bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment patterns and outcomes in ALK or ROS1 altered NSCLC: An ATOMIC Registry Study.
Authors: Marmarelis Melina Elpi , Grady Connor B. , Liu Geoffrey , Patel Devalben , Liu Stephen V. , Bravo Montenegro Gabriela Liliana , Patil Tejas , Nieva Jorge J. , Herrmann Amanda , Marrone Kristen , Lam Vincent K. , Sun Fangdi , Dowell Jonathan , Velcheti Vamsidhar , Nguyen Matthew , Miller Kelsey Leigh , Iams Wade Thomas , Hwang Wei-Ting , Camidge D. Ross , Aggarwal Charu
Published: June 2022

9077

Background: New tyrosine kinase inhibitors (TKIs) targeting ALK and ROS1 alterations in non-small cell lung cancer (NSCLC) have emerged over the last decade. Given the rarity of these genetic changes in NSCLC, data on long term outcomes with sequential therapies are limited. Methods: We conducted a multicenter retrospective cohort study of patients with metastatic NSCLC and ALK or ROS1 alterations across 12 Academic Thoracic Oncology Medical Investigators Consortium (ATOMIC) sites between 1/29/2007 and 3/31/2021. Data were abstracted from the electronic medical record. Median time to treatment discontinuation (TTD) of 1st TKI, overall survival (OS), and time to brain metastases were estimated using Kaplan-Meier methodology from start date of 1st TKI. Results: 566 patients with ALK (n = 464) or ROS1 (n = 102) were included. The majority (ALK: 426/464, 92%; ROS1: 88/102, 86%) received a TKI at some point during therapy (1st line TKI n = 262 ALK, 48 ROS1). Crizotinib was the most common 1st TKI (ALK: 57%; ROS1: 88%). Following crizotinib, alectinib (64%) and lorlatinib (41%) were the most common subsequent TKIs for ALK and ROS1, respectively. Alectinib (38%) and entrectinib (10.2%) were the 2nd most common initial TKIs used in ALK and ROS1, respectively. Additional treatment patterns presented in table. With a median follow up time of 31.1 (ALK, 95% CI, 27.6-35.0) and 32.6 (ROS1, 95% CI, 25.7-39.6) months, median OS from start of 1st TKI was 53.3 (ALK, 95% CI, 40.0-68.9) and 42.0 (ROS1, 95% CI, 31.8-NA) months. Out of the 321 patients with brain imaging prior to 1st line therapy, 40% (105/262, ALK) and 39% (23/59, ROS1) had CNS disease. Median time to development of brain metastases from start of 1st TKI in those without previous CNS disease (ALK: 278; ROS1: 58) was 30.0 (ALK, 95% CI, 25.3-39.1) and 27.0 (ROS1, 95% CI, 18.2-NA) months. Median TTD of 1st TKI was 11.2 (ALK) and 10.8 (ROS1) months. Conclusions: This is the largest retrospective cohort of NSCLC patients with ALK or ROS1 rearrangements treated in the real world setting. CNS metastases are common and subset analyses by agent and by year of diagnosis will be presented. Median time to CNS metastasis of > 2 years supports revision of the NCCN guidelines to include regular surveillance brain MRIs in this population. [Table: see text]
Crizotinib in ROS1-rearranged lung cancer (EUCROSS): Updated overall survival.
Authors: Michels Sebastian Yves Friedrich , Franklin Jeremy , Massuti Bartomeu , Sebastian Martin , Felip Enriqueta , Grohé Christian , Rodriguez-Abreu Delvys , Bischoff Helge , Carcereny Enric , Corral Jesús , Insa Amelia , Reck Martin , Rothschild Sacha , Provencio Mariano , Scheffler Matthias , Hellmich Martin , Nogova Lucia , Büttner Reinhard , Rosell Rafael , Wolf Juergen
Published: June 2022

9078

Background: ROS1 rearrangements are found in approximately 1% of non-small cell lung cancer (NSCLC) patients. Prospective clinical trials showed high efficacy of crizotinib in this molecular subset. Lately, we reported an overall response rate (ORR) of 70% and a median progression-free survival (PFS) of 19.4 months for patients treated within the EUCROSS trial (Michels et al. Clin Oncol, 37(15_suppl):9066-9066, 2019). Here we present an updated analysis of the overall survival. Methods: EUCROSS is a European multi-centre, single arm phase 2 trial (Clinicaltrial.gov identifier: NCT02183870). Key eligibility criteria were ≥18 years of age, advanced/metastatic lung cancer, centrally confirmed ROS1-rearranged (fluorescence-in situ hybridisation) and no or stable brain metastases at baseline. Crizotinib was given at a dose of 250 mg twice daily. Primary endpoint of the trial was investigator-assessed ORR in the response-evaluable population (Response Evaluation Criteria in Solid Tumors, version 1.1), with secondary endpoints of PFS and overall survival (OS). Results: Of the 34 patients who received at least one dose of crizotinib (intention-to-treat population, ITT), 30 were included the primary efficacy analysis set (PAS). After a median follow-up of 55.9 months, 13 (43%) patients in the PAS and 15 (44%) in the ITT had died. Median OS was not reached in either group (95% CI, 17.1-NR and 20.3-NR, respectively). OS was negatively correlated with the presence of brain metastases (Log-rank p = 0.1805) and TP53 mutations (Log-rank p = 0.015). Detailed listings of the survival rates are depicted in Table. No new safety signals were observed. Owing to the approval of crizotinib by the European Medicines Agency, all patients who were still on treatment by January 24th 2018 (n=8), were prescribed crizotinib outside the trial. Conclusions: Updated OS highlights the efficacy of crizotinib in patients with ROS1-rearranged lung cancer. Patients with co-occurring TP53 mutations or brain metastases had worse outcomes and represent challenging populations. Clinical trial information: NCT02183870. [Table: see text]
Molecular characterization of NF1-mutated NSCLC and clinical outcomes.
Authors: Gates Christopher , Sdrimas Konstantinos , Elliott Andrew , Borghaei Hossein , Xiu Joanne , Walker Phillip , Vanderwalde Ari M. , Liu Stephen V. , Bustamante Alvarez Jean Gabriel
Published: June 2022

