bluuebunny/crossref_metadata_2025 huggingface dataset:
Multi-ethnic genome-wide association study to identify a novel locus for susceptibility to immune-related adverse events from immune checkpoint inhibitors.
Authors: Huang Yiqing , Zhao Joseph J , Wong Alvin , Tay Sen Hee , Ang Yvonne Li'en , Goh Boon Cher , Soo Ross A. , Aminkeng Folefac
Published: July 2024

3090

Background: Immune-related adverse events (IrAEs) arising from immune checkpoint inhibitors (ICIs) can be unpredictable. As genomic variation underlies both disease susceptibility and drug responses, genomic markers may predict for the development of IrAEs. We perform a pioneering pharmacogenomic study across a multi-ethnic Asian patient population to uncover genomic biomarkers associated with IrAEs from ICIs. Methods: From March 2018 – July 2023, cancer patients treated with ICIs from the National University Cancer Institute Singapore and Tan Tock Seng Hospital were recruited. IrAEs were characterized and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5. DNA was extracted and genotyped by Infinium Global Screening Array (700K markers). Statistical analyses were performed by SVS/HelixTree, PLINK and R. Genetic association was performed by logistic regression (additive model), accounting for all possible confounding factors. Bonferroni corrected P < 1.28E-07 (0.05/390,925 SNPs passed QC) was considered statistically significant. Results: Genome-wide association study (GWAS) was conducted amongst 507 patients of Asian Ancestry (Chinese, Malay, Indian and Others). Median age was 63. Majority were male (66.5%), Chinese (76.7%), ECOG PS 0-1 (40.1%) and had stage IV cancer at diagnosis (67.2%). Non-small cell lung cancer (37.1%), renal cell carcinoma (12.2%) and hepatocellular carcinoma (7.7%) were the three most common cancers. Top four ICIs used were pembrolizumab, nivolumab, durvalumab and atezolizumab, respectively (47.1%, 23.9%, 12.5%, 11.3%). 0.8% of patients received dual ICIs concurrently. Median duration of treatment was 142 days and median follow-up was 147 days. IrAEs were seen in 43.7% of patients. Skin (24.1%), endocrine (8.1%) and hepatotoxicity (6.1%) were the most common IrAEs. 4.9% of patients had grade ≥3 toxicity, of which skin (3.6%), hepatotoxicity (3.0%) and pulmonary toxicity (1.8%) were the most common. Multi-ethnic GWAS analysis identified one potential novel genetic locus associated with CTCAE grade ≥3 IrAEs. chr3:163402331 rs146525069; P = 7.29E-08, OR (95%CI) = 17.08 (5.40- 54.04); minor allele = A, 10.91% in Cases vs 0.71% in Controls. Conclusions: This pharmacogenomics GWAS uncovered a novel locus for susceptibility to serious immune-related adverse events from immune checkpoint inhibitors. Further pharmacogenomic discovery/replication and functional validation studies are currently on-ongoing. Our study provides a potential biological mechanism for IrAEs and a step towards more effective clinical translation of pharmacogenetic testing to personalize ICI use.
Characterization of diverse targetable ERBB2 alterations in 512,993 patients with solid tumors.
Authors: Liu Dazhi , Keller-Evans Rachel B , Schrock Alexa B. , Drilon Alexander E. , Jee Justin , Li Bob T.
Published: July 2024

3129

Background: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) that has demonstrated activity against a range of HER2-expressing and HER2-mutant (mut) solid tumors. We present an extensive landscape of ERBB2 alterations (alt) that may predict sensitivity to HER2-targeted therapies in development with a focus on mutations and cancer types without approved indications. Methods: We queried institutional databases (MSKCC and Foundation Medicine, Inc.) of comprehensive genomic profiling (CGP) performed on solid tumor tissue samples using either MSK-IMPACT (N=83,332; MSK) or FoundationOne/FoundationOne CDx (N=429,661; FMI) and on patient-matched liquid biopsies using FoundationOne Liquid CDx (N=1,922). ctDNA tumor fraction (ctDNA TF) on FoundationOne Liquid CDx was estimated using a composite algorithm. Clinicopathological characteristics and treatment outcomes were annotated for MSK-IMPACT samples. Results: ERBB2 activating alt were detected in 6.6% (n=28,508) and 5.0% (n=4,133) of tumors in the FMI and MSK cohorts, respectively. In FMI tissue samples, ERBB2 alt were most prevalent in gastroesophageal (GEC; 18.1%), bladder (18.0%), salivary gland (14.1%), breast (12.7%), and uterine (12.1%) cancers. The cancer types with the largest number of ERBB2mut tumors, specifically, included NSCLC (n=1,618, 1.9%), breast (n=1,565, 3.5%), colorectal (CRC; n=1,221, 2.3%), bladder (n=855, 8.8%), and GEC (n=660, 3.4%). Across these 5 cancers, ERBB2 mut were most commonly located in the kinase domain (KD; 58%), followed by the extracellular domain (ECD; 28%) and transmembrane domain (TMD; 2%). Rare splice site mut and in-frame deletions resulting in exon 16 loss (Ex16Alt) were also observed (n=76, <0.1%). ERBB2 mut were found to be mutually exclusive with other RTK/MAPK driver oncogenes including: EGFR, KRAS, ALK, MET, BRAF, and RET in NSCLC; FGFR1 in breast cancer; BRAF in CRC; and FGFR3 in bladder cancer. In patient-matched liquid biopsy samples, sensitivity for detecting ERBB2 amplifications (amp; 33.3%, 43/129) was lower than for detecting ERBB2 mut (72.3%, 47/65) across select cancers. However, sensitivity for detection of both alts was improved in liquid samples with elevated ctDNA TF (≥1%), increasing to 52.6% (40/76) for amp and 97.3% (36/37) for mut. In the MSK cohort, 110 of 986 (11.2%) patients with ERBB2 mut non-NSCLC tumors received one or more HER2-targeted therapies, including ADCs. Clinical responses to HER2-targeted therapies were observed in patients harboring KD mut (n=10), ECD mut (n=6), TMD mut (V659E, n=1), and in 1 patient with a V697L mut. Conclusions: CGP detects diverse ERBB2activating alt at a high incidence in solid tumor types beyond NSCLC. These represent patient populations who may benefit from HER2-directed therapies. Trials of novel HER2-targeted agents are necessary to refine our understanding of the biological dependency of HER2 alterations.
Triplet combination treatments with pembrolizumab (pembro) for anti–PD-(L)1–refractory advanced melanoma: Preliminary results of the phase 1/2 KEYMAKER-U02A study.
Authors: Dummer Reinhard , Grob Jean-Jacques , Robert Caroline , Shapira-Frommer Ronnie , Lebbe Celeste , Ascierto Paolo Antonio , Dalle Stéphane , Hamid Omid , Meyer Nicolas , Khattak Muhammad Adnan , Hill Andrew Graham , Cohen Jonathan , Curigliano Giuseppe , Di Giacomo Anna Maria , Del Vecchio Michele , Jang Sekwon , Singh Rohini , Peng Xuan , Diede Scott J. , Long Georgina V.
Published: July 2024

