poor versus good lifestyle, while mean HDL was lower (-13, 95% CI= -8- -18) mg/dL. Conclusions: While the risk of CVRFs among cancer survivors are associated with high genetic risk and cancer therapies, healthy lifestyle choices may partially ameliorate perturbations in CVRFs even among those with high genetic risk. Our findings highlight the importance of developing interventions targeting modifiable behaviors in this high-risk population. [Table: see text]
Expansion of the fertility preservation program to all newly diagnosed prepubertal oncology patients at a pediatric hospital.
Authors: Leavitt Antonia Pryor , Albritton Karen H. , Cazzell Mary , Stevenson Eleanor
Published: June 2023

10064

Background: As the majority of pediatric oncology patients survive their disease, generating a population of over 500,000 survivors in the United States, it is imperative to minimize the lifelong consequences of treatment, which includes temporary or permanent infertility caused by certain cancer treatments. Fertility preservation (FP), the opportunity to preserve one’s ability to have genetically-related children prior to damaging the reproductive system, is a young but rapidly expanding field and recent scientific advances have led to an expansion of options for prepubertal patients. A fertility consultation at diagnosis can provide patients and families with the opportunity to be informed regarding likelihood of gonadal dysfunction and to consider FP. Methods: After our pediatric hospital started to offer tissue cryopreservation, we initiated this evidence-based interventional quality improvement project. Our primary aim was to ensure that all newly diagnosed prepubertal oncology patients who met criteria for FP were correctly identified and offered an educational consultation and preservation. Inpatient admission lists and provider schedules were reviewed daily to identify patients. Treatment plans were discussed with providers to calculate infertility risk. All procedures were to be completed at the time of another procedure to increase likelihood of insurance coverage and minimize delays. Results: Between 07/15/22 and 11/30/22, 54 newly diagnosed prepubertal patients’ treatment plans were evaluated to determine treatment-related infertility risk using the Oncofertility Consortium Pediatric Initiative Network’s Risk Assessment tool. 15 patients were at a high level of significantly increased risk and were therefore eligible for consultation. 7 patients and their families received an educational consultation and 6 elected to undergo FP (3 TTCs; 3 OTCs). FP procedures did not cause a delay in starting treatment for any of these patients. 8 patients did not receive consultations. Reasons included the provider electing to proceed with treatment without consultation (4), the patient’s comorbidities (1), the inability to bundle FP with another procedure (1), and the family decision to decline consultation (1). Conclusions: Of the patients at high risk of infertility, only 46% received consultation with lack of referral prior to initiating treatment as the primary reason. Of the patients offered preservation methods, 86% elected to preserve their fertility, illustrating patient and family interest. Providers must acknowledge changes in practice and be informed on the impact that high-risk treatment protocols can have on fertility. An FP program with established policies processes can increase the likelihood that prepubertal patients at high risk for infertility are correctly identified, educated, and offered preservation.
CANKADO PRO-React eHealth support in patients with HR+ HER2- metastatic breast cancer receiving palbociclib and endocrine therapy and the affect on time to deterioration of quality of life: Primary outcome analysis of the multicenter randomized PreCycle trial.
Authors: Harbeck Nadia , Fasching Peter A. , Wuerstlein Rachel , Degenhardt Tom , Lüftner Diana , Kates Ronald E. , Schumacher Johannes , Raeth Philip , Hoffmann Oliver , Lorenz Ralf , Decker Thomas , Reinisch Mattea , Göhler Thomas , Staib Peter , Gluz Oleg , Schinkoethe Timo , Schmidt Marcus
Published: June 2023

