bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical and economic outcomes associated with upfront comprehensive genomic profiling in newly diagnosed advanced lung cancer in the United States from 2018-2020: Evidence from the SEQUENCE study.
Authors: Adeboyeje Gboyega , Caplan Eleanor , Xu Yihua , Chase Monica , Myer Nicole , Sheth Sheetal , Suehs Brandon T
Published: June 2022

9126

Background: As the number of approved molecularly-targeted therapies for the treatment of lung cancer increases, the debate continues as to whether a clinical strategy leveraging next-generation sequencing (NGS) comprehensive genomic profiling (CGP) to match patients to targeted treatments is advantageous versus a narrow/single-gene (N/S) panel testing. We examined clinical and economic outcomes of patients with advanced lung cancer (aLC) in the United States (US). Methods: In this retrospective study, newly diagnosed aLC patients aged 65-89 years were identified from a US Medicare Advantage plan from 2018-2020. Patients receiving genomic testing within 90 days of diagnosis and an FDA-approved pharmacotherapy cancer treatment after diagnosis were categorized by initial sequencing with NGS CGP (51+ genes) vs N/S (≤50 genes) panel testing using administrative claims based on previously validated algorithms. We assessed the proportion of patients with an inpatient or emergency department (INP/ED) visit for select outcomes (e.g., neutropenia) within 6 months of start of treatment, all-cause mortality, and PPPM (per patient per month) total healthcare costs through all available follow-up. Genomic testing costs within 90 days of cancer diagnosis were estimated using the Medicare fee schedule. Among patients with treatment within 30 days of testing, we assessed the proportion who did not switch treatment and were alive within 6 months. Descriptive analyses were conducted, and average effects were estimated using inverse probability weighted regression models. Results: We identified 3,532 patients who received genomic testing and pharmacotherapy cancer treatment (NGS CGP, n = 968; N/S, n = 2,564). Characteristics were similar between testing groups. The proportion of patients with INP/ED for outcomes of interest was similar following NGS CGP vs. N/S panels (15.0% vs. 17.8%; IRR [95% CI]: 0.76 [0.57 – 1.02]; p = 0.066), as were mortality (56.2% vs. 59.2%; HR: 1.05 [0.95 - 1.16]; p = 0.323) and PPPM costs (PPPM median cost difference -$575; ratio from regression 0.99, 0.94-1.04; p = 0.228). Among a subgroup of patients treated within 30 days of testing, a higher proportion receiving NGS CGP did not switch treatment and were alive after 6 months (47.6%) vs those receiving N/S panels (39.8%) (OR [95% CI]: 1.33 [1.12 - 1.59]; p = 0.001). Median genomic testing costs were $3,049 for NGS CGP vs. $218 for N/S testing. Conclusions: Outcomes were similar between patients receiving NGS CGP and N/S panel testing. Among patients with treatment within 30 days of testing, upfront NGS CGP was associated with fewer patients switching treatment and 6-month survival. Upfront testing with NGS CGP may represent a beneficial genomic profiling strategy as part of the initial management of patients with aLC.
Molecular testing and patterns of treatment in patients with NSCLC: An IASLC analysis of ASCO CancerLinQ Discovery Data.
Authors: Behera Madhusmita , Joseph Gregory , Rupji Manali , Huang Zhonglu , Bunn Becky , Wynes Murry , Switchenko Jeffrey M. , Scagliotti Giorgio V. , Higgins Kristin Ann , Tsao Ming Sound , Belani Chandra Prakash , Sequist Lecia V. , Ramalingam Suresh S.
Published: June 2022

9128

Background: Precision medicine has resulted in improved outcomes for non-small cell lung cancer (NSCLC); while molecular testing is considered critical for guiding treatment decisions for advanced stage NSCLC, adoption of testing in routine practice is variable. We analyzed the factors contributing to molecular testing and treatment patterns in patients with lung cancer. Methods: The ASCO CancerLinQ Discovery dataset was queried to identify patients diagnosed with lung cancer between the years 2010-2018. Data on demographics, tumor stage, histology and treatments were extracted, and receipt of molecular testing was investigated as the primary outcome. Univariate association of each clinicopathological variable with molecular testing outcome was performed using chi-square test for categorical variables and ANOVA test for numerical variables. A multivariable logistic regression analysis with backward selection at an alpha of 0.05 was reported. All analyses were conducted using SAS 9.4. Results: A total of 37,925 NSCLC patients with stage IV disease were analyzed. Patient characteristics: median age 65 years, 51% male, 68% white, 33.5% adenocarcinoma. Approximately 22% of all NSCLC patients had molecular testing results. In adenocarcinoma patients, 49% had molecular testing results available. In the stage IV group, 47% were treated with chemotherapy, 16% with immunotherapy and 3% with targeted therapy. On multivariable analysis, females were more likely to have molecular testing compared to males [(OR: 1.29 (1.22-1.37); p < 0.001]. Compared to White patients, Black patients were less likely to have molecular testing [OR: 0.89 (0.81-0.97); p = 0.009] and Asians were more likely to undergo testing [OR: 2.22 (1.79-2.75); p < 0.001]. Hispanic patients were more likely to undergo molecular testing compared to non-Hispanics [OR:1.24 (1.02-1.52); p = 0.03]. Additionally, treatment with immunotherapy [OR: 1.86 (1.72-2.01); p < 0.001] and targeted therapy [OR: 2.29 (2.00-2.64); p < 0.001] were associated with significantly higher likelihood of having molecular testing. These results were also confirmed on a subgroup analysis of adenocarcinoma patients. Conclusions: In this analysis of a US-based real-world dataset of stage IV NSCLC patients, White race and female sex are associated with higher likelihood of having molecular test performed. The percentage of patients undergoing testing remains sub-optimal.
A phase II clinical trial of camrelizumab (CAM, an IgG4 antibody against PD-1) combined with apatinib (APA, a VEGFR-2 tyrosine kinase inhibitor) and temozolomide (TMZ) as the first-line treatment for patients (pts) with advanced acral melanoma (AM).
Authors: Si Lu , Li Caili , Bai Xue , Zhou Li , Mao Lili , Cui Chuanliang , Chi Zhihong , Sheng Xinan , Lian Bin , Wang Xuan , Tang Bixia , Yan Xieqiao , Li Siming , Kong Yan , Dai Jie , Wei Xiaoting , Li Juan , Yang Fan , Pang Zheng , Guo Jun
Published: June 2022