9506

Background: Anti–PD-(L)1–refractory melanoma is a major challenge, and immunotherapy combination treatment may be useful in this patient population. The phase 1/2 KEYMAKER-U02A (NCT04305041) is a multi-arm, open-label, adaptive umbrella study designed to evaluate pembro + investigational agents for the treatment of anti–PD-(L)1–refractory melanoma. We report results from arm 1 (pembro + quavonlimab [qmab] (anti-CTLA4) + vibostolimab [vibo] (anti-TIGIT)), arm 2 [pembro + qmab + lenvatinib [len] (TKI)), and arm 3 (pembro + ATRA [all-trans retinoic acid]) of KEYMAKER-U02A. Methods: In all arms, adults had stage III/IV melanoma, ≥1 measurable lesion per RECIST v1.1, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and disease progression on anti–PD-(L)1 therapy alone or in combination. Pts were randomized equally to open arms. In arm 1, pts received pembro 200 mg IV Q3W + qmab 25 mg IV Q6W + vibo 200 mg IV Q3W. In arm 2, pts received pembro 400 mg IV Q6W + qmab 25 mg IV Q6W + len 20 mg PO QD. In arm 3, pts received pembro 400 mg IV Q6W + ATRA 150 mg/m2/day PO for 3 days Q3W. Pts received treatment for up to 2 y or until intolerable toxicity, disease progression, or pt withdrawal. Primary end points were safety and ORR per RECIST v1.1 by blinded independent central review (BICR). DOR per RECIST v1.1 by BICR was the secondary end point. PFS per RECIST v1.1 by BICR and OS were exploratory end points. Enrollment was planned for a maximum of 20 pts in each arm and enrollment could continue to up to 40 pts if an ORR of > 20% (5/20) was observed. Enrollment would then continue up to 100 pts if an ORR of ≥35% (14/40) was observed. Results: At data cutoff (Oct 18, 2022), 40 pts had been assigned to arms 1 and 2 and 20 pts to arm 3. Median (range) follow-up was 18.4 (1.7-24.5) mo in arm 1, 18.5 mo (1.6-25.4) in arm 2, and 2.7 mo (0.8-3.5) in arm 3. Efficacy is reported in the table. Treatment-related adverse events (TRAEs) occurred in 35 pts (88%) in arm 1, 38 pts (95%) in arm 2, and 15 pts (75%) in arm 3. Grade 3-5 TRAEs occurred in 11 pts (28%) in arm 1, 23 pts (58%) in arm 2, and 3 pts (15%) in arm 3; 1 pt in arm 2 died from a grade 5 TRAE (immune-mediated nephritis). Conclusions: Although objective responses were observed in some pts with anti–PD-(L)1–refractory melanoma, protocol-prespecified criteria for enrollment expansion were not met in any arm. The safety profile was manageable. Additional arms will be reported for this pt population with a high unmet need. Clinical trial information: NCT04305041 . [Table: see text]
Length of treatment after partial or complete remission in immunotherapy for metastatic melanoma: An EUMelaReg real world study.
Authors: Asher Nethanel , Mohr Peter , Ellebaek Eva , Bender Marc , Mangana Joanna , Kandolf Lidija , Gavrilova Iva , Ascierto Paolo Antonio , Gogas Helen , Rutkowski Piotr , Schadendorf Dirk , Bastholt Lars , Weichenthal Michael ,   EUMelaReg Consortium
Published: July 2024

9531

Background: A significant proportion of patients (pts) with non-resectable melanoma treated with immune checkpoint inhibitors (ICI) achieve durable remissions, but there is limited data on the optimal duration of ICI therapy in these pts. Therefore, the influence of the duration and maintenance of ICI therapy in pts with a partial (PR) or complete remission (CR) on further outcome was investigated. Methods: Primary objectives was the survival outcome after achieving PR or CR in non-resectable stage III/IV melanoma in relation to baseline prognostic variables and duration of maintenance treatment with ICIs in 1st line. This retrospective study evaluated melanoma cases from the EUMelaReg treatment registry, who achieved a best overall response (BOR) of PR or CR with either single agent anti-PD1 or combined anti-PD1/anti-CTLA4 in 1st line. Cases were stratified according to treatment duration after achieving a PR or CR: < 6 months (M), 6-12 M, > 12 M. To address immortal time bias, cases with early progression were cloned into all respectively compatible strata. These synthetical strata were further analyzed and compared by propensity score weighting, and robust confidence intervals were retrieved by bootstrapping techniques. Results: A total of 1,291 pts were included in the analysis. After cloning, 2,144 cases could be stratified to the synthetical arms of <6 M (26.5%), 6-12 M (31.4%) or >12 M (42.1%) treatment continuation after achieving PR or CR. Adjusted Kaplan-Meier estimates showed that treatment until progressive disease (PD) or > 12 M after remission resulted in prolonged progression-free (PFS) and overall survival (OS) compared to the < 6 M arm (hazard ratio (HR): 0.82 [95% confidence interval (CI): 0.6-0.9] and HR: 0.67 [95% CI: 0.5-0.9], respectively).This effect was more pronounced in PR (HR 0.66 for OS) than in (HR 0.84 for OS). Treatment for 6-12 M compared to < 6 M also showed a trend towards prolonged PFS and OS (HR: 0.85 [95% CI: 0.7-1.1] and HR: 0.82 [95% CI: 0.6-1.1], respectively). Conclusions: This study showed PFS and OS benefit for pts continuing on treatment for > 12 M or until progression after achieving PR or CR compared to pts treated for < 6 M. [Table: see text]
Using serial 18F-FDG PET/CT PERCIST response to predict responses to immune check point inhibitors in patients with advanced cutaneous squamous cell carcinoma.
Authors: Ladwa Rahul , Kenyon Sarrinder , Jagger Gillian , McGrath Margaret Louise , Cuscaden Claire
Published: July 2024