1008

Background: The multicenter, randomized phase IV Intergroup PreCycle trial (NCT03220178) evaluated the impact of CANKADO-based ePRO assessment on quality of life (QoL) in HR+/HER2- locally advanced or metastatic breast cancer (MBC) patients (pts) treated with palbociclib (P) and an aromatase inhibitor or P+fulvestrant. CANKADO PRO-React, an EU- registered medical device, is an autonomous application reacting to changes in pt self- reported QoL. Methods: Between 2017 and 2021, 499 pts (median age 59y) from 71 centers were randomized (2:1, stratified by therapy line) between an active (A; CANKADO PRO-React) or an inactive arm (B; inform; limited CANKADO functionality). 412 pts (271 A; 141 B) were available for analysis of the primary endpoint, i.e. time to deterioration (TTD) of QoL (10-point drop on FACT-G), using an Aalen-Johansen estimator for cumulative incidence function of TTD DQoL with 95% pointwise confidence intervals (CI). Secondary endpoints included PFS, OS, and DQoL (QoL deterioration). Results: In all pts (ITT-ePRO), a significantly decreased risk (HR 0.6982) for the CANKADO active arm A with 95% CI [0.5059, 0.9635] regarding DQoL was observed (p=0.03). In 1stL pts (n=295), the decreased risk for arm A was 0.7162 (0.4839, 1.06; p=0.09), in 2ndL pts (n=117) 0.6614 (0.3744, 1.168; p=0.2). Absolute pt numbers declined in later visits; until about visit 30, FACT- G completion rates were 80% and higher; mean total scores were similar between arms; the change from baseline showed a linear decline and a nearly constant offset in favor of arm A, particularly in 1st L. No significant differences in clinical outcome were observed between arms: Median PFS (ITT population) was 21.4 (95% CI 19.4-23.7) (A) and 18.7 (15.1.-23.5) months (B); median OS was not reached (A) and 42.6 months (B). Conclusions: PreCycle is the first multicenter randomized eHealth trial demonstrating a significant benefit of an interactive autonomous patient empowerment application on QoL in MBC pts receiving oral tumor therapy. Clinical trial information: NCT03220178 .
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.
Germline alterations in patients with lung cancer.
Authors: Govindan Ramaswamy , Navo Katie , Huang Minxuan , Chao Calvin Y. , Sankararaman Sumithra , BOLTON KELLY L , Cao Yin
Published: June 2023

10512

Background: Despite extensive knowledge about genomic alterations in tumor cells, less is known about germline alterations in patients with lung cancer. In this study, we explore the association between germline alterations in cancer-predisposition genes across lung cancer patients with different tumor histologies and smoking status. Methods: To compare the alterations in cancer-predisposing genes through germline profiling, we analyzed 11,740 tumors from primary Lung patients (any stage/ subtype) sequenced with Tempus xT tumor/normal matched assay (DNA-seq of 648 genes at 500x coverage, full transcriptome RNA-seq). Prevalence of pathogenic/likely pathogenic (P/LP) germline alterations in 46 genes was compared between smokers and non-smokers, non-smoker somatic EGFR altered (sEGFRalt) and non-smoker somatic EGFR wild-type (sEGFRwt), non-small cell lung histology (NSCLC) and small cell histology (SCLC), and lastly NSCLC sEGFRalt and NSCLC sEGFRwt. Due to the low prevalence of germline, most differences were insignificant, although statistics of interest are reported. Results: Of 10,419 lung cancer patients with known smoking status (89%) 8845 were smokers and 1574 non-smokers. MUTYH germline alterations were detected in 1.3% vs. 1.1%, ATM 0.7% vs. 1.0%, and EGFR < 0.1% vs. 0.4% in smokers and non-smokers with lung cancer respectively. Among non-smokers, 549 were sEGFRalt and 1025 were sEGFRwt. MUTYH germline alterations were detected in 1.1% non-smoker sEGFRalt vs. 1.1% non-smoker sEGFRwt, ATM 0.7% vs. 1.1%, and EGFR 1.1% vs. 0%. Germline EGFR was significant after FDR adjustment (q < 0.037). There were 10115 patients identified with NSCLC histology and 595 with SCLC histology. MUTYH germline alterations were detected in 1.3% NSCLC vs. 0.3% SCLC, ATM 0.8% vs. 0.3%, and BRCA2 0.7% vs. 0%. Of note, SCLC was more likely to be smokers than NSCLC (93% vs. 85%, p < 0.001). Among NSCLC, 1,141 were sEGFRalt and 8,974 were sEGFRwt. MUTYH germline alterations were detected in 1.6% NSCLC sEGFRalt vs. 1.3% NSCLC sEGFRwt, ATM 0.5% vs. 0.8%, EGFR 1.3% vs. 0%, and BRCA2 0.8% vs. 0.6%. Germline EGFR was significant after FDR adjustment (q < 0.001). A separate analysis of the United Kingdom Biobank data found the prevalence of P/LP germline alterations in the same 46 genes in 4.3% of 1132 smokers with lung cancer and 5.1% in 198 never-smokers with lung cancer. The most common germline alterations involved ATM (0.8%), BRCA 2 (0.79%), MUTYH (0.62%) among smokers and MUTYH (1.5%), and CHEK2 (1.01%) among non-smokers. Conclusions: Currently, there are no standard guidelines for germline analysis for patients with lung cancer. The Tempus database enables the identification of pathogenic or likely pathogenic germline alterations in a variety of lung cancer subtypes along with their distribution frequency among various groups. The findings suggest that germline P/LP alterations in the select panel of 46 genes occur infrequently across subgroups of lung cancer.
Famitinib for familial adenomatous polyposis-associated aggressive desmoid tumors: A single-center exploratory study.
Authors: Ge Sai , Li Jian , Shen Lin , Wang Zhenghang , Li Huajun , Wang Xicheng
Published: June 2023