9086

Background: NF1 is a tumor suppressor gene that regulates the RAS-MAPK and mTOR pathways. Co-mutations previously observed with NF1-mutations (mt) include TP53, KRAS, EGFR and rarely HER2, STK11, and PIK3CA mutations. We report a comprehensive molecular characterization with clinical outcomes analyses for NF1-mt non-small cell lung cancer (NSCLC). Methods: Next-generation sequencing (NGS) of DNA (592-gene or whole exome) and RNA (whole transcriptome) was performed for NSCLC patient (pt) samples (n = 10,310) submitted to a CLIA-certified laboratory (Caris Life Sciences, Phoenix, AZ).. RAS-MAPK and PI3K-AKT-MTOR signaling were assessed by transcriptional signatures of pathway activation (MAPK pathway Activation Score [MPAS], Wagle, 2018; and GSEA Hallmarks collection, respectively)., PD-L1 by immunohistochemistry (IHC, positive: TPS ≥1%), high tumor mutational burden (TMB) defined as ≥10 mut/Mb, and deficient mismatch repair/high microsatellite instability (dMMR/MSI-High) was assessed by IHC/NGS. Overall survival (OS) was obtained from insurance claims. Statistical significance was determined using Chi-square & Wilcoxon rank sum tests. P-value adjust for multiple hypothesis testing (Benjamini-Hochberg). Results: NF1-mt were identified in 1,045 NSCLC samples (10.1%). Concurrent KRAS, EGFR, ERBB2, BRAF or MET alterations are noted in Table 1, with no ROS1, RET or ALK fusions identified. Compared to NF1-wt, NF1-mt NSCLC was associated with increased RAS-MAPK expression (3.0-fold, P < 0.0001), while PI3K-AKT-MTOR-signaling was not significantly increased (2.1-fold, P = 0.12). Rates of TMB-High (51.7% vs 32.5%, P < 0.0001), PD-L1+ (69.1% vs 58.8%, P = 0.06), and dMMR/MSI-High (1.7 vs 0.7%, P < 0.05) were higher in NF1-mt samples. OS and duration on treatment from the start of Pembrolizumab (HR: 1.0 and 1.0, respectively) or other IOs (HR: 0.9 and 1.0, respectively) were not significantly different between NF1-mt and NF1-wt patients, However, among NF1-mt samples, high TMB and TP53-wt were associated with better OS (HR 0.6, P < 0.05 each). Conclusions: NF1-mt patients rarely harbored actionable NSCLC driver co-alterations. NF1-mt cases showed increased activation of RAS-MAPK axis, which may represent a potential pathway to target with MEK inhibitors. NF1- mt are responsive to immunotherapy and better outcomes are seen with high TMB and absence of TP53 mutations. Further work is warranted to determine the influence of actionable drivers on targeted therapy outcomes in NF1-mt NSCLC. [Table: see text]
Subgroup analysis in patients (pts) with non-squamous (N-Sq), EGFR-wild type (wt), second/third-line NSCLC from the global phase (Ph) 3 trial DUBLIN-3 (BPI-2358-103) with the plinabulin/docetaxel (Plin/Doc) combination versus Doc alone.
Authors: Han Baohui , Feinstein Trevor , Shi Yuankai , Chen Michael , Huang Lan , Mohanlal Ramon W. , Sun Yan
Published: June 2022

9090

Background: With PD-1/PD-L1 inhibitors moving to first line in NSCLC, 2nd/3rd line NSCLC is a severe unmet medical need, dominated by docetaxel-based therapies with > 40% severe neutropenia and limited survival. Plin, a novel immune-enhancing small molecule, enhances dendritic cell maturation and T-Cell proliferation. In the ITT population, the Plin/Doc combination had superior Efficacy (mOS; HR = 0.82, p = 0.0399), Safety (lower Gr3/4 AE rate/pt/year (yr); p = 0.038) and better Quality of Life (QTWiST; p = 0.026) versus (vs) standard of care (SoC) Doc alone in advanced and metastatic NSCLC pts in DUBLIN-3 (Han, ESMO 2021) who failed platinum therapy. Here we report on the N-Sq pts subgroup. Methods: DUBLIN-3(NCT02504489) was a randomized, single-blind (pts only), active controlled Ph3 study in 2nd/3rd line stage IIIB/IV, EGFR wt NSCLC pts with a measurable lesion (RECIST 1.1) in the lung, and ECOG ≤ 2, conducted in US, Australia and China. Pts (n = 559) were randomized 1:1 to Plin/Doc or Doc/Placebo (21-day (D) cycle (C)). Doc (75 mg/m2 on D1 and Plin 30 mg/m2 on D1 and D8 were given by IV infusion. A post-hoc analysis of median Overall Survival (mOS) and restricted mean survival time (RMST) from K-M curves, OS rate at 24,36 and 48 month (Mo), and grade 4 neutropenia (Gr4N) rates was performed for the N-Sq patients (n = 153 for Plin/doc and n = 178 for Doc). Results: Baseline characteristics were balanced between both groups. Primary and key secondary objectives in the ITT population were met (Han, ESMO 2021). Plin/Doc was well tolerated. Estimated Adverse Event Rate per Year [95% CI] was 1.43 [1.13,1.81] for Plin/Doc versus 2.77 [2.33,3.28] for Doc alone (p < 0.001). The median OS benefit is 2.6 months (p = 0.023). The table below summarizes the results for the N-Sq subgroup. Conclusions: The addition of Plin to Doc was superior to SoC Doc alone for efficacy and safety in the clinically relevant subgroup of non-squamous EGFR-wild type, 2nd/3rd line NSCLC pts. Clinical trial information: NCT02504489. [Table: see text]
Capecitabine in pretreated metastatic pulmonary lymphoepithelioma-like carcinoma: A retrospective study.
Authors: Cheung Gavin Tin Chun , Cheung Ka Man , Chow James Chung Hang , Au Kwok Hung , Yiu Harry Ho Yin
Published: June 2022