9508

Background: PD-1 monotherapy as the first line stand treatment for advanced melanoma yields an objective response rate (ORR) of < 20% in AM. Although multiple clinical trials are ongoing testing TMZ/APA, TMZ/PD-1 and APA/PD-1 combo therapies in AM, the reported ORR (range 17-23.8%) are far from satisfactory. We therefore conducted a phase II study of CAM/APA/TMZ combo in this subtype aiming for improved efficacy. Methods: We performed a single center, single arm phase II study (NCT04397770) testing the efficacy and safety of CAM/APA/TMZ combo as first-line therapy in pts with advanced AM. The primary endpoint was ORR per RECIST1.1, secondary endpoints included progression free survival (PFS), disease control rate (DCR), overall survival (OS), and safety. All pts received iv CAM (200mg q2w), iv TMZ (200mg/m2 d1-5, q4w) and po APA (250mg qd) until disease progression or intolerable toxicity. Results: By Jan 2022, fifty pts were enrolled (48 evaluable), the median follow-up was 12.1 mo (IQR 8.4-14.5). Thirty-one pts achieved CR/PR as the best response (including 1 CR and 30 PR), the ORR was 64.6% (95% CI 49.4-77.4%). The DCR was 95.8% (95%CI, 84.6-99.3%). Both the median PFS and OS was not reached (NR); 6-mo and 12-mo PFS rate was 81.7% (95%CI 71.6-93.3%) and 62.9% (95%CI 48.4-81.7%), respectively; 12-mo OS rate was 82.3% (95%CI 68.2-99.2%). The incidence of treatment-related adverse events (TRAEs) was 94% (47/50). Of 50 patients, the most common grade ≥3 TRAEs included γ-glutamyl transferase elevation (24.0%), direct bilirubin elevation (22.0%), aspartase transaminase elevation (20.0%), alanine transaminase elevation (16.0%), and hypertriglyceridemia (14.0%). No treatment-related deaths occurred. Conclusions: The CAM/APA/TMZ combination demonstrated promising efficacy as the first-line treatment for pts with advanced AM, and was generally well tolerated. Phase III randomized control trial is warranted. Clinical trial information: NCT04397770.
Long-term outcomes of a phase II trial of neoadjuvant immunotherapy for advanced, resectable cutaneous squamous cell carcinoma of the head and neck (CSCC-HN).
Authors: Gross Neil D. , Ferrarotto Renata , Amit Moran , Nagarajan Priyadharsini , Yuan Ying , Bell Diana , Johnson Jason M. , Morrison William H. , Rosenthal David Ira , Glisson Bonnie S. , Johnson Faye M. , Mott Frank , Esmaeli Bita , Diaz Eduardo , Gidley Paul , Goepfert Ryan , Lewis Carol M. , Wargo Jennifer Ann , Weber Randal S. , Myers Jeffrey
Published: June 2022

9519

Background: In a pilot phase II trial, we investigated the use of neoadjuvant immunotherapy to induce a pathologic response in patients with stage III/IV (M0) cutaneous squamous cell carcinoma of the head and neck (CSCC-HN). Here, we report the long-term outcomes according to pathologic response. Methods: Patients with newly diagnosed or recurrent stage III/IV (M0) (AJCC 8th Ed) CSCC-HN were treated with 2 doses of cemiplimab 350 mg intravenously every 3 weeks prior to surgery. The primary endpoint was overall response rate (ORR) per RECIST v1.1. Secondary endpoints included safety, pathologic response, disease-free and overall survival. Results: Of 20 patients enrolled, 7 (35%) had recurrent disease and 12 (60%) were stage IV on presentation. Neoadjuvant immunotherapy was generally well-tolerated and there were no surgical delays. Adverse events (AEs) were observed in 7 (35%) patients; 1 (5%) grade 3 diarrhea, 6 (30%) ≤ grade 2 AEs. ORR by RECIST was 30%. However, 85% (17/20) achieved a pathologic response (≤50% viable tumor), with pathologic complete response (pCR) in 11 (55%), major pathologic response (MPR, ≤10% viable tumor) in 4 (20%) and pathologic partial response (pPR, >10% and ≤50% viable tumor) in 2 (10%). Patients with a pCR did not receive planned radiotherapy after surgery. Patients who did not have a pathologic response (> 50% viable tumor) either progressed and died (1, 5%) or developed recurrence (2, 10%) despite surgery and adjuvant radiation or chemoradiation. At a median follow up of 34.5 months (range: 7.7-42.7), none of the patients who achieved a pathologic response have recurred. Conclusions: Consistent with other cancer types, pathologic response to neoadjuvant immunotherapy is durable in patients with advanced, resectable CSCC-HN. Adjuvant radiation therapy may be spared in patients who achieve a pCR and warrants further investigation. Clinical trial information: NCT03565783.
Efficacy and safety of cosibelimab, an anti–PD-L1 antibody, in patients with metastatic cutaneous squamous cell carcinoma.
Authors: Clingan Philip R. , Brungs Daniel , Arnold Susan , Coward Jermaine , Fourie Samuel J. , Harris Dean Laurence , Kurochkin Andrii , Ladwa Rahul , Malan Niel , Mant Andrew Michael , McGrath Margie , Sharma Vinay , Shue Hong , Tazbirkova Andrea , Oliviero James , Desai Jayesh
Published: June 2022