9548

Background: The role of serial 18F-FDG-PET/CT imaging in predicting long term efficacy of PD-1 targeted immune checkpoint inhibitor (ICI) in advanced cutaneous squamous cell carcinoma (cSCC) is unknown. This study aims to correlate PET PERCIST response with time to progressive disease. Methods: This was a single-centre retrospective study of patients treated with ICI for advanced cSCC who had baseline and serial FDG-PET/CT within 4-months of commencement of ICI. PERCST 1.0 was calculated by two radiologists independently and classified into complete metabolic response (CMR), partial metabolic response (PMR), stable metabolic disease (SMD), and progressive metabolic disease (PMD). The primary endpoint was time to progression from commencement of ICI. Progression was determined by a multidisciplinary team combining clinical and radiological assessments. Results: Of the 242 patients treated with ICI for advanced cSCC during 2018-2023, 83 (34%) patients had a serial FDG PET. Of these, 53 patients met the inclusion criteria of ≤4-months from ICI to second PET. CMR (54.7%), PMR (15.1%), SMD (11.3%) and PMD (18.9%) were seen as initial responses by PERCST 1.0. With a median follow-up of 8-months (1-55), progressive disease as determined by the multidisciplinary team was observed in 11 patients (21%). For these 11 patients, the 4-month PERCST 1.0 response was measured as CMR (n=1), PMR (N=1), SMD (N=2) and PMD (N=7). The median TTP was significantly higher in CMR/ PMR vs SMD/PMD (55 vs 4-Months, P<0.001). At data cut off, 94.6% (N=35) of patients with a 4-month PET PERCST 1.0 CMR/ PMR assessment did not progress clinically. Clinical response was maintained at a minimum of 12-months in 94.7% (n=18) of those responding. Conclusions: Rate of CMR and PMR in advanced cSCC is high with ICI. Early PET CMR/ PMR appears to predict long term durable responses. Incorporation of PET/CT into the assessment of response in cSCC may help guide treatment decisions by early identification of those patients not responding to ICI.
Atezolizumab (A), cobimetinib (C), and vemurafenib (V) in patients (pts) with BRAFV600 mutation–positive melanoma with central nervous system (CNS) metastases (mets): Final results and exploratory biomarker analysis from the phase 2 TRICOTEL study.
Authors: Dummer Reinhard , Levesque Mitchell , Bellini Elisa , Chen Marissa , Hu Youyou , Wong Tiffany , Stassen Katja , Duhard Pauline , Yan Yibing , Tawbi Hussein A.
Published: July 2024

9550

Background: Primary analysis results from the phase 2 TRICOTEL study showed intracranial activity with the triplet combination of A + C + V in pts with BRAFV600-mutated melanoma with CNS mets (1). Here, we report final analysis results and exploratory biomarker analyses for pts with BRAFV600-mutated melanoma in the triplet combination cohort from TRICOTEL. Methods: Eligible pts were aged ≥18 y and had melanoma, MRI-confirmed CNS mets ≥5 mm in ≥1 dimension, and no prior systemic treatment for metastatic disease. Pts received A (840 mg on days 1 and 15 of each 28-d cycle) + C (60 mg once daily for 21 d on, 7 d off) + V (720 mg twice daily) except in cycle 1, during which A was withheld. Tumor tissue and circulating tumor DNA (ctDNA) samples collected at baseline (cycle 1, day 1) and ctDNA at the time of progressive disease (PD) were profiled for mutations using next-generation sequencing. Tumor tissue was profiled using a pipeline programmed for MelArray, and ctDNA was measured based on the tissue genetic profile. Results: A total of65 pts were enrolled in the triplet combination cohort. At final analysis, median follow-up was 12.4 mo. Per independent review committee (IRC) assessment, intracranial ORR (confirmed by assessments ≥4 wk apart) was 38% (95% CI, 27–51) and median intracranial PFS was 5.1 mo (95% CI, 3.7–6.9) (Table). Median OS was 13.4 mo (95% CI, 10.7–16.9). No new safety signals were observed since primary analysis. Mutations were detected in baseline ctDNA samples of 60 pts (5 pts not reported) and showed high prevalence of NF1, NRAS, and GNAI2 mutations; relative to tumor tissue, 11 additional BRAF mutations were detected in ctDNA at baseline. Acquired mutations in AKT1 were detected in ctDNA at PD. Median OS shortened in pts with >2 versus ≤2 mutated MAPK pathway genes in ctDNA at baseline (9.1 vs 14.5 mo; hazard ratio, 2.0 [95% CI, 1.0–3.7]; p<0.05). In tumor tissue, baseline mutations in PIK3C2A and PLEKHG4 were enriched in nonresponders, while RAD51B mutations were enriched in responders. Conclusions: Combination A + C + V had clinical intracranial activity in pts with BRAFV600-mutated melanoma with CNS mets. Exploratory biomarker analyses in this small cohort demonstrate the presence of ctDNA in pts with melanoma and CNS mets and provide insight into mutations associated with response and resistance to the triplet combination. 1. Dummer R et al, Lancet Oncol 2023. Clinical trial information: NCT03625141 . [Table: see text]
The efficacy and safety of toripalimab combined with anlotinib in the first-line treatment of Chinese patients with metastatic melanoma.
Authors: Ye Ting , Li Linqing , Fan Li , Cao Rubo , Li Xianan , Chen Jing
Published: July 2024