9093

Background: Pulmonary lymphoepithelioma-like carcinoma (LELC) is a rare disease, sharing common histological features with the undifferentiated subtype of nasopharyngeal carcinoma (NPC), and being under-represented in non-small cell lung cancer trials and clinical guidelines. While gemcitabine-based platinum doublet chemotherapy is more established in 1st line treatment of stage IV disease, there is limited evidence for subsequent treatment strategy. Oral capecitabine is one of the active agents in metastatic NPC, and was observed to have encouraging outcomes in pulmonary LELC. Methods: All consecutive patients with pulmonary LELC in 2010 – 2019 treated in a tertiary institution were reviewed. Patients with metastatic disease who progressed after gemcitabine-based platinum doublets and treated with capecitabine were included. Capecitabine was given at 1250 mg/m2 twice daily for 14 days followed by 7 days of rest in each cycle. Treatment response was monitored by clinical history, physical examination and imaging. Treatment was continued till drug holiday, intolerance or disease progression. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Clinical predictors for PFS and OS were analyzed using log-rank test and the Cox proportional hazard model. Results: Of the 140 LELC patients identified, 36 patients satisfied the above inclusion criteria (14 male, 22 female). Median age was 58.6 years old (range 41.5 – 75.6). All patients had an ECOG performance score of 0 or 1. 16 patients (44.4%) received 2 or more lines of prior systemic treatment. Median capecitabine cycles received was 5 (range 2 – 68). Objective response rate was 27.8% (complete response: 5.6%; partial response: 22.2%), disease control rate was 75.0%. With a median follow-up of 15.3 months (range 1.8 – 82.6), the median PFS and OS were 5.4 months (95% CI, 2.1 – 8.8) and 15.4 months (95% CI, 10.0 – 20.7) respectively. Capecitabine was generally well tolerated, with 22.2% grade 3 or above side effects, and 5.6% treatment termination due to intolerance. Bone and distant lymph node (LN) involvement were significant predictors of poorer PFS on multivariate analyses (bone: HR 3.24, 95% CI 1.44 – 7.29, p=0.004; distant LN: HR: 2.62, 95% CI 1.14 – 6.02, p=0.024). Age, sex, smoking history, number of treatment lines, and other sites of disease involvement were not significant predictors. Conclusions: This is to date the largest reported cohort of capecitabine in pre-treated metastatic pulmonary LELC. Capecitabine is effective and well tolerated, and should be considered as a treatment option after 1st line platinum-based chemotherapy. Future studies are warranted to delineate the optimal treatment pathway of this rare disease entity.
Matching-adjusted indirect comparison (MAIC) of mobocertinib versus amivantamab in patients with non–small cell lung cancer (NSCLC) with EGFR exon 20 insertions (ex20ins).
Authors: Ou Sai-Hong Ignatius , Prawitz Thibaud , Lin Huamao Mark , Hong Jin-Liern , Tan Minal , Proskorovsky Irina , Hernandez Luis , Jin Shu , Zhang Pingkuan , Lin Jianchang , Patel Jyoti D. , Nguyen Danny , Neal Joel W.
Published: June 2022

9115

Background: Mobocertinib (mobo) and amivantamab (ami) are FDA-approved treatments for patients (pts) with locally advanced or metastatic NSCLC with EGFR ex20ins whose disease progressed on or after platinum-based chemotherapy. An unanchored MAIC was used to compare confirmed overall response rate (cORR), duration of response (DoR), progression-free survival (PFS) and overall survival (OS) between mobo and ami. Methods: Clinical outcomes were compared in platinum-pretreated pts with EGFR ex20ins+ NSCLC treated with mobo 160 mg QD in a phase I/II single-arm study (NCT02716116, cut-off 1 Nov 2020, n=114) or with ami 1,050 mg (1,400 mg, ≥80 kg) in a phase I single-arm study (NCT02609776, cut-off 8 June 2020, n=81). Differences in baseline characteristics reported in both studies, including age, race, sex, smoking status, Eastern Cooperative Oncology Group, histology, sites of metastasis (brain, bone and liver), time from advanced diagnosis, number of prior lines of therapy, prior immuno-oncology therapy, prior EGFR tyrosine kinase inhibitor treatment and prior EGFR ex20ins targeted therapy, were adjusted with MAIC. Results: After MAIC weighting all reported baseline characteristics were balanced between mobo and ami. OS and cORR per investigator assessment (INV) were similar between mobo and ami (Table). cORR per independent review committee (IRC) was numerically higher for ami (odds ratio [OR]=0.64, p value=0.230). For PFS per IRC, the adjusted hazard ratio (HR) was numerically favorable for mobo (HR=0.82, p value=0.417). Among the responders, DoR was longer for mobo (DoR per INV: HR=0.44, p value=0.049; DoR per IRC: HR=0.56, p value=0.149). Conclusions: Mobo and ami appear to have overall similar efficacy. As each has a different mechanism of action and route of administration, they provide multiple options in the treatment of EGFR ex20ins+ NSCLC. Clinical trial information: NCT02716116. [Table: see text]
NeoTrio: Randomized trial of neoadjuvant (NAT) pembrolizumab (Pembro) alone, in sequence (SEQ) with, or concurrent (CON) with dabrafenib plus trametinib (D+T) in resectable BRAF-mutant stage III melanoma to determine optimal combination of therapy.
Authors: Long Georgina V. , Carlino Matteo S. , Au-Yeung George , Spillane Andrew John , Shannon Kerwin Frank , Gyorki David E. , Howle Julie R. , Ch'ng Sydney , Gonzalez Maria , Saw Robyn P.M. , Pennington Thomas , Lo Serigne N. , Scolyer Richard A. , Menzies Alexander M.
Published: June 2022