9537

Background: Programmed death receptor-1 (PD-1)–blocking antibodies are approved as monotherapy treatment for patients (pts) with metastatic or locally advanced cutaneous squamous cell carcinoma (CSCC) who are not candidates for curative surgery or radiation. Cosibelimab is a high-affinity, fully human programmed death ligand-1 (PD-L1)–blocking antibody with a functional Fc domain capable of inducing antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) against tumor cells. Study CK-301-101 (NCT03212404) is a global, multicenter, multicohort, pivotal trial that enrolled pts with select advanced cancers for treatment with cosibelimab. Here we present the primary analysis of the registration-enabling expansion cohort in pts with metastatic CSCC. Methods: Adult pts with Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 who had metastatic (nodal and/or distant) CSCC not amenable to local therapy were eligible to participate. Cosibelimab was administered as a fixed dose of 800 mg every 2 weeks (Q2W) intravenously. The primary endpoint was confirmed objective response rate (ORR; complete response [CR] + partial response [PR]) assessed by independent central review according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and the key secondary endpoint was duration of response. Results: Seventy-eight pts with metastatic CSCC were treated with cosibelimab and comprise the efficacy and safety populations (59M/19F; median age: 71 years). The confirmed ORR was 47.4% (95% CI: 36.0, 59.1; 6 CRs and 31 PRs) and the median duration of response was not reached at the time of data cutoff (median duration of follow-up: 15.2 months), with 76% of responses ongoing (range: 1.4-31.8+ months). The Kaplan–Meier estimated probability of maintaining a response at 6 and 24 months was 88.1% and 72.5%, respectively. Treatment-related adverse events (TRAEs) were reported in 54 pts (69.2%); 7 pts (9.0%) experienced at least 1 grade 3 TRAE (no grade 4 or grade 5 TRAEs were reported) with the most common being increased serum lipase in 2 pts. Conclusions: Treatment with cosibelimab monotherapy resulted in a robust ORR with durable responses and demonstrated a predictable and manageable safety profile in pts with metastatic CSCC, supporting its use in the treatment of this cancer. Clinical trial information: NCT03212404.
EMRseq: Registry-based outcome analysis on 1,000 patients with BRAF V600–mutated metastatic melanoma in Europe treated with either immune checkpoint or BRAF-/MEK inhibition.
Authors: Weichenthal Michael , Svane Inge Marie , Kandolf Sekulovic Lidija , Mangana Joanna , Mohr Peter , Marquez-Rodas Ivan , Schmidt Henrik , Ziogas Dimitrios C. , Bender Marc , Ellebaek Eva , Urch Kristina , Shalamanova-Deleva Gergana , Gavrilova Iva , Espinosa Enrique , Dummer Reinhard , Rutkowski Piotr , Ascierto Paolo Antonio , Gogas Helen , Schadendorf Dirk , Bastholt Lars ,   EUMelaReg Consortium
Published: June 2022

9540

Background: In BRAF mutated metastatic melanoma, potential outcome differences for different choices of 1st line treatments including immunotherapy or BRAF-/MEK inhibition are not completely understood. We therefore analyzed the treatment patterns and outcome of systemic therapies for patients BRAF mutated metastatic melanoma. Methods: From the EUMelaReg treatment registry, patients fulfilling the following inclusion criteria were consecutively included until a number of 1,000 evaluable cases was reached. 1) Patients with metastatic melanoma and BRAF V600 mutation 2) First line treatment with either combined BRAF-/MEK or immune checkpoint inhibition (ICI) with PD-1 single agent or combined PD-1/CTLA-4 antibodies. Multivariable cox regression analysis as well as propensity score based weighting were used to control for bias from baseline imbalances. Primary outcomes of interest were overall survival (OS) and 2nd line PFS (PFS-2), stratified for upfront treatment decision of ICI versus targeted therapy. PFS-2 was defined as the interval from start of first line treatment to a progression after a 2nd line treatment or death of any cause. Further endpoints were evaluated including time on treatment (ToT), time to next treatment and 2nd line treatments. Results: In total 529 (52.9 %) patients received BRAF/MEK-i, and 471 (47.1%) ICI. For various co-variates there were significant imbalances between strata, including number of metastatic sites, AJCC substage, serum LDH, and ECOG performance status, with more favorable prognostic variables for patients receiving immunotherapy. The ORR for BRAF/MEK-i was significantly higher than for ICI (53.3% vs. 42.0%; p=0.0004), but for OS and PFS2 the adjusted hazard ratios were significantly in favor for ICI (HR 0.62 and 0.66, respectively; p <0.0001). In 2nd line, patients switching from ICI to BRAF/MEK-i had again markedly higher ORR than patients switching vice versa (57.7% vs. 19.9%; P<0.0001), and also significantly longer unadjusted PFS (8.1 vs. 3.1 months; p <0.0001) and OS (15.7 vs. 10.6 mths; p=0.01) after start of 2nd line treatment. Conclusions: The two cohorts had imbalances on key prognosis variables. After adjustment for these imbalances, upfront ICI still resulted in significantly longer OS as compared to BRAF/MEK-i. Due to the nature of real-world observational data causing inherent imbalances in the treatments cohorts and being unable to account for potential unknown confounders, outcome may still be biased despite adjustment efforts.[Table: see text]
Preferences for adjuvant immunotherapy in patients with resected stage III melanoma: A discrete choice experiment.
Authors: Livingstone Ann , Menzies Alexander M. , Howard Kirsten , Stockler Martin R. , Morton Rachael L.
Published: June 2022