9560

Background: Acral, mucosal and non-CSD melanoma are the major subtypes in Chinese melanoma patients, with poor response to antiprogrammed cell death-1 (PD-1) monotherapy. Anti PD-1 monoclonal antibodies combined with anti-angiogenesis agent have showed synergistic effects mechanically and a promising response rate. Here, we report efficacy and safety of toripalimab combined with anlotinib in Chinese patients with metastatic melanoma. Methods: Patients with metastatic acral, mucosal and non-CSD melanoma received toripalimab 240mg intravenously every 3 weeks combined with anlotinib 12 mg orally once a day for first 2 weeks every 3 weeks as first-line treatment, until disease progression or unacceptable toxicity. All patients were enrolled from the Cancer Center of Union Hospital, affiliated to Tongji Medical College of Huazhong University of Science and Technology and Hunan Cancer Hospital. Results: From January 2021 to January 2024, a total of 47 patients were enrolled in this study. Subtypes were 16 patients with acral melanoma, 21 patients with mucosal melanoma, and 10 patients with non-CSD melanoma. Average age was 59.7 ±10.1 years old. The median follow-up was 26.5 months (95% CI: 20.6, 32.4 months). Among the 46 efficacy evaluable patients, the objective response rate (ORR) and disease control rate (DCR) were 23.9% and 80.4%, respectively. Median duration of response was 14.4 months (95% CI: 7.5, 21.3). The median progression-free survival (PFS) of all 47 patients was 5.7 months (95% CI 4.2 to 7.2 months); and the median OS was 14.4 months (95% CI 7.3 to 21.5 months). The median PFS of patients with M1a stage is 24.4 months, statistically longer than M1b (5.1 months), M1c (6.6 months) and M1d (4.0 months). The median PFS of acral, mucosal and non-CSD melanoma were 6.6m, 5.1m, 5.2m respectively with no statistical difference, and these is no difference of PFS between gender and age. In terms of safety, treatment-related adverse events (TRAEs) for all grades occurred in 76.6% (36/47) of patients, and grade 3 or 4 occurred in 4.3% (2/47) of patients. The incidence of immune-related adverse reactions (irAE) was 23.4% (11/47) for all grades, the most common irAEs (≥2%) included hypothyroidism, immune-associated hepatitis and rash. Conclusions: Toripalimab combined with anlotinib displays good efficacy and well-tolerant safety profiles in the treatment of patients with metastatic melanoma. Further biomarker analysis was ongoing.
Optimal neoadjuvant treatment and prognostic factors in patients with HR-positive/HER2-positive early or locally advanced breast cancer: A national real-world study in China.
Authors: Liu Zhenzhen , Zhu Jiujun , Wang Chengzheng , Lu Zhenduo , Chen Xiuchun , Li Lianfang , Sun Xianfu , Zhang Chongjian , Qiao Jianghua , Yan Min
Published: July 2024

e12514

Background: Few data have been reported regarding breast cancer (BC) population characterized by HR+/HER2+ especially in a real-world setting in China. This analysis aimed at identifying differences in short-term treatment outcomes of different neoadjuvant therapy (NAT) regimens, effects of the demographics and clinical features on short-term outcomes of NAT, and further understanding the prognostic factors related to those outcomes in HR+/HER2+ early (EBC) or locally advanced BC (LABC) pts by using dataset from National Cancer Information Database (NCID) in China. Methods: This retrospective, multicenter, real-world study used electronic medical record data from NCID. We analyzed HR+/HER2+ EBC or LABC Chinese pts who were initially diagnosed between Jan 1, 2019 and May 31, 2022 and received NAT followed by surgery during study period. Primary endpoints included total pathological complete response (tpCR) and breast pCR (bpCR). Secondary endpoints included disease-free survival (DFS) and event-free survival (EFS). Results: 3792 pts from NCID covering 51 hospitals, 26 provinces met inclusion criteria and were included. After controlling for age and post-surgery N staging, 1-, 2- and 3-yr DFS was similar between trastuzumab (T) and T+pertuzumab (P) NAT subgroup (92.79%, 87.20% and 83.32% vs 94.83%, 88.82% and 87.88%; p=0.1120). 1-, 2- and 3-yr EFS was higher in T+P subgroup (T vs T+P: 85.24%, 82.35%, 77.01% vs 90.86%, 89.65%, 82.78%; p = 0.0003). Logistic regression multivariate analysis showed improved tpCR and bpCR was independently positively associated with receiving T+P NAT (vs T: both p < 0.0001), platinum NAT (vs anthracycline: p = 0.0071 and 0.0122, resp.), while negatively associated with receiving no targeted therapy (vs T: p = 0.0002 and < 0.0001, resp.), ≥ 65 yrs (vs > 40 yrs, < 64 yrs: p = 0.0116 and 0.0290, resp.), or post-surgery ER positive (vs negative: both p < 0.0001). Conclusions: HR+/HER2+ EBC or LABC gained short- and long-term benefit from HER2 dual-blockade therapy in clinical practice. Prognostic factors for improved tpCR and bpCR included T+P and platinum NAT, whereas ≥ 65 yrs and post-surgery ER+ were predictive of decreased tpCR and bpCR. [Table: see text]
Cost-effectiveness of adjuvant abemaciclib and ribociclib in high-risk, hormone receptor–positive, early breast cancer in India.
Authors: Sra Manraj Singh , Sasi Archana , Batra Atul , Bakhshi Sameer , Ganguly Shuvadeep
Published: July 2024