9503

Background: Combination anti-PD(L)1 and BRAF/MEK-targeted therapy (TT) improves PFS in stage IV melanoma vs TT. In stage IV melanoma recent data suggest immunotherapy 1st until progression, rather than BRAF-TT, improves OS, and induction TT upfront adds little benefit. NeoTrio explored the optimal combination of BRAF-TT and anti-PD1 using the NAT platform in pts with stage III melanoma (NCT02858921). Methods: 60 pts with resectable, RECIST measurable stage III (no in-transit) BRAFV600-mutant melanoma were randomized 1:1:1 to 3 arms of 6 wks of NAT followed by complete lymph node dissection (CLND): A) Pembro ALONE (200mg Q3W x 2); B) SEQ - D+T (150mg bd + 2mg od) for 1 wk followed by pembro (200mg x 2); C) CON – D+T+pembro (doses as SEQ). Pts had 46 wks pembro post-CLND. Primary endpoint was the pathological response rate (pRR) and pathological complete response (pCR) at wk 6. Secondary endpoints; RECIST RR at wk 6, event-free survival (EFS), RFS, OS, adverse events (AE) and translational endpoints. Results: At data cutoff 2 Jan 2022, 20 pts per arm had similar baseline characteristics; overall 42% female, med age 53 yrs, 82% BRAF V600E, 62% clinical N1b. Med f/u was 20 months (95% CI 17-31). The pCR rate and pRR were highest in CON arm, and similar in ALONE and SEQ arms (Table). Events (progression before surgery, recurrence after surgery or death) were highest in ALONE arm at this 1st analysis (Table). Assessment of the durability of path response subtypes in each arm is ongoing. Most common Rx related AE were fatigue (65%, 70%, 70%, ALONE, SEQ and CON respectively), pyrexia (0%, 25%, 85%) and rash (50%, 35%, 35%). Gd 3/4 AE occurred in 30%, 25% and 55%, respectively; pyrexia and hepatitis were common in CON during NAT. Rx interruptions during NAT occurred in 0, 3 and 19 pts, respectively; 1, 0 and 8 pts permanently discontinued. Post NAT surgical operability was the same or improved in 81%. Longitudinal analysis of melanoma tissue, microenvironment and microbiome is ongoing. Conclusions: CON D+T+pembro achieved the highest pRR, pCR rate, but with greater toxicity. Recurrences were seen in those with pCR/near pCR in BRAF-TT containing arms, but not in pembro ALONE, in keeping with previous data of NAT with checkpoint inhibitors vs BRAF-TT. Short course of D+T prior to PD1 did not improve path response, despite previous translational data showing increased tumour infiltrating T-cells early-during treatment with D+T. Follow up is ongoing. Clinical trial information: NCT02858921. [Table: see text]
Phase II study SECOMBIT (sequential combo immuno and target therapy study): A subgroup analysis with a longer follow-up.
Authors: Ascierto Paolo Antonio , Mandalà Mario , Ferrucci Pier Francesco , Guidoboni Massimo , Rutkowski Piotr , Ferraresi Virginia , Arance Ana Maria , Guida Michele , Maiello Evaristo , Gogas Helen , Richtig Erika , Fierro Maria Teresa , Lebbe Celeste , Helgadottir Hildur , Melero Bermejo Ignacio , Palmieri Giuseppe , Giannarelli Diana , Grimaldi Antonio Maria , Dummer Reinhard , Chiarion-Sileni Vanna
Published: June 2022

9535

Background: To investigate the best sequential strategy, we started the SECOMBIT study, a randomized three parallel arms phase 2 study (NCT02631447). We used the combination of encorafenib/binimetinib (E+B) as targeted therapy (T-T) and the combination of ipilimumab/nivolumab (I+N) as immunotherapy (I-O). We explored the two different sequences and the “sandwich” strategy with a short course of target therapy, switched by combo immunotherapy at the best response, and not at progression of disease. In our previous report we have observed a trend in favor of the arms where I-O was given as first, confirmed by the first report of the DreamSeq study, a phase III study which compared the two different sequences with T-T and I-O. Here we updated the study data with a subgroup analysis. Methods: From Nov 2016 to May 2019, 37 centers in 9 countries enrolled 251 patients with untreated, metastatic BRAFV600 melanoma. Patients were randomized to Arm A [E+B until PD, followed by I+N], or Arm B (I+N until PD, followed by E+B) or Arm C (E+B for 8 weeks, followed by I+N until PD, followed by E+B). The overall survival (OS) is the primary endpoint of the study. Secondary endpoints included total progression-free survival (tPFS), 2- and 3-years survival rate, best overall response rate, duration of response, biomarkers evaluation. Results: The study primary endpoint was met in each arm with at least 30 patients alive at 24 months. The median follow-up estimated with the reverse Kaplan-Meier method was 37.1 months (IQR: 32.8-46.4). The OS at 2 and 3 years was calculated in the three arms for all patients, and in the subgroups normal or elevate LDH level and < 3 or ≥ 3 metastatic sites. OS and tPFS rates at 2 and 3 years are shown in the table. Conclusions: With a 37.1 months median follow-up, 2 and 3-years OS as well as tPFS rates are higher in Arm B and C. In line with recent findings, the SECOMBIT results confirm a better trend in favor of Arm B and C treatment sequence. The analysis of the secondary endpoints is ongoing. Clinical trial information: NCT02631447. [Table: see text]
Efficacy and tolerance of systemic therapies in metastatic melanoma of unknown primary versus known cutaneous: A multicenter retrospective study from the MelBase French Cohort.
Authors: Rousset Perrine , Dalle Stéphane , Mortier Laurent , Dereure Olivier , Dalac Sophie , Dutriaux Caroline , Leccia Marie Thérèse , Legoupil Delphine , Descamps Vincent , De Quatrebarbes Julie , Grob Jean-Jacques , Saiag Philippe , Maubec Eve , Stoebner Pierre-Emmanuel , Granel Brocard Florence , Arnault Jean-Philippe , Allayous Clara , Oriano Bastien , Lebbe Celeste , Montaudie Henri
Published: June 2022