9558

Background: Adjuvant immunotherapy has revolutionized the management of resectable melanoma, substantially reducing the risk of recurrence but at the risk of immune-related adverse events (AE). This study aimed to quantify patients' preferences for adjuvant immunotherapy, the influence of varying levels of key attributes, and baseline characteristics associated with preferences. Methods: We performed a discrete choice experiment (DCE), including patients with resected stage III melanoma considering or having received adjuvant immunotherapy. Patients chose between twelve randomly presented choice tasks of two alternative options (adjuvant immunotherapy versus observation without adjuvant immunotherapy). The two options varied across two-three levels of six attributes: chance of 3-year melanoma recurrence, mild, permanent, or fatal AE, drug regimen, and out-of-pocket costs. We calculated the marginal rate of substitution (MRS, how much an individual was willing to trade one attribute for preferred levels of another) and willingness-to-pay (WTP, maximum price to trade their preferred attributes) per year. Results: One hundred and sixteen patients completed the DCE. Patients chose adjuvant immunotherapy over observation without adjuvant immunotherapy in 70% of choice tasks. Patients preferred adjuvant immunotherapy with reduced probabilities of recurrence (OR 0.76, 95% CI 0.70-0.83, p<0.001), fatal AE (OR 0.60, 95% CI 0.44-0.80, p=0.006), permanent AE (OR 0.94, 95% CI 0.89-0.99, p=0.046), and lowered out-of-pocket costs, for those with lower incomes (OR 0.63, 95% CI 0.47-0.85, p=0.003) and higher incomes (OR 0.84, 95% CI 0.15-4.86, p=0.064). Patients accepted an increase in their chance of mild AE from 1% to 37% (OR 2.06, 95% CI 1.13-3.78, p=0.019) in return for adjuvant immunotherapy. Willingness-to-pay was lower for patients with incomes that were lower rather than higher: US$595 (95% CI US-$555 to 1,305) and US$1,638 (95% CI US$ -1,235 to 3,419) per year for adjuvant immunotherapy with an absolute reduction of 1% in the 3-year risk of recurrence. Conclusions: Almost three-quarters of patients preferred adjuvant immunotherapy over observation without adjuvant immunotherapy. Patients were more likely to select immunotherapy if the risk of melanoma recurrence and the chance of fatal AE were reduced. Understanding patient preferences and acceptable trade-offs for adjuvant immunotherapy may allow better-informed decisions for individuals and assist policymakers in decisions about access and subsidization of effective and expensive treatments.
Safety and efficacy of combined melphalan percutaneous hepatic perfusion (M-PHP) and ipilimumab plus nivolumab (IPI+NIVO) in metastasized uveal melanoma (mUM): First results of the phase Ib part of the CHOPIN trial.
Authors: Tong Thaïs M.L. , Burgmans Mark C. , Speetjens Frank M. , van Erkel Arian R. , van der Meer Rutger W. , van Rijswijk Carla S.P. , Jonker Mare A. , Roozen Inge C.F.M. , Lutjeboer Jacob , van Persijn-van Meerten Els L. , Martini Christian H. , Zoethout Remco W.M. , Tijl Fred G.J. , Blank Christian U. , Kapiteijn Ellen
Published: June 2022

9560

Background: Uveal melanoma (UM) is the most frequent intraocular malignant tumor in adults. Approximately 50% of all patients (pts) will develop metastatic disease in the liver. Until now, there is no systemic therapy that has been shown to improve overall survival (OS), apart from tebentafusp. M-PHP is frequently applied for liver-only UM. However, the majority of pts eventually develops extrahepatic disease after M-PHP. IPI+NIVO has been shown to induce up to 20% response rates in mUM. Our observations that checkpoint inhibition was most effective on extrahepatic UM disease has led to the CHOPIN trial testing the combination of M-PHP and IPI+NIVO. Here we present the safety and efficacy data of the phase 1b part of CHOPIN. Methods: Adult pts with confirmed measurable hepatic mUM and WHO PS 0-1 were included. Two courses of 6 weekly M-PHPs (melphalan 3mg/kg, max 220mg) were combined with four courses IPI+NIVO three-weekly escalating the dosing from 1mg/kg each IPI+NIVO (cohort 1) to IPI 1mg/kg + NIVO 3mg/kg (cohort 2). Primary endpoint was safety of IPI+NIVO plus M-PHP. Secondary endpoints were best overall response (BOR) according to RECIST 1.1, progression-free survival (PFS), and OS. Results: 7 pts were included (4 male, median age 63.6 years (range 50-74)). Both cohorts were tolerated with no dose-limiting toxicities or deaths. Grade III/IV adverse events (AE) were observed in 2/3 pts in cohort 1 and in 3/4 pts in cohort 2 consisting of SIRS, febrile neutropenia, cholecystitis, neutropenia, thrombopenia, leukopenia, increased transaminases and fever. Grade I/II immune-related AEs occurred in all pts (myositis, hypothyroidism, hepatitis and dermatitis). BOR was 1 complete response, 5 partial responses and 1 stable disease accounting for an objective response rate (ORR) of 85.7%. At a median FU time of 20.2 months, 4 pts have an ongoing response. Currently the median PFS is 22.4 months, and all pts are still alive. Conclusions: Combining M-PHP with IPI+NIVO is safe at a dosing of IPI 1 mg/kg and NIVO 3 mg/kg and very promising ORR, PFS and OS have been observed. The randomized phase II part comparing M-PHP versus M-PHP+IPI+NIVO is currently recruiting. Clinical trial information: NCT04283890.
Plasma methylated DNA markers of cutaneous melanoma: Association with PET/CT-positive disease.
Authors: Meves Alexander , Taylor William R. , Berger Calise K. , Mahoney Douglas W. , Burger Kelli , Quattrocchi Enrica , Doering Karen A. , Gonser Anna M. , Cao Xiaoming , Heilberger Justin , Gysbers Brianna J. , Foote Patrick H. , Katerov Viatcheslav E. , Allawi Hatim T. , Kisiel John B.
Published: June 2022

