bluuebunny/crossref_metadata_2025 huggingface dataset:
Factors associated with the occurrence of myocardial infarction in patients treated for melanoma.
Authors: Pan Xianying , Verma Devashish , Zhang Jiayin , Zhang Yifan , Ma Xiaomei
Published: June 2022

10562

Background: Treatments for melanoma increasingly involve the use of immune checkpoint inhibitors (ICIs), which are associated with cardiac toxicities. Our study aims to examine predictors of myocardial infarction (MI) in melanoma patients receiving treatment. Methods: The United Healthcare (Optum Clinformatics) Closed Claims + Lab Results Database (01/2007 – 03/2021) was used to examine factors potentially associated with the occurrence of hospitalized MI in melanoma patients. Adult patients were included if they: 1) had ≥12 months of continuous insurance coverage at baseline; 2) had ≥2 outpatient or ≥1 inpatient claims with an International Classification of Diseases (ICD) code indicative of melanoma; 3) received ≥1 type of cancer treatment (surgery, chemotherapy, radiotherapy, ICI, or targeted therapy); 4) had a claim with a melanoma ICD code within 5 days before the first cancer treatment; and 5) had no history of MI at baseline. Baseline was defined as the year prior to the first date of treatment; MI occurrence was identified from inpatient claims. We conducted a time-to-event (MI) analysis using a multivariate Cox proportional hazards regression model, with backward selection and death as a competing risk. Results: A total of 42,101 patients (58.8% male; median age of 68 yrs at baseline) were included in the study. Of these, 954 patients (2.3%) experienced a MI, and 5,578 (13.2%) died before having a MI. Compared with patients who underwent surgery only, those who received multiple treatments with an ICI were more likely to have a MI (hazard ratio [HR] = 1.25, 95% confidence interval [CI]: 1.01-1.55; Table). Men had a higher risk than women (HR = 1.47, 95% CI: 1.27-1.71), as did older people (compared with 65-74-yr-olds, HRs were 0.24, 0.49, 1.41, and 2.06 for <55-, 55-64-, 75-84-, and ≥85-yr-olds, respectively; all P<.05). Being Asian and having certain comorbidities at baseline were also associated with a higher MI risk (Table). Conclusions: In this retrospective cohort analysis of patients with melanoma, we observed an increased risk of MI among patients who received multiple treatments with ICIs, compared with surgery only. More research is needed to further elucidate predictors of MI events related to cancer treatment. [Table: see text]
The increasing incidence of alcohol-related cancers in young adults in the United States: Who is most at risk?
Authors: Rohatgi Atharva , Liao Cheng-I , Caesar Michelle Ann , Johnson Caitlin Ruth , Chan Joshua Elbridge , Kapp Daniel Stuart , Chan John K
Published: June 2022

10563

Background: To evaluate incidences and trends of alcohol-associated cancers in United States adults over the last 18 years. Methods: Data was extracted from the United States Cancer Statistics database from 2001 to 2018. SEER*Stat Joinpoint Regression program 4.8.1 was used to calculate incidences and trends. Average annual percentage change (AAPC) was used to describe trends. Based on the ICD-O-3 criteria, liver, colon, oral cavity, esophagus, and pharynx cancers were classified as alcohol-related cancers. Results: Over the last 18 years, the incidence of alcohol-associated cancers decreased overall in males and females by 0.9% every year (p < 0.001). Alcohol-associated cancers increased significantly in younger patients under the age of 39 years old (p < 0.001). Based on race, Black men and women had the highest incidence at 135.17/100,000 followed by 132.50 in White individuals, 105.84 in Hispanic individuals, and 104.28 in Asian individuals. By region, the incidence was found to be the highest in the Midwest at 132.89/100,000 and lowest in the West at 120.33. Based on cancer types, the most common alcohol related cancer was colorectal cancer with an incidence at 36.49/100,000 in 2018, followed by oral cavity cancers at 11.69, liver cancer at 6.76, esophagus cancer at 4.51, and larynx cancer at 2.92. Of all these types of cancers, liver cancer had the highest annual increase at 2.43% (p < 0.001). Using a projection model, we found that liver cancer is estimated to surpass colorectal cancer by the year 2035. On intersectionality analysis, White men and women in the Northeast between the ages of 75-79 had the highest incidence of alcohol-associated cancers at 584.10/100,000 in 2018. However, over the last 18 years, White men and women in the South between the ages of 20-24 had the highest annual increase at 4.08% (p < 0.001). Conclusions: Over the last 18 years, alcohol-related cancers increased in the younger patients, particularly those residing in the South. Liver cancer is increasing at the highest rate.
A five-year epidemiological profile of patients with cancer managed by a Haitian cancer program.
Authors: Bernard Joseph , Henderson Rebecca Rose , Pierre Lenz Sacha Christyl , Alexis Lynn Gabrielle , Gilbert Doukens Patrick , DeGennaro Vincent
Published: June 2022