9556

Background: Melanoma of unknown primary (MUP) account for 3% of all melanomas. Clinical outcome of advanced MUP in the era of novel therapies including immunotherapies (ICI) and targeted therapies (TT) have been only scarcely studied, whereas a possibly different biologic background might introduce changes in its management. Recent retrospective studies suggested that patients with advanced MUP could benefit at least as much from novel therapies as patients with known primary cutaneous melanoma (cMKP). Methods: Based on the nationwide MelBase prospective database (NCT02828202) this retrospective study included patients with advanced melanoma treated with first-line ICI, TT or CT. MUP was defined by upfront occurrence of (sub)cutaneous, nodal and/or visceral metastasis without any known prior or concomitant primary tumor. Patients with primary mucosal or ocular melanoma were excluded. Both progression-free survival (PFS) and overall survival (OS) were analyzed as co-primary variables in MUP vs cMKP, stratified by treatment subset (ICI vs TT vs CT vs whole cohort). Secondary variable was treatment-related toxicity. Multivariate analyses and propensity score analysis were performed. Objective: To investigate the efficacy and safety of systemic treatments (ICI, TT and chemotherapy (CT)) in patients with advanced MUP comparatively to stage-matched cMKP. Results: A total of 1882 patients were analyzed, including 265 (14.1%) MUP. Most patients were treated with first-line ICI. Median follow-up was 16 months. Patients in the MUP cohort more often displayed unfavorable initial prognostic factors (Table). PFS and OS did not significantly differ in MUP compared to MKP patients (p=0.73 and p=0.93 respectively). Stratification of cohorts by treatment type and application of propensity score did not lead to data modification. Treatment-related toxicity rate and severity did not differ between MUP and MKP, regardless of treatment type. Conclusions: Our results suggest that advanced MUP should be managed with similar strategies as advanced MKP. In our cohort, MUP patients benefited from novel therapies as much as MKP patients despite less favorable baseline prognostic factors. Exploratory studies investigating mutational burden and host immunity are needed to identify the underlying mechanisms. [Table: see text]
The effect of breast radiotherapy parameters (XRT), chemotherapy regimens (CT) and dual anti-HER2 monoclonal antibodies (MoAb) on the development of cardiac dysfunction (CD) among patients with HER2-positive breast cancer from Saudi Arabia.
Authors: Abusanad Atlal M. , Iskanderani Omar , Al-hajeili Marwan R. , Ujaimi Reem
Published: June 2022

e12508

Background: Treatment with anti-HER2 therapy can cause CD. The effect of breast XRT, heart dose and V25 of the heart and CT regimen on developing CD is controversial. The impact of these variables in developing CD among patients with HER2-positive breast cancer (BC), receiving CT plus anti-HER2 MoAb was evaluated in routine clinical practice. Methods: Patients with HER2-positive BC between 2015-2019 were included, retrospectively. CD is defined as a drop in (EF%) of at least 10 % points from baseline and/or below 50% at any point of the time during follow-up. The association of CD and various variables was examined with a significance level of < 0.05. Results: Data from 224 female patients were analyzed with a mean age at diagnosis of 51 +12, BMI 29.6 ± 6.4, BSA 1.74 ± 0.19, 53% with left BC, 63% had non-metastatic BC, 52% with comorbidities, 11% had prior IHD medication use in 48%; metformin in 15% and B-blockers in 5%, 9.4% smoker, 70% had a mastectomy, 18% lumpectomy and 12% no surgery, 58% received XRT. The cumulative incidence of CD was 33% during follow-up noting that the first and subsequent drops of EF at any point of time during the follow-up was counted as a new event even for the same patient. The univariate analysis of factors influencing the risk of CD is shown in Table. However, the initial significance of CT regimen and whether the patient received breast XRT or otherwise, did not translate into significance on multivariate analysis with a P-value = 0.198 & 0.326, respectively. Conclusions: XRT mean heart dose and V25 of the heart, anthracycline-based CT did not influence the risk of CD among this cohort. Likewise, the dual anti-HER2 therapy with trastuzumab and pertuzumab and the number of trastuzumab cycles did not influence CD. It is reassuring to demonstrate the safety of these approaches in real-life clinical practice.[Table: see text]
The Breast Cancer Index Registry Study: Initial analysis of the first 1,000 patients.
Authors: O'Shaughnessy Joyce , Encarnacion Carlos A. , O'Neal Brandon , Wong Jenna , Siuliukina Natalia , Sanft Tara B. , Jankowitz Rachel Catherine , Pegram Mark D. , Treuner Kai , Fox Jenny R.
Published: June 2022