9567

Background: Cutaneous melanoma surveillance is important to identify low-volume systemic disease, but imaging is costly and poorly accessible to patients; frequent skin checks lack sensitivity and specificity. We aimed to establish clinical feasibility of a liquid biopsy blood test, which quantifies validated, melanoma-specific, methylated DNA markers (MDMs), previously discovered, and reported by our team, using tissue extracted DNA. Methods: We prospectively collected blood from adult patients with histologically confirmed melanoma metastases and no other internal malignancies (within 5-years) who underwent surveillance by FDG-PET/CT (N = 88). Blood from age- and sex balanced cancer-free controls (N = 100) were compared. From PET/CT, we extracted the number of organs involved, SUV-max, and largest tumor diameter. Unequivocal metastasis was defined as SUV ≥ 4 and largest diameter > 5 mm. Because PET/CT is inadequate for the screening of brain metastases, we excluded the brain from the analysis. MDMs ( chr11.149, HOXA9, chr20.210, FLJ22536, CLIC5, SIX4, chr7.155, chr17.730, chr1.110) were assayed using target enrichment long-probe quantitative-amplified signal assays, normalized to B3GALT6, in blinded fashion. Using a logistic regression approach and nine candidate MDMs, we calculated the sensitivity for detecting patients with metastasis on PET/CT at 100% specificity. Results: 52/88 (59%) of melanoma patients showed evidence of metastasis on PET/CT at the time of blood draw. At 100% specificity, a panel of 4 MDMs ( HOXA9, chr20.210, chr17.730, chr1.110) yielded a sensitivity of 86.5% (45/52 cases) vs. 100 cancer-free controls. When applying this model to the 36 PET/CT-negative patients, specificity was as high as 97.2% (35/36 cases) while maintaining a sensitivity of 86.5% (one patient with a positive test result had a complete metabolic response to binimetinib / encorafenib prior to negative PET/CT). For patients with ≥ 2 organs involved by metastasis, sensitivity was 100% (29/29 cases). False-negative cases had metastasis in single organs and were characterized by minimal tumor burden and oral corticosteroid use. One false-negative patient had localized stage III disease without known primary melanoma. Conclusions: Plasma MDM levels appear highly concordant with FDG-PET/CT in patients with metastatic cutaneous melanoma. A liquid biopsy approach has potential to lower cost and improve patient access to surveillance. Additional prospective studies in larger intended use cohorts are needed to validate our results.
Utility of adjuvant chemotherapy in early-stage, estrogen receptor-positive breast cancer patients under 50 years with a 21-gene recurrence-score of 16-25: A retrospective analysis using the National Cancer Database.
Authors: Ashok Kumar Prashanth , Wang Dongliang , Huang Danning , Sivapiragasam Abirami
Published: June 2022

e12501

Background: The TAILORx trial showed that addition of adjuvant chemotherapy (AC) to endocrine therapy (ET) had no advantage in estrogen receptor (ER)+, HER2-, node negative (N0) breast cancer (BC) patients with an intermediate (11-25) 21-gene recurrence-score (RS). However, a subgroup analysis revealed that in women ≤ 50 years, AC had a lower rate of distant recurrence if the RS was 16-25. Using a large national database, we studied the utilization of AC in the aforementioned subset. Methods: The 2004-2018 National Cancer Database BC cohort was used to include female patients of 18-50 years. Inclusion criteria were N0, M0 patients with any T stage, RS 16-25, ER+/PR± and HER2-. Patients who received neoadjuvant chemotherapy were excluded. Logistic regression was used to evaluate AC utility trends. Kaplan-Meier (KM) and multivariate (MV) propensity score (PS) weighted Cox model were used to compare survival between patients without and with AC use. Results: Of the 15,792 patients, 4808 (30.45%) received AC. Median RS was 18 and 21 in patients without and with AC. Factors associated with AC use were higher T stage, poor and moderately differentiated tumors, age <40, care at an academic center, Caucasian race, patients undergoing mastectomy, regional lymph node (RLN) surgery, ET and Radiation Therapy (RT). KM survival at 10 years was better with AC [96.2% vs 91.6%]. Patients without AC had worse survival [Hazard Ratio (HR)=1.683, 95% Confidence Interval (CI): 1.392-2.036, p<0.0001] (Table). Conclusions: In this analysis,AC use had a 5% improvement in 10 year overall survival, in contrast to TAILORx trial which only showed a disease free survival benefit. Whether the benefit was due to direct cytotoxicity or ovarian function suppression effect of AC remains to be seen. In clinical practice, AC use is determined based on patient and tumor characteristics. Limitations of our study include non-population-based data and the possibility of cofounding despite the use of PS matching. [Table: see text]
Baseline GP2 immune response as an independent prognostic factor in a phase IIb study evaluating HER2/neu peptide GP2 (GLSI-100) versus. GM-CSF alone after adjuvant trastuzumab in HER2-positive women with breast cancer.
Authors: Patel Snehal , McWilliams David , Thompson Jaye , Patel Mira , Daugherty F. Joseph
Published: June 2022