10564

Background: Cancer epidemiology in Haiti is poorly understood. The national cancer registry is not functional, and data reported by GLOBOCAN are estimations that do not totally reflect the reality of cancers in Haiti. The aim of this study was to present the five-year epidemiology of malignancies managed by one of the main cancer programs in Haiti. Methods: A retrospective study was conducted on patients aged 15 years old and above with pathological and/or clinical diagnosis of cancer managed from January 2016 to December 2020 at Innovating Health International (IHI), a cancer center located in Port-au-Prince, Haiti. The chart review collected variables such as age, gender, date of admission and cancer type in order to present this epidemiological profile of cancers. Results: Overall, 3060 patients with cancer were managed during the study period. 84.4% of the patients were female and 15.6% male. The mean and median ages of the study population were respectively 52.5 [range: 15 –92] and 53.0 years. Adolescents and young adults (15-39 years old) represented 18.9 % of this cohort and geriatric cases (≥ 65 years old) were 21.0%. Breast cancer was the most common type (n = 1391, 45.5%%), followed by gynecological cancers (n = 746, 24.4%) with cervical cancer representing 77.5 % of these cases (n = 578); gastrointestinal cancers (n = 252, 8.2%) dominated by colorectal (n = 92, 36.5%) and gastric cancer (n = 58, 23.0%); head and neck cancers (n = 129, 4.2%); hematological malignancies (n = 128, 4.2%) with lymphomas representing 60.9% of the cases (n = 78); sarcomas (n = 114, 3.7%), urological cancers (n = 73, 2.4%) with prostate cancer representing 56.1% of the cases; skin cancers including melanoma (n = 60, 1.9%); lung cancer (n = 24, 0.8%); thyroid cancer (n = 13, 0.4%) and central nervous system (CNS) cancers (n = 6, 0.2%). 4.1% of the patients (n = 124) had a cancer of unknown primary (CUP). Breast (53.5%), cervical (28.9%) and gastrointestinal (5.0%) cancers were the most common types among women, while gastrointestinal (25.8%), hematological (16.1%), head and neck (14.7%) and urological (12.6%) cancers were the most diagnosed among men. Conclusions: Cancer mainly affects Haiti’s young, active and female population. Breast and cervical cancers were the most prevalent in this retrospective cohort regardless of the age group. The under-representation of prostate and other urological malignancies, lung cancer, acute leukemias and CNS cancers was likely due to underdiagnosis, misdiagnosis, under-referral or early mortality. An active cancer registry is needed to better evaluate the real cancer burden in Haiti.
Exploring "the healthy immigrant effect" among elderly Asian patients with cancer: A nationwide population-based assessment.
Authors: Nayak Manan , Nguyen Paul , Braun Ilana , Schutt Russell K.
Published: June 2022

10567

Background: Asian Americans are the fastest-growing immigrant group in the U.S. As the oldest immigrant group on average, they are at heightened risk for cancer and other diseases. This study explored whether the risk is mitigated by the healthy immigrant effect (HIE), an epidemiological phenomenon that has been well documented among Latino immigrants. Evidence of a healthy immigrant effect among Asians as a whole or in specific Asian subgroups is limited, and almost none focus on the elderly with a cancer diagnosis. This original research study examines the evidence for an HIE in a large ethnically diverse sample of elderly persons with a cancer diagnosis. Methods: This is a retrospective observational study utilizing data collected across 14 regions of the U.S. SEER-Medicare Health Outcomes Survey (SEER-MHOS), a linked dataset sponsored by the NCI and the Center for Medicare & Medicaid Services. Logistic regression analyses were conducted to examine HIE among Asians in the aggregate and subgroups of Asians for smoking and body mass index (BMI), using survey language and ethnic concentration as proxies for nativity. Results: Asians, in the aggregate, had comparable social backgrounds and had better health behaviors (i.e., lower smoking and BMI) than non-Hispanic Whites. When Asians were disaggregated, Hawaiians and Japanese had higher smoking and obesity rates than Chinese. A protective effect was observed among Asians in the aggregate living in an ethnic enclave with lower smoking prevalence and lower BMI. Chinese respondents opting to complete surveys in their native language or living in ethnic enclaves were less likely to be overweight, but no significant associations were found in relation to their smoking. Conclusions: Support for a healthy immigrant effect was largely consistent for Asians in the aggregate with respect to both language and ethnic concentration, but support was mixed among subgroups of Chinese patients. The presence of the HIE suggests that the health status and needs of recent Asian immigrants seeking oncologic care may be different than Asians who have been in the U.S. longer. These findings suggest a need for community-based efforts to encourage preservation of a healthier living style observed among first-generation immigrants.
The disproportionate burden of cancer associated with social behaviors in young women in the United States.
Authors: Johnson Caitlin Ruth , Liao Cheng-I , Chan Ava , Tian Chunqiao , Darcy Kathleen M. , Kapp Daniel Stuart , Chan John K
Published: June 2022