e12513

Background: The Breast Cancer Index (BCI) is a gene expression-based biomarker that reports two results: BCI Predictive [BCI (H/I)], which predicts benefit from extended endocrine therapy (EET), and BCI Prognostic, which combines the Molecular Grade Index (MGI) with BCI (H/I) to provide individualized risk of both late (5-10 years) and overall (0-10 years) distant recurrence. The NCCN clinical practice guideline recommends use of BCI for prediction of benefit from EET in early stage, hormone receptor positive (HR+) breast cancer patients. Methods: The BCI Registry study was designed to prospectively evaluate the long-term clinical outcome, medication adherence and quality of life in HR+ early-stage breast cancer patients receiving BCI testing as part of routine clinical care. The BCI registry will enroll approximately 3,000 patients after completion of 4-7 years of primary adjuvant endocrine therapy. Patients will be followed for disease recurrence for at least 10 years from diagnosis. Patients extending endocrine therapy will be assessed annually for medication adherence. To evaluate the impact of BCI results on EET decision making, both the physician and patient will complete Decision Impact Questionnaires. Clinicopathological data are collected within the ClinCapture electronic data capture system. The BCI Registry Study is registered on ClinicalTrials.gov under NCT04875351. Results: The BCI Registry Study completed enrollment of the first 1,000 patients in January 2022. Clinical data were available for 942 patients (76.8% T1; 51.3% grade II; 75.4% N0). BCI test results were reported for 842 patients. 315 patients (37.4%) were classified as BCI (H/I)-High and 527 patients (62.6%) as BCI (H/I)-Low. Further, in node-negative (N0) patients, BCI classified 314 N0 patients (47.9%) with high risk for late distant recurrence and 342 patients (52.1%) with low risk. In node-positive (N1) patients, BCI classified 138 patients (74.2%) as high risk for late distant recurrence and 48 patients (25.8%) as low risk. The associated clinicopathological factors are shown in the table. Conclusions: The analysis of the first 1,000 BCI Registry patients confirms the expected distribution of clinicopathological factors. BCI by H/I status and prognostic risk groups are consistent with previous clinical validation studies. Clinical trial information: NCT04875351. [Table: see text]
A randomized trial of pegylated recombinant human granulocyte-colony stimulating factor to prevent febrile neutropenia in breast cancer after chemotherapy.
Authors: Zhang Lina , Li Yuntao , Fan Zhonglin , Wang Meiqi , Hui Tianli , Zhang Yanshou , Gao Chunhui , Zhang Jing , Zhang Guoshuan , Kong Xiangshun , Geng Cuizhi
Published: June 2022

e12516

Background: The purpose of this study was to evaluate the incidence of febrile neutropenia (FN) in breast cancer patients with pegylated recombinant human granulocyte-colony stimulating factor (PEG-rhG-CSF) administration at 48 or 24 hours after chemotherapy for primary prevention. Methods: Patients with stage I-III invasive breast cancer who were scheduled to receive 4 cycles of adjuvant chemotherapy with EC regimen (epirubicin combined with cyclophosphamide) were eligible for this multicenter, open-label, randomized trial. Patients were randomized (1:1) to receive PEG-rhG-CSF (Jinyouli) 48 hours (48h group) or 24 hours (24h group) after the end of each cycle of chemotherapy. The primary endpoint was the incidence rate of FN. The secondary endpoints included the incidence rates of grade 3/4 neutropenia, chemotherapy dose reduction and chemotherapy delay due to neutropenia, antibiotic administration, the pain (bone, muscle, or joint), and the relative dose intensity (RDI) of the chemotherapy. Results: The preliminary results enrolled 197 patients including 96 in the 48h group and 101 in the 24h group. 78.1% of 48h group patients and 73.3% of 24h group patients completed four cycles of chemotherapy. The incidence rates of FN were 2.1% in the 48h group and 4.0% in the 24h group respectively. FN occurred in the first two cycles in the 48h group, while in the 24h group, it occurred only in the first cycles. The incidence rate of grade 3/4 neutropenia was 27.1% in the 48h group and 51.5% in the 24h group respectively. There was no delay in chemotherapy due to neutropenia in the two groups. The incidence rate of chemotherapy dose reduction due to neutropenia was 2.1% in the 48h group and 1.0% in the 24h group respectively. 2 (2.1%) patients in the 48h group and 4 (4.0%) patients in the 24h group received antibiotics. The mean RDI of each cycle of chemotherapy was 91.3% in the 48h group and 91.5% in the 24h group, respectively. The incidence rate of all grades pain (bone, muscle, or joint) was 25.0% in the 48h group, and 20.8% in the 24h group. With regard to 3 or higher grade pain, 1 (1.0%) patient in the 48h group experienced bone pain and 1 (1.0%) patient in the 24h group experienced muscle pain. Conclusions: Preliminary results suggest a similar effect of PEG-rhG-CSF administration at 48 or 24 hours after chemotherapy in primary prevention of FN in breast cancer patients receiving EC chemotherapy regimen. Recruitment is ongoing and updated data will be presented. Clinical trial information: ChiCTR1800019516. [Table: see text]
Prognostic role of the stromal tumor-infiltrating lymphocytes (TILs) in women with early ER+/HER2+ breast cancer (BC) in whom adjuvant chemotherapy (ChT) was omitted.
Authors: Jeric Horvat Valentina , Manevski Damjan , Gazic Barbara , Drev Primoz , Matos Erika , Ribnikar Domen , Seruga Bostjan
Published: June 2022