e12519

Background: Delayed type hypersensitivity (DTH) skin tests to GP2 were conducted in the randomized, active-controlled, single-blinded, multicenter Phase IIb trial investigating GLSI-100 (GP2+GM-CSF) administered in the adjuvant setting to node-positive and high-risk node-negative breast cancer patients with tumors expressing HER2. Previously it has been reported that subjects with baseline response to GP2 by DTH were more likely to experience a recurrence sooner than those without a positive baseline response. It was of interest to determine if this response was independent of other known prognostic factors. Methods: Patients were randomized and received GLSI-100 (500 mcg GP2: 125 mcg GM-CSF) or control (GM-CSF only) via 6 intradermal injections every 3-4 weeks as part of the Primary Immunization Series (PIS) for 6 months and 4 booster injections every 6 months thereafter. GP2 DTH skin tests were placed at baseline and after the 6th dose. After 48-72 hours, the largest perpendicular diameters of induration were measured and the orthogonal mean was calculated. Induration of over 5mm was considered a positive response. The relationship between prognostic factors such as demographic and disease characteristics and the baseline DTH response were investigated by logistic regression. Results: The study enrolled 180 patients who were HER2 3+ positive and low HER2 expressors (1-2+). After 5 years of follow-up, the Kaplan-Meier estimated 5-year DFS rate in the 46 HER2 3+ patients treated with GLSI-100, if completing the PIS, was 100% versus 89.4% (95% CI:76.2, 95.5%) in the 50 patients treated with GM-CSF (p = 0.0338). Just under 23% of subjects experienced an immune response to GP2 by DTH at baseline. The incidence was similar in patients who were HER2/neu positive and those considered low expressors and was equally distributed across GLSI-100 and placebo-treated subjects. Known prognostic factors such as hormone receptor status, stage at presentation, node status, etc. were evenly distributed across subjects that experienced a baseline DTH response to GP2 and those who did not. Each prognostic factor was investigated in a logistic model to determine if it predicted baseline DTH immune status. The prognostic factors did not predict baseline DTH immune response in the logistic models. There appears to be no correlation between baseline immune response to GP2 and known prognostic factors. Conclusions: Baseline GP2 immune response as measured by the delayed-type hypersensitivity test may be an independent prognostic factor for recurrence. Knowledge of this GP2 immune response may identify a patient with increased risk of rapid recurrence. Clinical trial information: 00524277.
Adjuvant trastuzumab and vinorelbine (TV) for early-stage HER2+ breast cancer.
Authors: McLaughlin Shannon , Nakajima Erika , Isakoff Steven J. , Shin Jennifer , Moy Beverly , Bardia Aditya , Kuter Irene , Spring Laura
Published: June 2022

e12521

Background: The anti-HER2 antibody trastuzumab has vastly improved outcomes for women with early stage and advanced HER2+ breast cancer (BC) when used in combination with chemotherapy. Anthracycline and taxane-based regimens have historically made up the chemotherapy backbone for patients with localized HER2+ BC, though recent evidence suggests anthracyclines can be safely omitted. The single arm phase II APT trial established trastuzumab and paclitaxel as the standard adjuvant regimen for small HER2+ tumors. However, paclitaxel requires weekly treatment, causes alopecia, and has high rates of neuropathy and hypersensitivity reactions. In patients with metastatic HER2+ BC, the combination of trastuzumab and vinorelbine (TV) is effective and well tolerated. There is a need for alternative regimens for patients with HER2+ early-stage BC, especially for those with contraindications to anthracycline and taxane-based regimens. We conducted a retrospective study of patients with early stage HER2+ BC treated with adjuvant TV to evaluate a non-anthracycline/taxane-based, alopecia-sparing regimen. Methods: Clinicopathological characteristics, treatment details, and outcomes of patients with localized HER2+ BC treated with adjuvant TV for from 2007 to 2021 at a large academic medical institution were collected. Study endpoints included invasive disease-free survival (IDFS), overall survival (OS), and safety/tolerability. IDFS and OS were measured from start date of TV treatment to date of event or last follow-up, respectively. 5-year survival rates were generated in GraphPad Prism. Results: A total of 25 patients were treated with TV. All patients received trastuzumab at standard dosing and vinorelbine at a starting dose of 25 mg/m2 on days 1/8 of a 21-day cycle with 4 planned cycles. Median age at diagnosis was 61 years (range: 36-81). 88% of patients had anatomic pathologic Stage IA BC and 12% Stage IIA BC. Of the 25 patients, 24 of them opted to pursue TV due to concerns over alopecia, neuropathy, and other toxicities while 1 patient had received prior adriamycin and therefore opted for TV. With a median follow-up time of 68 months (5.7 years), the 5-year rate of survival from invasive disease was 90.9%, with 1 local and 1 distant recurrence. The 5-year overall survival was 100%. 76% of patients completed 4 cycles of TV without dose holds or delays and 92% completed 4 cycles without dose reductions. 2 patients required hospitalization during treatment with TV due to toxicity (diarrhea attributed to V, rigors/fever attributed to T). No patients experienced alopecia or long-term neuropathy. Conclusions: Trastuzumab in combination with vinorelbine in the adjuvant, early-stage setting for HER2+ BC is effective and well-tolerated and warrants further exploration as an alternative to taxane-based regimen.
Impacts of subtypes on clinical feature and outcome of male breast cancer.
Authors: Lee Jieun , Lee Keun Seok , Sohn Joohyuk , Lee Kyung-Hee , Jung Kyung Hae , Byun Jae Ho , Koh Su-Jin , Lee Kyoung Eun , Lim Seungtaek , Kim Hee Jun , Won Hye Sung , Park Hyung Soon , Lee Guk Jin , Hong Soojung , Baek Sun Kyung , Lee Soon Il , Choi Moon Young , Woo In Sook
Published: June 2022