10513

Background: Desmoid tumour (DT) is a common extra-intestinal manifestation of familial adenomatosis polyposis (FAP), with high risk of recurrence and became the second leading cause of FAP patients’ death. The treatment of FAP-associated DTs are limited. Famitinib is a orally bioavailable, tyrosine kinase inhibitor against VEGFR-2, PDGFR, c-kit, and FGFR, and has shown antitumor activity in these patients (pts). Methods: This is a prospective, single arm study of FAP pts with progressing DT per RECIST v1.1, treated with famitinib 20 mg QD since 11/2021. The primary endpoint was objective response rate (ORR), with secondary endpoints of safety, progression-free survival (PFS), and quality of life (EORTC QLQ C30). We also collected the FFPE slices of DTs to test both genetic and proteomic backgrounds of pts with different therapeutic results. Results: Between Nov 24, 2021 and Aug 8, 2022, 11 pts were enrolled and evaluated every 9 weeks. The median follow-up time was 9.4 m (6.6 to 14.9 m). The median age was 36 (28-53) and 45% were male. Nine pts were diagnosed with intra-abdominal (IA) tumors while two had extra-abdominal (EA) DTs. Eight had stage III-IV DTs with rapid growth and severe symptoms. 10 of them had history of intestinal resection. Two pts were treated with dacarbazine and epirubicin before enrollment, while one patient received radiotherapy before famitinib. Five pts achieved partial response (PR) and six achieved stable disease (SD), with a median time to response of 7.0 months. The ORR was 45.5% and the disease control rate (DCR) was 100%. The 6-month PFS rate was 91%. The ORR of pts with IA DTs was 55.6%. Of adverse events (AEs) with famitinib, 87% were grade 1/2, the most frequently reported being hypertension (73%), neutropenia (64%), bilirubinemia (55%) and proteinuria (36%). Mean global health status/QoL before and after 6 months’ treatment was 58.3 vs 75.8 ( P= 0.09). Of all 11 pts, germline APC mutations scattered from codon 457 to 1578, and five of them detected somatic APC mutations from codon 547 to 1896 in DTs. Correlative study analysis will be presented. Conclusions: Famitinib demonstrated promising efficacy and a favorable safety profile in FAP-associated aggressive DTs.
Real-world outcomes and safety in patients with VHL associated tumors receiving belzutifan.
Authors: Chidharla Anusha , Fleer Ryan , Murphy Madison , Brunk Kelly , Holzbeierlein Jeffrey , Kasi Anup , Parikh Rahul Atul
Published: June 2023