e12516

Background: Incorporating adjuvant cyclin-dependent kinase (CDK) 4/6 inhibitors abemaciclib and ribociclib along with endocrine therapy has been shown to improve invasive disease-free survival (iDFS) for hormone receptor-positive (HR+) human epidermal receptor 2 negative (HER2-) early breast cancer (EBC). This study assesses the cost-effectiveness of this strategy, along with adjuvant aromatase inhibitors (AI) from an Indian perspective. Methods: A Markov chain model evaluated the cost-effectiveness of abemaciclib and ribociclib with letrozole compared to letrozole alone for HR+/HER2- EBC from a payer perspective in India. Key measures included lifetime quality-adjusted life years (QALY), life-years (LY), and total costs. This study explores two scenarios for effectiveness: a best-case (BC) scenario, where the benefit of CDK4/6 inhibitors in improving iDFS lasts a lifetime, and a worst-case (WC) scenario, where benefits disappear after 5 years. Probabilistic sensitivity analyses (PSA) were used to account for simulation uncertainty. Results: In the BC scenario, abemaciclib added 2.17 QALY and 4.96 LY, costing $27,756.65 more. Ribociclib in the BC scenario added 0.98 QALY and 2.58 LY, with added costs of $20,494.6. The incremental cost-effectiveness ratio for abemaciclib and ribociclib surpassed the willingness to pay threshold for in India in both scenarios (Table). At current market prices there is 0% probability of cost-effectiveness of abemaciclib and ribociclib. The cost of abemaciclib and ribociclib needs to be reduce by 78.61% and 87.19%, respectively to achieve cost-effectiveness. Conclusions: The combination of adjuvant abemaciclib or ribociclib with letrozole is not cost-effective for HR+/HER2- EBC in India in either the best or worst-case scenario.[Table: see text]
The efficacy of primary progesterone on survival in early breast cancer: A real world scenario.
Authors: Joshi Shalaka Prakash , Engineer Mitchelle , Vanmali Vaibhav , Siddique Shabina , Hawaldar Rohini W. , Badwe Rajendra A.
Published: July 2024

e12522

Background: Surgery performed during progestogenic milieu improves survival in breast cancer patients. We previously proved efficacy of pre-operative progesterone in high-risk, operable breast cancer. In another multicenter randomized trial, intra-operative peri-tumoral local anesthetic injection showed 29% reduction in mortality. In this study, several patients had also received progesterone injection since this is adopted as standard of care across some centers including ours. We assessed the effectiveness of pre-operative progesterone in patients who were randomized in the local anesthetic study. Methods: We analyzed 1583 patients randomized on the local anesthetic study during December 2011-October 2018 with respect to receipt of progesterone. All patient who had breast lump of ≥2cm and/or node positive were eligible to receive progesterone injection before surgery. Kaplan Meier curves were plotted along with Cox regression analysis to study factors affecting disease-free and overall survival. Results: Of 1583, 454 patients did not receive, and 1129 patients received progesterone before surgery. The median age of whole cohort was 51 years, median pT size was 3 cm, 45% were node positive, 60% ER/PR+ and 24%TNBC. At median follow-up of 68 (0·5-72) months in surviving patients, there were a total of 292 DFS events (progesterone arm-193, no-progesterone arm-99). The 5-year disease-free survival (DFS) was 86.5% in the progesterone arm and 79.2% in the no-progesterone arm (HR-0.57,0.45-0.73, P<0.001). The 5-year overall survival (OS) was 90.5% in the progesterone arm and 82.8% in the no-progesterone arm (HR-0.47,0.36-0.63,P<0.001). On Cox Regression analysis (Table), administration of progesterone injection was an independent prognostic factor for DFS (HR-0.53,0-41-0.70, p<0.001) and OS (HR-0.44,0-32-0.60, p<0.001) both. Conclusions: The receipt of pre-operative progesterone improved outcomes in the setting of another randomized trial. It should be administered to all high risk (T2/N1) breast cancer patients who are planned for surgery first. [Table: see text]
Real-world (RW) risk of recurrence among patients (pts) diagnosed with stage II-III HR+/HER2− early breast cancer (EBC) treated with endocrine therapy (ET) in the US.
Authors: Razavi Pedram , Ahmed Mehnaj , Roush Ashley , Parikh Rohan , Hitchens Abigail , Shen Sherry , Safonov Anton , Jhaveri Komal L. , Robson Mark E. , Peacock Nancy Walker , Ma Yanjun , Santarsiero Elizabeth Chertow , Ganapathy Vaidyanathan , Shah Rohan M. , Amefule Adaeze Q. , Lteif Agnes , Blakely L. Johnetta
Published: July 2024