e12526

Background: Adjuvant systemic therapy in women with early ER+/HER2+ BC usually includes ChT, trastuzumab (T) and endocrine therapy (ET). High level of TILs is associated with better outcome in HER2+ disease. Here we explore the outcome and prognostic role of TILs in women with early ER+/HER2+ BC in whom ChT was omitted. Methods: Women with ER+ (IHC ≥ 1%) and HER2+ (IHC3+ and/or FISH ratio ≥ 2.0) early BC who underwent surgery between years 2006 and 2016 at the Institute of Oncology Ljubljana and did not receive adjuvant ChT were eligible for this study. Hematoxilin and eosin slides of primary tumors were retrieved and evaluated for the percentage of stromal TILs. Distant disease-free survival (DDFS) was estimated by the Kaplan-Meier method. The association between DDFS and TILs level was explored in the Cox proportional hazard model. Relative survival was used for estimating the probability of dying due to the breast cancer or other causes. Results: During the 10-year period 86 (29.4%) out of 292 women with early ER+/HER2+ BC who underwent surgery did not receive adjuvant ChT. ChT was omitted due to the stage I disease (n=30), comorbidities (n=25), older age (n=19), refusal of treatment (n=9) and other causes (n=3). Five (5.8%) and 81 (94.1%) women received T and ET, respectively. Their median age was 65.8 yrs (IQR 55.7, 75.6 yrs) and 45 (52.3%) had stage I disease. There were 53 (61.6%), 24 (27.9%) and 9 (10.4%) women with low (<10%), intermediate (≤10% to <40%) and high (≥ 40%) level of TILs, respectively. After median follow-up of 10 years 28 events (distant recurrence or death) occurred. The 10-year DDFS for those who did not receive ChT due to the stage I disease, comorbidities and older age was 91% (95% CI, 0.79 to 1.00), 38% (95% CI, 0.18 to 0.75]) and 26% (95% CI, 0.10 to 0.66) (p˂0.0001), respectively. After excluding women with stage I disease the estimated probability of dying due to the breast cancer and due to other causes was 26.7% and 26.5%, respectively. Overall, for every 10% increase in TILs the risk of distant recurrence or death was reduced for 18% (HR=0.82; 95% CI, 0.64 to 1.05) (p=0.11). In the multivariable Cox model, higher TILs level was a significant predictor of better DDFS (HR 0.75; 95% CI, 0.57 to 0.98) (p=0.041) (Table). Conclusions: Women with stage I ER+/HER2+ BC who do not receive adjuvant ChT and T but do receive adjuvant ET may still have a very good outcome. In contrast, survival of women who do not receive adjuvant ChT and T for other reasons is poor; however, only a half of those deaths are related to BC. TIL is a favourable prognostic biomarker which might be helpful when de-escalation of systemic therapy in women with ER+/HER2+ BC is considered.[Table: see text]
Clinical audit of breast cancer patients under 40 years of age: A single institution experience.
Authors: Kate Shruti , Patil Roshan , Nagarkar Rajnish Vasant , Randive Makarand Arun , Valame Shaunak , Ramesh Yasam Venkata
Published: June 2022

e12533

Background: Age is an important risk factor for breast cancer (BC). The younger age (< 40 years) is associated with unfavorable tumor biology. This is a retrospective analysis of young breast patients treated from 2012-2020 at a comprehensive cancer centre. Methods: Data regarding demography, clinical presentation, histopathological features, molecular profiling, treatment details, and outcomes were retrieved from medical records. All time-to event outcomes were analyzed using Kaplan-Meir method. Results: A total of 134 patients (< 40 years) with BC were included. Median age of the study cohort was 37 years (range: 22-40 years) with a female predominance (98.5%). Most of the patients presented with locally advanced BC (51%) followed by early BC (43%) and metastatic BC (6%). The mean tumor size and positivity lymph nodes of our non-metastatic patients were 3.86±1.90 cm and 3.3±3.98, respectively. The molecular classification revealed most of the patients were of Basal-like BC (TNBC, 40%) followed by Luminal A (33%), Luminal B (14%) and Her-2 (13%), respectively. Germline BRCA testing was positive in 22% patients (10/45). At a median follow-up of 51 months, 3 and 5-year Kaplan-Meier estimates of overall survival were 67.2% and 44.7%, respectively. Conclusions: Breast cancer is a heterogeneous disease with varied survival depending on multiple factors. Early diagnosis and timely appropriate management, as per clinical and molecular profile provides acceptable outcome.
Bisphenol A exposures and hormone concentrations in a cohort of women receiving aromatase inhibitor therapy for breast cancer.
Authors: Robien Kimberly , Kirstein Mark N. , Pawloski Pamala A. , Shapiro Alice C.
Published: June 2022

e12535

Background: Bisphenol A (BPA), a widely used chemical in plastics production, has been shown to have estrogenic activity, although it is unclear whether BPA exposure alters effectiveness of aromatase inhibitor (AI) treatment among women with breast cancer. In vitro studies have indicated that at higher concentrations (≥10-4 μM), BPA inhibits aromatase expression and activity, whereas at environmentally relevant concentrations (≤10-8 μM), BPA increases aromatase expression and activity. Few in vivo studies have investigated the association between BPA exposure and estrogen concentrations among non-pregnant women. This pilot study among post-menopausal women receiving AI therapy evaluated whether BPA is detectable in participants’ urine, and the association between BPA and hormone concentrations. Methods: This study was ancillary to a larger intervention study (ClinicalTrials.gov NCT01509079), and participants provided informed consent for this ancillary study under a protocol approved by the institutional review boards of Park Nicollet Institute/HealthPartners and the University of Minnesota. AI adherence during the 4 weeks prior to the baseline visit was monitored through weekly diaries. Participants were instructed to collect spot urine collections in sterile, BPA-free polypropylene containers in the 24 hours prior to the baseline study visit. Serum hormone concentrations were measured using serum collected at the baseline study visit. The Breast Cancer Prevention Trial - Musculoskeletal Symptom (BCPT-MS) scale was used to assess AI-associated musculoskeletal syndrome symptoms at the baseline study visit. Results: Fourteen women agreed to participate in the pilot study, however one participant’s data was excluded due to substances interfering with BPA measurement. BPA was detected in urine from all 13 remaining participants. Geometric mean urinary BPA concentration (1.55 mcg/g creatinine, 95% confidence interval (CI): 0.98-2.45) was higher than concentrations reported for females (1.36 mcg/g creatinine, 95% CI: 1.23-1.51) in the 2013-14 National Health and Nutrition Examination Survey biomonitoring data. Age, body mass index, and percent body fat did not differ between women above or below the study median urinary BPA concentrations (1.49 ng/mL). Women with BPA concentrations >1.49 ng/mL had consistently lower serum estrone (5.0 vs. 7.0 pg/mL, p=0.15), estradiol (2.8 vs. 3.6 pg/mL, p=0.04), and testosterone (21.5 vs 23.8 ng/dL, p=0.28) concentrations compared to women with lower BPA concentrations. No statistically significant differences in BCPT-MS scores were observed between women with higher vs. lower urinary BPA concentrations. Conclusions: These preliminary findings suggest that BPA exposures may work in concert with AIs to lower serum estrogen levels. However, further research is needed to confirm these findings.
Decreased bile acid metabolism and association with prognosis reflecting microbiome in tumor microenvironment involved in cancer cell proliferation in breast cancer.
Authors: Wu Rongrong , Yu Irene , Tokumaru Yoshihisa , Asaoka Mariko , Oshi Masanori , Ishikawa Takashi , Takabe Kazuaki
Published: June 2022