e12528

Background: The treatment of male breast cancer (MBC) has been extrapolated from female breast cancer (FBC) because of its rarity despite their different clinicopathologic characteristics. We aimed to investigate the distribution of intrinsic subtypes based on immunohistochemistry (IHC), their clinical impact, and treatment pattern in clinical practice through a multicenter study in Korea. Methods: We retrospectively analyzed clinical data of 248 MBC patients 18 institutions across the country from January 1995 to July 2016. Results: The median age of MBC patients was 63 years (range: 25–102 years). Among the 148 patients that underwent intrinsic subtype classification, 61 (41.2%), 44 (29.7%), 29 (19.5%), and 14 (9.5%) were luminal A, luminal B, HER2, and triple-negative breast cancer (TNBC), respectively. TNBC patients showed inferior survival compared with those with other subtypes. Of the 221 patients with operable breast cancer, 108 (48.6%) received adjuvant chemotherapy and 52 (23.5%) received adjuvant radiation therapy. Most hormone receptor-positive patients (166 patients, 82.6%) received adjuvant endocrine treatment. Five-year completion of adjuvant endocrine treatment was associated with superior disease-free survival (DFS) in patients classified with an intrinsic subtype (hazard ratio [HR] = 0.19, 95% confidence interval [CI] 0.005–0.65, P = 0.008) and in all patients (HR = 0.16, 95% CI 0.05–0.54, P = 0.003). Conclusions: Distribution of subtypes of MBC was similar to FBC and luminal type A was most common. Overall survival tended to be improved for luminal A subtype although there was no statistical significance. Completion of adjuvant endocrine treatment was associated with prolonged DFS in intrinsic subtype classified patients. MBC patients have tended to receive les treatment. MBC patients should be treated with standard guideline as FBC patients receive.
The correlation analysis of 21-gene assay use in uninsured and underrepresented minorities with estrogen receptor (ER) positive HER2 negative breast cancer.
Authors: Jeon Hyein , Kim Eileen , Subramanian Megana , Suarez-Ligon Adriana , Jaloudi Mohammed
Published: June 2022

e12531

Background: 21-gene breast cancer recurrence-score assay (Oncotype DX) have been used to predict recurrence risks and guide adjuvant chemotherapy. However, access to such tests is limited, especially in a population concentrated with uninsured and underserved patient populations. Previously equations such as the Magee equation has been proposed to predict correlation of the recurrence score and the estimated recurrence score with high concordance rate. This study examines the concordance of such an assay to predicted scores in uninsured and underrepresented minority heavy public hospital. Methods: We performed a retrospective chart review of 68 women with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer seen at University Hospital (public safety net hospital in Newark, New Jersey with greater majority of the patient population consists of underrepresented minorities such as Black/African Americans and Latino/Hispanics). 6 patients did not have pathology records, 9 patients did not have the Oncotype information available, and 4 patients were waiting on the results. Of the pre-menopausal eligible patients, two did not have any treatment or follow up information available and were included as part of the correlation assay, however, no. Results: Of the 47 eligible patients with follow-up information, 13 had a low recurrence score of up to 10 if post-menopausal and up to 15 if pre-menopausal, 22 had an intermediate recurrence score of 11 to 25 if post-menopausal and 16 to 25 if pre-menopausal, and 12 had a high recurrence score of greater than 26 according to the national comprehensive cancer network guidelines. The Pearson correlation between the Magee predicted score and Oncotype recurrence score was 0.73 (p < 0.001). All patients received hormone therapy and 5 patients total had recurred. 2 were pre-menopausal and had received adjuvant chemotherapy. 3 were post-menopausal in low and intermediate categories who had not received adjuvant chemotherapy. Conclusions: This study shows a high correlation between the predicted Magee score and Oncotype recurrence score. This reflects a possible use in the prediction scoring system as another resource for prognostication and guidance in treatment especially in the underinsured population.
Using a multimodal approach to elucidate racial disparities in breast cancer biology by integrating tumor imaging and -omics data.
Authors: Liadis Nicole , Earnest Tyler M , Braun Eduardo , Antony Anu K. , Hallock Micahel J , Team The SimBioSys , Cook Daniel
Published: June 2022

e12541

Background: Race-related differences in breast cancer incidence and clinical outcome have been well documented, with many studies focusing on socioeconomic determinants contributing to African American (AA) breast cancer patients having higher mortality rates. Far less is understood about the underlying biological differences in tumors between AA and Caucasian patients. In recent years, there have been more and more individual accounts identifying specific somatic mutations or observed breast tumor behaviors associated with racial disparities in breast cancer. Understanding how these specific observations coincide to give rise to alternative tumor biology in AA women, remains a challenge. Given the multifactorial nature of cancer, we have developed a platform that integrates the combinatorial phenotypic, molecular, and biological hallmarks of cancer. Our technology combines imaging and multi-omics data, providing a systematic approach for understanding race-specific biological differences and how they contribute to patient survival. Methods: Imaging and transcriptomic data from 1108 patients were integrated within the SimBioSys TumoScope biophysical modeling software to understand racial differences in tumor biology, coordinated tumor behavior, and corresponding patient outcome. Results: AA patients have tumors that display higher growth rates, characteristically have higher adipose tissue around the tumor, higher spatial variation in drug/ nutrient delivery, and increased tumor stiffness. We also identified biological features, including tumor/gland density and intertumoral heterogeneity that are prognostic for overall survival even when accounting for race and cancer subtype. Conclusions: Our results outline characteristic biological features that along with race and FDA breast cancer subtype may promote the disproportionately poor survival rates observed in AA breast cancer patients. This is the first study demonstrating a systematic approach being used to elucidate race-specific biological difference that may coordinate to impact patient survival. Our findings emphasize the importance of accounting for racial disparities and patient-specific biology to develop tailored intervention strategies and personalize race-specific clinical management of breast cancer.
Brain 18-FDG-PET patterns in early breast cancer subtypes: Relationship with headache.
Authors: De Sanctis Rita , Antunovic Lidija , Benvenuti Chiara , Jacobs Flavia , Gaudio Mariangela , Ilieva Mariya , Viganò Alessandro , Chiti Arturo , Santoro Armando
Published: June 2022