10515

Background: Belzutifan, a small molecule HIF-2α inhibitor was FDA approved for the treatment of VHL-associated renal cell carcinoma (RCC), CNS hemangioblastomas and pancreatic NET (pNET). The approval was based on the results from the phase 2, open-label, single-group trial, enrolling 61 patients at approximately 12 study sites (Srinivasan, 2021). Objective responses were seen in 49% patients with VHL associated RCC, 63% patients with VHL-associated CNS hemangioblastomas, and 83% of patients with VHL-associated pNET. Common adverse events included anemia, fatigue, renal dysfunction, nausea, and elevated glucose levels. There is currently very limited data on real-world outcomes using belzutifan in VHL patients. Methods: After obtaining IRB approval, we retrospectively evaluated the efficacy and safety of Belzutifan for patients with VHL disease and renal cell cancer and/or VHL-associated tumors who received Belzutifan between August 2021 and January 2023 at KU Cancer center. Results: A total of 16 patients are started on Belzutifan treatment. The baseline characteristics include median age of 45 years, including 8 (50%) females and 8 (50%) males. Patients with VHL-associated RCCs were seen in 15 patients (n = 15), VHL-associated pNET (n = 13), and CNS hemangioblastomas (n = 13). Patients were started on belzutifan 120mg daily. The patients underwent bloodwork and clinic follow-up every 6-8 weeks, and response assessment was done in 11/15 patients who had follow-up scans at 6-month intervals. Objective Response to Belzutifan in any of these VHL-associated tumors was seen in 9 of 11 patients (81%), and 1/11(9%) had progressive disease (PD). Objective response in patients with VHL-associated RCC was observed in 8/11 (72%) patients and 2/11 (18%) with partial response (PR), and 6/11 (54%) with stable disease (SD). Responses observed in patients with pancreatic lesions were 1/11 patients (9%) with CR, 1/11 (9%) with PR, and 5/11 (45%) with SD. Patients with CNS hemangioblastomas 4/9 (44%) had SD. Safety was assessed in all the patients. The predominant side effect was anemia 12/16 (75%) and fatigue 11/16 (68%). Other side effects reported are fogginess 4/16 (25%), nausea 2/16 (12.5%), dizziness 2/16 (12.5%), and shortness of breath 2/16 (12.5%). Dose reduction to 80mg was needed in 2/16 (12.5%) patients due to moderate fatigue, hypoxia in one, and dysgeusia, respectively. Conclusions: Our real-world outcomes analysis of patients with VHL-associated tumors who are treated with Belzutifan shows an improved objective response when compared to the initial clinical trials, which is promising for patients. The analysis based on our real-world data shows the superior objective response in VHL-associated RCCs with Belzutifan, with a manageable safety profile. These findings reinforce Belzutifan as an effective treatment option for this patient population but warrant confirmation in a larger sample.
Early real-world (RW) experience with a multi-cancer early detection (MCED) test.
Authors: Westgate Candace , Kingsbury Dallas , Poliak Martin , Lipton Jordan , McMillin Matthew , Malinow Louis B. , Matrana Marc Ryan , Beausang John F. , Stanley Geoff , Shaknovich Rita , Venstrom Jeffrey M. , Kurtzman Kathryn , Shukla Vershalee
Published: June 2023