e12539

Background: Bile acids are metabolized by the gut microbiome and are involved in fat absorption. Contrary to their carcinogenic role in gastrointestinal cancers, bile acids have been reported to inhibit cancer cell proliferation in breast cancer. We hypothesized that activation of bile acid metabolism is associated with a better prognosis based on previous reports regarding the antitumor effects of bile acids in breast cancer cells. Methods: A total of 6050 patients from three large open primary breast cancer cohorts (GSE96058, METABRIC, and TCGA) were analyzed by bile acid metabolism scores calculated by gene set variation analysis, and the association with the microbiome of the breast cancer tumor microenvironment in TCGA was also investigated. Results: We found that disease free, disease specific and overall survival was significantly improved in the high bile acid metabolism group, which was validated by three large breast cancer cohorts. However, apoptosis, ROS, and unfolded protein response gene sets were not found to be enriched in the high bile acid metabolism group, despite the expectation that oxidative stress-induced apoptosis would lead to improved survival. Several metabolic pathways and pathways associated with bile acid production and regulation were enriched in this group. On the other hand, Ki67 and nuclear grade were higher, and several cell proliferation-related gene sets were upregulated in the low bile acid metabolism group, especially the G2M checkpoint in all cohorts. In association with the higher cell proliferation, the low bile acid metabolism group showed higher mutation load, immune activation, and infiltration of anti-cancer immune cells. We further investigated that the composition of the microbiome in each group and four species that demonstrated significant abundance in the high bile acid metabolism group and three species in the low bile acid metabolism group. Surprisingly, almost all the cell proliferation-related gene sets from Hallmark were enriched in the three microorganisms-rich groups specific for low bile acid metabolism breast cancer. This was not the case for the microorganisms specific to high bile acid metabolism. Conclusions: Clinical relevance of bile acid metabolism in breast cancer is that low bile acid metabolism with abundant Lactobacillus, Ruegeria, and Marichromatium is associated with highly proliferative cancer and worse survival, rather than the growth suppression effect of bile acids.
Artificial intelligence-powered human epidermal growth factor receptor 2 (HER2) analyzer in breast cancer as an assistance tool for pathologists to reduce interobserver variation.
Authors: Jung Minsun , Song Seung Geun , Cho Soo Ick , Jung Wonkyung , Oum Chiyoon , Song Heon , Ma Minuk , Park Seonwook , Pereira Sergio , Song Sanghoon , Paeng Kyunghyun , Yoo Donggeun , Ock Chan-Young , Sung Ji-Youn , Kim So-Woon
Published: June 2022

e12543

Background: Human epidermal growth factor receptor 2 (HER2) expression is a predictive marker for HER2-targeted therapy in breast cancer patients. Interobserver variation in the interpretation of HER2 levels exists among pathologists, thus a method to increase the consistency of evaluation is needed. This study aimed to evaluate the performance of the artificial intelligence (AI)-based Lunit SCOPE HER2 in assisting pathologists to evaluate HER2 expression levels in breast cancer. Methods: Lunit SCOPE HER2 was developed with a 1.04 x 1010 μm2 area and 7.31 x 105 tumor cells from 1,133 HER2 immunohistochemistry stained whole-slide images (WSI) of breast cancer, annotated by 113 board-certified pathologists. The AI model was developed based on a semantic segmentation algorithm, which consists of two atrous spatial pyramid pooling blocks for tissue level classification and for tumor cell level classification. To validate the model, a total of 209 HER2 WSIs diagnosed with breast cancer were obtained from Kyung Hee University Hospital in Korea and were assigned as an external validation set. Three board-certified pathologists evaluated slide level HER2 expression (3+, 2+, 1+, and 0) twice, first without AI assistance and second, with it. The second reading was performed for WSIs where the pathologist's reading showed discrepancy with the AI model. Results: In the external validation set, all pathologists scored the same HER2 grade in 103 WSIs (49.3%), and the Fleiss kappa value was 0.512. The HER2 grade from the AI model and pathologists was the same in 151 WSIs (72.2%), and the weighted kappa value was 0.844. The pathologists re-evaluate 43, 63, and 83 WSIs, respectively. After AI assistance, all pathologists scored the same HER2 grade in 156 WSIs (74.6%), and the Fleiss kappa value increased to 0.762 (Table). Conclusions: This study demonstrates that an AI-powered HER2 analyzer can help achieve consistent HER2 expression level evaluation in breast cancer by reducing interobserver variability. Thus, the AI model can be applied as an assistance tool for pathologists in HER2 grade evaluation.[Table: see text]