e12560

Background: Brain metabolic response on 18F-fuorodeoxiglucose(FDG)-PET in breast cancer (BC) patients is not routinely investigated, although several bidirectional relationships have been described between BC (and BC therapies) and brain functions. For example, common forms of headaches, as migraine (Mi) and tension-type headache (TTH), seem to be oddly distributed among BC subtypes and possibly influence the outcome. Methods: We recruited patients with early BC referring to IRCCS Humanitas Research Hospital who received neoadjuvant chemotherapy. Demographic data, BC characteristics and headache diagnosis were recorded, through detailed interview and instrumental investigation. Ki67 was considered high if above 20%. All patients underwent dedicated 18F-FDG PET scan for the evaluation of brain metabolism. Semiquantitative image analysis was performed using Cortex ID software (GE), comparing patient’s scan with a control group by the means of Z-score. The difference between patients’ subgroups were assessed using One-way ANOVA model. Results: Twenty-three patients were recruited. The median age was 52.5±10.8 years; 65.2% were postmenopausal, 30% premenopausal, and one patient perimenopausal. Ten patients were diagnosed as triple-negative BC, 6 as HER2-positive and 7 as Luminal B/HER2+. Nearly 70% (16/23) of patients had high Ki67 values. All patients had ECOG PS 0. Ten patients were diagnosed with TTH, 9 with migraine of whom two with aura, and four patients had no headache. Eleven patients had active headache at the moment of the study. At the whole brain level, we found a significant increase of brain metabolism in the left hemisphere of BC patients with high Ki-67 (p=0.007). Moreover, the same result was found in parietal cortex and in general associative areas bilaterally. Instead, HER-2 positive BC patient showed a reduced metabolism in right temporal cortex compared to HER-2 negative (p=0.04). Grading and other tumor characteristics did not influence FDG-PET uptake. BC patients with TTH had a reduced activity in right medial frontal lobe compared with migraine patients (p=0.01). Those with an active headache had increased activity in posterior cingulate and reduced activity in visual networks (p=0.03). Conclusions: Although exploratory, this study suggests that BC subtypes could present different metabolic pattern of cerebral activity, particularly in dominant hemisphere and associative areas. The high prevalence of headache in our sample does not affect the above pattern, but it is associated with an altered activation in other networks, mainly cingulate and visual cortex, which are well-known areas involved in primary headache.
Differences in tumor microenvironment between HER2-positive and HER2-negative breast cancer.
Authors: Gong Chang , Lin Qun , Cen Yinghuan , Fang Xiaolin , Shi Yu , Chen Letian , Luo Qing , Duan Zhuxi
Published: June 2022

e12562

Background: The tumor microenvironment of breast cancer is extremely complex, which containing different types of lymphocytes, macrophages, NK cells and other immune cell subtypes. At present, the relationship between immune cell subtypes and molecular subtypes of breast cancer is still unclear. Methods: Tumor tissue samples of 20 breast cancer patients were collected from January 2020. Then the density (number of positive cells/mm2) and ratio of immune cells in intratumoral area and stromal area were detected by multiple fluorescence immunohistochemistry (mIHC), the detection range was included CD3+T cells, CD4+T cells,CD8+T cells,PD-1+CD8+T cells,Tregs,M1/M2 tumor associated macrophages (TAM), PD-L1+CD68+TAM,B cells,CD56bright NK cells and CD56dim NK cells and so on. The immune cell subtypes of all area were included both intratumoral area and stromal area. Graphpad prism (version 7.01) was used for t test and the statistical significance was set at p=0.05. Results: These 20 patients were divided into two groups, HER2 positive (n=8) and HER2 negative group (n=12). The density of CD3+T cells in all area (including intratumoral area and stromal area) of tumor tissue in HER2 positive breast cancer patients were significantly higher than that of HER2 negative breast cancer patients (median density, HER2 positive group vs. HER2 negative group=2998 vs. 1520/mm², p=0.031) as well as the CD8+T cells (median density, HER2 positive group vs. HER2 negative group=536 vs. 175/mm², p=0.015). Meanwhile, the density of Tregs in all area of tumor tissue in HER2 positive breast cancer patients was also significantly higher (median density, HER2 positive group vs. HER2 negative group=119 vs. 27/mm², p=0.022).However, there was no significant difference in the other subtypes of immune cells infiltrated in tumor tissue between HER2 positive and HER2 negative samples, such as CD4+T cells, M1/M2 macrophages, B cells and so on (p＞0.05). Conclusions: Our research indicates that the patterns of immune cell subtypes in different types of early breast cancer are different. Further exploration of the immune microenvironment in different molecular types of breast cancer may provide additional targets for immunotherapy.