e12533

Background: Despite improved management of HR+/HER2− EBC, pts experience recurrences while on or up to decades after ending standard-of-care (SOC) ET. Addition of adjuvant (adj) cyclin-dependent kinase 4/6 inhibitors (CDK4/6is), ribociclib and abemaciclib, to SOC ET resulted in significant improvement of outcomes in pts with HR+/HER2− EBC at risk of recurrence. In NATALEE, ribociclib showed invasive disease-free survival (iDFS) benefit in a broader population, including select node-negative (N0) disease. This RW study describes short-term recurrence in pts with HR+/HER2− stage II-III EBC treated with SOC adj ET ± chemotherapy (CT) in the last decade in the US, prior to use of adj CDK4/6is. Methods: A medical record review from large academic (Memorial Sloan Kettering Cancer Center) and community (Tennessee Oncology) oncology practices was conducted. Adult women with stage II-III HR+/HER2− BC (AJCC 8) who underwent surgical resection and initiated adj ET between Jan 2012 and Dec 2018 were included. Pts were randomly selected for equal distribution by year of adj ET initiation. Study measures were summarized descriptively. Kaplan-Meier method was used to estimate 3-, 5-, and 7-y iDFS and distant disease–free survival (DDFS). Results: Medical charts of 992 pts were analyzed (median follow-up from initiation of adj ET, 6.3 y). Median age was 58 y. Most pts (76.7%) had stage II disease at diagnosis, 64.0% received CT, and 34.2% were premenopausal. In total, 35.8% of pts were N0. Among all N0 pts, ≈41.4% had high-risk tumor features, as defined by NATALEE: >5 cm, 9.3%; 2-5 cm with G3, 25.9%; 2-5 cm with G2 + high genomic risk, estimated at 6.2%. N1(1-3) and N2/N3 (≥4) involvement was seen in 46.8% and 17.4% of pts, respectively. Analyses of iDFS/DDFS showed cumulative risk of invasive disease recurrence, predominantly distant disease, over 7 y in 21.4% across all stage II/III pts and 25.7% among the N0 pts meeting NATALEE criteria. Conclusions: This RW analysis from 2 major academic and community centers in the US confirms pts with stage II-III HR+/HER2− EBC, including select pts with N0 disease, experience considerable risk of recurrence, as early as during the adj treatment period cumulating over time. These findings warrant the consideration for tolerable treatment escalation for pts with stage II-III HR+/HER2− EBC.
An overview of psychological analysis of patients with breast cancer undergoing total mastectomy and breast conservation surgery and its impact on objectified body consciousness at a tertiary care cancer centre.
Authors: Somashekhar S.P. , Jaiswal Richa , Rajgopal Ashwin K. , Fernandes Aaron Marian , Chandrashekar Rohit Kumar C.
Published: July 2024

e12537

Background: Breast cancer is the most common cancer among females, and surgery plays a central role in its treatment. Surgical treatments may have a negative psychological impact on women’s mental health regarding their body image. The purpose of this study was to compare the psychological health insights pertaining to objectified body consciousness scores before and after the surgery and also to observe whether these scores were comparable across the surgery types. Methods: This retrospective qualitative study included 706 breast carcinoma patients who underwent either Breast Conservation Surgery or Total Mastectomy at Manipal Cancer Centre, between the years 2020-2021. A validated questionnaire of Objectified Body Consciousness was used to obtain responses at diagnosis and at 6 months postsurgery and final scores were calculated for both instances. Two sample t- tests/analysis of variance and Chi-square tests were used to compare continuous and categorical variables respectively. Results: Out of total 706 breast cancer patients, 402 patients underwent Breast Conservation Surgery and 304 underwent Total Mastectomy procedure. A statistically significant change was seen in the mean Objectified Body Consciousness Score (14.22±15.44) for all patients when compared pre-operatively (72.72±11.38) and postoperatively (60.15±17.58). This change was higher in the Total Mastectomy group (29.38±11.53). Also, statistically significant rise in scores was seen with increasing age. There was a statistically significant difference between BCS and Total Mastectomy groups with respect to the distribution of age group, marital status, types of cancer, stage and grade of cancer, NACT administration and postoperative mean objectified body consciousness scores of patients (p-value <0.05). Conclusions: We could affirmatively conclude in our study that younger breast cancer patients and all patients who underwent a total mastectomy, had more psychological apprehension with the body image post-surgery, signifying these groups should be encouraged by healthcare professionals to reach out for counselling at the earliest. Knowing the pre-operative Objectified Body Consciousness scores and the type of surgery the patient is going to undergo, will help us to streamline categorical psycho-educational programs for each group and personalise our healthcare professionals to encourage women to reach out to social support groups and directed counselling at the earliest. This will help women adapt to their transformed life and be mentally prepared for the changes that are expected post-surgery.
Major pathologic response and long-term clinical benefit in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer after neoadjuvant chemotherapy.
Authors: ji Lei , Chen Xi , Qian Xiaoyan , Xiao Min , Li Qing , Li Qiao , Wang Jiayu , Fan Ying , Luo Yang , Chen Shanshan , Ma Fei , Xu Binghe , Zhang Pin
Published: July 2024

e12608

Background: Rates of pathological complete response (pCR) are much lower in patients with hormone receptor–positive (HR+) /HER2-negative (HER2-) breast cancer than in those with HER2-positive and triple-negative breast cancer (TNBC). The majority of HR+/HER2- breast cancer patients can also achieve long-term survival despite not attaining pCR, indicating limited prognostic value of pCR in this population. This study aimed to identify novel pathologic end points for predicting long-term outcomes in HR+/HER2- breast cancer after neoadjuvant chemotherapy. Methods: We analyzed HR+/HER2- breast cancer patients with stage II-III tumors who underwent curative surgery after neoadjuvant chemotherapy from three hospitals. Major pathologic response (MPR), defined as the presence of Miller-Payne grades 3-5 and positive lymph node ratio of ≤10%, was used as a pathological evaluation indicator. MPR evaluates the extent of residual invasive carcinoma in both the breast and axillary lymph nodes following neoadjuvant therapy. We assessed the association between MPR and event-free survival (EFS) and performed Multivariable Cox regression to identify independent factors associated with EFS. Results: From January 2010 to December 2020, 386 patients were included in the final analysis. The median age was 46 years. 244 patients (63.2%) were premenopausal, with 271 (70.2%) patients diagnosed with stage III disease. The predominant neoadjuvant chemotherapy regimen was anthracycline combined taxane (79.3%). 28 patients (7.3%) achieved pCR and 118 patients (30.6%) achieved MPR. The median duration of follow-up was 54.4 months. Multivariate analysis showed that PR expression, Clinical stage, Miller–Payne grades and Positive lymph node ratio were independent prognostic factors for EFS (all P values <0.05). The prognostic effect of MPR remained in multivariable models (hazard ratio (HR), 0.45; 95% confidence interval (CI), 0.26–0.76; P = 0.008), with 5-year EFS of 87% vs. 68% in the non-MPR group. In non-pCR patients, those who achieved MPR exhibited a similar EFS compared with pCR patients (HR, 2.25; 95% CI, 0.51–9.84; P = 0.28). Conclusions: MPR was a novel pathologic end point for prognostic evaluation in HR+/HER2- breast cancer after neoadjuvant chemotherapy. Compared to pCR, MPR may hold greater applicability in the prognosis evaluation.
A propensity-matched analysis of the efficacy and safety of neoadjuvant inetetamab and pertuzumab with paclitaxel and carboplatin (TCbIP) on locally advanced HER2-positive breast cancer.
Authors: Jiang Mingxia , Chai Yue , Liu Jiaxuan , He Maiyue , Wang Yipeng , Xue Yang , Xing Zeyu , Zhang Mengqi , Zhou Shihan , Ma Fei , Wang Jiayu , Yuan Peng , Xu Binghe , Li Qiao
Published: July 2024