10519

Background: An MCED test (Galleri, GRAIL, LLC, Menlo Park, CA) intended to complement recommended screening has been in clinical use since 04/2021. Here, we report RW clinical experience across age, sex, ordering site, and use case with the initial ~53,000 tests. Methods: This cell-free DNA-based MCED test uses a targeted methylation assay and a machine learning classification algorithm to detect a cancer signal (CS) and predict CS origin (CSO). This report includes tests returned from 04/20/2021 to 12/31/2022 on individuals aged ≥22 years (yrs) and excludes tests from clinical studies and sites limiting external data sharing, and repeat tests. Systematic collection of outcomes for cases with a “CS detected” (CSD) result was completed for a limited subset and continues via a rigorously controlled quality assurance (QA) program. Results: Tests were ordered and processed from across all US states (results returned, 98.9%; mean turnaround time, 6.7 business days). Among the 53,134 tests with results returned, CSD rate (CSDR) was was 1.0% (95% CI, 0.9-1.0; 510/53134), generally higher in males (1.1% [1.0-1.2; 313/29201]) vs females (0.8% [0.7-0.9; 197/23933]), and comparable to expected CSDR (males 1.07%; females 0.96%) as modeled based on MCED test performance and cancer incidence from SEER. CSDR increased with age (Table), which was a significant predictor of CSDR (p < 2e-13). In males and females, 67.4% and 61.9% of CSOs represented cancers without (w/o) recommended population screening, respectively. Early data from the QA program from an initial limited subset of CSD cases showed that a CSD result was associated with a diagnosis of invasive cancer across multiple cancers (eg, anus, breast, esophagus, head and neck, liver/bile duct, lymphoma, ovary, pancreas, plasma cell neoplasm, prostate, sarcoma), including stage I and II cancers. Conclusions: RW experience with the MCED test was consistent with previous large-scale clinical studies with an average CSDR of 1.0%, which increased with age. The test detected a CS and predicted CSO across multiple cancers, including early-stage cancers and cancers w/o recommended screening. This indicates that the MCED test can reliably detect a CS, which is essential to support population screening. Follow-up of CSD cases is ongoing through the QA program and will allow for future reporting of RW outcomes. [Table: see text]
HER2 persistence after treatment with T-DXd in breast and gastrointestinal cancers.
Authors: Drago Joshua Z. , Pareja Fresia , Jhaveri Komal L. , Walsh Elaine M. , Ku Geoffrey Yuyat , Maron Steven Brad , Janjigian Yelena Y. , Robson Mark E. , Reis-Filho Jorge S. , Modi Shanu , Razavi Pedram , Chandarlapaty Sarat
Published: June 2023

1052

Background: T-DXd is a HER2-targeted antibody drug conjugate approved for treatment of advanced HER2-positive breast and gastroesophageal cancers and HER2-low breast cancers. The prevalence of HER2 loss after exposure to T-DXd is unknown and has implications for treatment strategies in refractory patients. Methods: We investigated clinically reported HER2 immunohistochemistry (IHC) scoring on post-treatment tissue biopsies from patients who received at least 2 cycles of T-DXd as of 2/2023. IHC was performed using mAB clone 4B5 (Ventana) and scored by ASCO/CAP guidelines on a scale of 0 to 3+. MSK-IMPACT next generation sequencing (NGS) was performed on paired pre- and post-treatment samples when available. Statistics are descriptive. Results: A total of 62 patients with breast, gastroesophageal, or colon cancer had available post-treatment biopsies. The majority (n = 51) had breast cancer, including 32 with HER2-positive and 19 with HER2-low disease. Median time on therapy was 30 weeks in HER2-positive and 21 weeks in HER2-low breast cancer. All 32 patients with HER2-positive breast cancer had detectable HER2 expression by IHC on post-treatment biopsies (median IHC score 2+; range 1+ to 3+). Of those with HER2-low breast cancer, 12 (63.1%) patients had detectible IHC after treatment. Of the 7 with IHC scores of zero, 3 also had scores of zero on the most proximal pre-treatment biopsies. Seven patients with gastroesophageal and 3 with colorectal cancer were included, with a median time on therapy of 12 and 9 weeks respectively, of which 1 (9%) exhibited HER2-loss after treatment. Among all patients with HER2-positive cancers, the rate of complete HER2-loss by IHC after exposure to T-DXd was 2.3%. Thirty-two patients had paired genomic analysis, including 25 breast and 7 gastrointestinal cancers. No change was observed in the fraction of genome altered (p = 0.0736, q = .327) or tumor mutational burden (p = 0.139, q = .487) with T-DXd exposure. Changes in ERBB2 copy number did not show clear directionality, with 15 patients (46.7%) exhibiting ERBB2 amplification pre-treatment and 12 (37.5%) post-treatment, the sum of 3 temporal gains and 6 losses of ERBB2 amplification across the threshold of 1.8. Conclusions: HER2 remained detectable by IHC in the majority of patients treated with T-DXd in this cohort, especially those with HER2-positive cancers. These findings suggest that resistance to T-DXd may occur via target-independent factors, and that HER2 could still be exploited therapeutically in these populations. Further prospective studies using quantitative assays are needed to confirm these hypotheses. [Table: see text]