e12609

Background: Inetetamab is an Fc segment-modified innovative anti-HER2 monoclonal antibody. It has been proven to be effective and safe in HER2-positive advanced breast cancer. However, its efficacy and safety in the neoadjuvant treatment of HER2-positive locally advanced breast cancer (LABC) remains to be validated. This study aimed to evaluate the efficacy and safety of Inetetamab-based neoadjuvant therapy (TCbIP). Methods: In this prospective cohort study, we investigated the efficacy and safety of TCbIP in neoadjuvant therapy for HER2-positive LABC, and compared with TCbHP regimen (trastuzumab combined with pertuzumab, paclitaxel, and carboplatin) with propensity score matching (PSM). Thirty-four patients (clinical stage IIA-IIIC, HER2-positive LABC) were prospectively enrolled in this study and treated with the TCbIP regimen. The primary endpoint was total pathological complete response (tpCR). Adverse events (AEs), objective response rate (ORR), and near-pCR were key secondary endpoints. Results: The pCR rate of 28 patients who finished surgery was 60.7%, and was comparable and slightly higher (60.7% vs. 53.6%, P = 0.510) than the TCbHP group in PSM. The ORR was 96.4% and DCR reached 100.0%. The most common ≥grade 3 AE was neutropenia (21.4% vs. 11.9%, P = 0.350). No significant reduction in left ventricular ejection fraction was observed, and no patient withdrew from treatment due to AEs. Conclusions: Neoadjuvant therapy with TCbIP resulted in good efficacy and safety in patients with HER2-positive LABC, and might be another promising option for neoadjuvant treatment. Clinical trial information: NCT05749016 .
Use of an AI-powered visualization platform to support precision clinical decision-making in patients with breast cancer undergoing neoadjuvant chemotherapy.
Authors: Reid Vincent , Weitz Michelle , Biancalana Matthew , Cole John A. , Rosen Barry
Published: July 2024

e12618

Background: Chemotherapy to reduce cancer burden and tumor size ("downstaging") is widely used in neoadjuvant treatment of early-stage breast cancer (ESBC) and can have a dramatic impact on selection of further treatment courses, including surgery. The resulting decision-making process between physicians and cancer patients requires detailed and effective communication of the patient's disease status, and clear presentation of this information in Tumor Board settings. Artificial intelligence (AI) -powered visualization platforms offer the potential to aid in evaluating breast tumor location and morphology, and accordingly optimize treatment. Additionally, these tools offer enhanced communication with patients regarding future treatment options, particularly serving as clinical decision support (CDS) tools. Methods: We assessed the performance of an AI platform that employs dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to render three-dimensional (3D) visualizations of breast tumors and 5 additional chest tissues on an independent validation dataset comprise of 100 ESBC cases with ground-truth tumor labels vetted by 2 breast-specialized radiologists. The platform provides 3D depictions of the tumor and its multi-tissue context, as well as functionalities for quantifying tumor morphology, tumor-to-landmark structure distances, excision volumes, and approximate surgical margins. We subsequently evaluated the tool's utility in a real-world setting to understand how the tool impacts clinical decision-making and patient communication, specifically around surgical planning in the context of neoadjuvant chemotherapy (NACT). Results: The platform generated accurate 3D tumor maps, as evidenced by a median Dice score of 75.6% and a median Hausdorff distances of 15.1 mm relative to the radiologist validation set. The automatic longest tumor dimension calculations were linearly correlated with radiologist direct measurements (Pearson correlation coefficient = 0.78) and had a median absolute difference of 6.3 mm. We found strong overlap between the platform’s ground-truth convex hulls, as shown by a median Dice score of 81.5%. When used by a skilled breast-specialized surgeon, the tool enabled rapid and intuitive patient-physician communication of the location and extent of disease, and potential degrees of downstaging to breast-conserving surgery. Conclusions: Detailed 3D tumor and surrounding multi-tissue depictions offer both qualitative and quantitative comprehension of cancer topology and may aid in formulating an optimal treatment approach for breast cancer treatment. We show that detailed depictions enhance communication between physicians and patients and may aid in streamlining decision-making.
Achieving World Health Organization Global Breast Cancer Initiative targets: A situational analysis and action plan in Nigeria.
Authors: Romanoff Anya , Olasehinde Olalekan , Okereke Chukwuma Eze , Agodirin Olayide S , Ali Nuhu , Irowa Omorodion , Muhammad Abubakar Bala , Sunday Nweke Nneka , Wuraola Funmilola Olanike , Owoade Israel Adeyemi , Kahn Rivka , Kalvin Hannah L , Lynch Kathleen , Di Bernardo Matteo , Fitzgerald Grace , Mango Victoria , Vreeman Rachel , Anderson Benjamin O. , Kingham T. Peter , Alatise Olusegun Isaac ,   African Research Group for Oncology (ARGO) Consortium
Published: July 2024

e13782

Background: Breast cancer [BC] is the leading cause of cancer incidence and mortality in Nigerian women, with five-year survival of 44% vs. 90% in the US. The World Health Organization [WHO], through the Global Breast Cancer Initiative [GBCI], endorses a 3-pillar program that promotes early-stage detection, timely diagnosis, and expeditious treatment. We performed a situational analysis to understand predictors of achieving WHO targets in Nigeria as a basis for implementing an action plan. Methods: We conducted a cross-sectional study using a prospective multi-institutional BC patient database in Nigeria (funded by ASCO), which was expanded sequentially from a single institution in May 2022 to seven institutions representing all geopolitical zones by May 2023. All newly diagnosed BC patients enrolled in the database from 2022-2024 were included. We analyzed univariate associations with WHO GBCI key performance indicators [KPIs] using logistic regression and global p-values. Results: Five-hundred and seventy-one patients were included. Median age was 48 years (IQR 40,56). Conclusions: The utilization of a multi-institutional BC database inclusive of all geopolitical zones in Nigeria provides vital insight for monitoring progress toward WHO targets. Our findings suggest that breast health clinical encounters (through CBE or mammogram) prior to developing BC are associated with reduced diagnostic delays and early-stage BC diagnosis. For those with BC, multiple touchpoints with the healthcare system are associated with increased delays and late-stage diagnosis, which justifies the need for developing patient navigation programs. [Table: see text]
Health resource utilization expenditures in oncology within a virtual primary cancer survivor care clinic.
Authors: Litton Gregory J. , Librett John , Kosinski Mark , Rendas-Baum Regina , Gentile Jessica
Published: July 2024

e13785

Background: Unprecedented cancer treatment efficacy has led to high rates of disease sequelae. Lancet recently declared the failure to care for the human dimensions of cancer treatment a "humanitarian crisis." To address this humanitarian crisis, real-world economic evidence can improve patient access to whole person care through insurance reimbursement policies. Methods: We implemented a virtual primary cancer survivor care clinic that follows ASCO and NCCN guidelines for cancer survivors with emphasis on mental health, nutrition, physical activity, and sleep optimization. Our clinic utilizes medical oncologists, physician associates, mental health therapists, registered dietitians, and occupational therapists. Patient reported outcomes (PRO) monitor health status and inform treatment pathways. To reduce test fatigue, we use the SF12 Vitality Enhanced scale (SF12v2). The SF12v2 measures physical functioning, activities of daily living, pain, vitality, social functioning, and mental health. Total medical expenditures (MEs) is the sum of payments for hospital inpatient events, emergency room visits, home care, prescribed medicines, office-based and out-patient visits, and medical equipment. Patient SF12v2 summary scores predict a patient's total MEs. A one-point better physical component summary score and mental component summary score are associated with 2% lower MEs; 3 and 5 point score increases are associated with 10% and 18% lower MEs. Results: Patients were referred from a Utah community oncology clinic, other medical clinics, or self-referred (N=99). The mean patient age was 52 years. 84% were female, 16% were male. At enrollment, 35% had started treatment, 21% were on post treatment aromatase therapy or adjuvant hormonal therapy, 65% were post treatment. Baseline PRO reveal significant disease burden: 82% report poor mental health; 72% report poor physical health; 79% report poor cognitive health; 83% report sleep disorders. For patients who completed at least three PRO measurement time points (n=54): 91% had a positive clinical outcome for mental health; 70% had a positive clinical outcome for physical health; 89% had a positive clinical outcome for cognitive health; 76% had a positive clinical outcome for sleep health. As a result of these extraordinary outcomes, 74% of patients had lower predicted MEs. The average predicted reduction in MEs was 16% with an average annual savings of $1,629.49. Conclusions: Cancer is associated with high disease sequelae and high MEs. We believe this is the first study that reports real-world clinical evidence and predicts MEs for patients enrolled in a virtual primary cancer survivor care clinic. Real-world evidence demonstrates both clinically significant improvements in HRQoL and reductions in patient MEs. These results can inform insurance reimbursement policies, ensuring equitable access to cancer survivor care.
Evidence to support ePRO-based patient care in survivorship for outpatient with advanced upper gastrointestinal cancer.
Authors: Wang Xin Shelley , Shen Shu-En , Kamal Mona , Letona Elizabeth , Cleeland Charles S.
Published: July 2024

e13789

Background: The patients with advanced upper gastrointestinal (UGI) cancer reported multiple symptom burdens at diagnosis and after failing multiple chemotherapy lines. Assessing the readiness of patient-reported outcome (PRO) parameters to support evidence-based pathways for monitoring and managing outpatients is an unmet clinical need to integrate PRO into routine outpatient care for UGI cancer patients. This study aims to identify the most relevant PRO parameters that represent the high symptom burden and functioning impairment overtime during chemotherapy for advanced UGI cancer. Methods: Eligible UGI adult cancer patients (N=111) for a new line of chemotherapy were enrolled. Multiple symptoms were assessed electronically for 36 weeks, using The M.D. Anderson Symptom Inventory GI module (MDASI-GI). Longitudinal symptoms burden was analyzed using mixed-effect models adjusted for age, sex, performance status (PS) (good vs. poor PS ( ECOG 0-1 vs. 2-4). Results: Patients who contributed with more than baseline PROs were included in the analysis (n=92). Of those patients, 43 were treatment-naïve, and 49 had received prior therapy. The primary tumor sites include esophageal (32%), gastroesophageal junction (GEJ) (25%), or gastric (40%). All patients at baseline reported the following symptoms at a severe level (score ≥7 on a 0-10 MDASI-GI scale): fatigue, lack of appetite, pain, disturbed sleep, drowsy, and inability to eat. There was no significant difference in the composite score of these symptoms overtime, regardless of disease groups or treatment status at baseline. Patients with poor PS reported a statistically significant severe composite score baseline ( P=.04). Patients who stayed longer in the study during their survivorship reported a decreased prevalence of moderate to severe symptoms (score of ≥ 4) from 51% at baseline to 40% at 12 weeks, 34% at 24 weeks, and to 28% at 36 weeks. Over time, treatment naïve patients had more severe numbness/tingling, while previously treated group had more severe distress. Conclusions: This longitudinal prospective study during survivorship in patients undergoing chemotherapy for advanced UGI cancer provides a set of most distressing symptom burdens that need to be monitored as part of outpatient care. These data support establishing symptom management pathways for routine use of ePRO for screening and triage of, and linking those symptoms to toxicities after chemotherapy for UGI cancer patients.