10575

Background: To evaluate the incidences and trends of social determinant risk factor-associated cancers in the United States from 2001 to 2018. Methods: Social determinant risk factor-associated cancers, as classified by the CDC, were included: obesity, alcohol, tobacco, physical inactivity, and human papillomavirus (HPV). Data was obtained from the United States Cancer Statistics program from 2001-2018. SEER*Stat 8.3.9.2 and Joinpoint regression program 4.9.0.0 were used to calculate incidences and trends of cancers per 100,000. The age-adjusted incidence (AAI) was adjusted by the US 2000 standard population. Results: Over the 17-year study period, a total of 28,175,859 cancers were identified. Of these, 51.4% developed in men and 48.6% in women. Over 65.8% were risk factor-associated cancers and 34.2% were unrelated to these factors. Of note, over 60.1% of risk factor-related cancers developed in women compared to 39.9% in men. Although the incidence of risk factor associated cancers did not significantly change at 413.2/100,000 in women, this incidence decreased by 1.15% annually ( P< 0.001). The age-specific incidences decreased in older (> 50 years) men and women. Of the younger (20-45 years) group, these risk factor-associated cancers increased from 91.5 to 97.3/100,000 with an annual increase of 0.4% ( P< 0.001) in younger women; there was no change for younger men on trend analyses over the study period. Conclusions: Over 65% of cancers in the US were associated with social determinants of health. There is a disproportionate burden of risk factor-associated cancers in women with increasing rates in younger age groups. Further research is needed to better understand the rationale of these important trends.
Patient-reported outcomes among males undergoing prostate cancer germline testing: Interim results from the Prostate Cancer Genetic Risk, Experience, and Support Study (PROGRESS) Registry.
Authors: Giri Veda N. , Hartman Rebecca L. , Gross Laura , Keith Scott W.
Published: June 2022

10595

Background: Indications for prostate cancer (PCA) germline testing (GT) have greatly expanded, necessitating thousands of men to seek genetic evaluation through traditional genetic counseling and alternate delivery approaches. Therefore, there is an important need for patient-reported outcomes among men undergoing genetic testing which has been understudied. PROGRESS (Prostate Cancer Genetic Risk, Experience, and Support Study) was therefore developed to garner men’s experience with PCA germline testing. Here we provide an interim update on recruitment and results from registry participants. Methods: PROGRESS is a patient-driven registry of clinical, genetic, and patient-experience information among men undergoing PCA genetic testing. Survey covers demographic information, PCA history, mode of genetic counseling, satisfaction, decisional conflict, intention to share genetic results with family and physicians, attitude towards genetic testing, knowledge of cancer genetics, medical literacy, and numeracy. Descriptive statistics summarized results with counts and percentages for categorical variables and mean and standard deviation for continuous variables. All analyses were performed with SAS 9.4 (Cary, NC). Results: Current enrollment is 217 participants. Among 140 men with complete demographics, 93.57% are White, 98.6% non-Hispanic/Latino, 85% with bachelor’s degree or higher. Among 143 respondents, 60% reported a diagnosis of PCA. Among 85 men who reported on Gleason score, 24.7% had Gleason > = 8. Regarding family history, 23.5% reported a 1st/2nd degree relative with PCA and 58.1% reported a 1st/2nd degree relative with any cancer. Among 150 men who reported genetic results, 40.7% had a genetic mutation, 18% reported having a VUS, and 10.7% reported not knowing their results. Among 185 men who reported on mode of genetic evaluation, 58.4% met with a genetics professional and 21.7% reported their doctor had discussed genetic testing. Satisfaction was high (n = 121) (highest score 30; mean score 27.92 + 2.73) and decisional conflict was low (n = 138) (mean score 26.07 + 10.18; range 16-80). Majority of 140 respondents discussed their results with their family (93.6%). Knowledge of cancer genetics was modest, with correct responses among 140 respondents of 50.1% + 28.1. Conclusions: Current participants of the PROGRESS Registry report high satisfaction with their genetic evaluation process. However, resources are needed to increase knowledge and understanding of genetic results. Greater engagement of African American males is critically needed to garner diverse perspectives and develop resources for men and their families applicable across populations. Target goal of the registry is 500 males; men can be referred to participate in the PROGRESS Registry at www.progressregistry.com .
TP53 pathogenic variants with low allele fraction in germline genetic testing.
Authors: Wu Yanqin , Fan Wenzhe , Xue Miao , Tang Yiyang , Peisu Suo , Yang Bo , Huang Tanxiao , Zhang Jing , Li Jiaping
Published: June 2022

10600

Background: Blood or saliva DNA generally considered to be representative of germline genome in genetic cancer risk assessment. However white blood cells from these samples may also include somatic origin DNA due to postzygotic variation or, most commonly, clonal hematopoiesis (CH). Low variant allele fraction (VAF) found in germline genetic testing suggest the possibility of somatic variant and may lead to misinterpretation of genetic risk. TP53, of which germline pathogenic variants are associated with Li-Fraumeni syndrome (LFS), is frequently mutated in CH. This analysis investigated characteristics of TP53 pathogenic variants with low VAF. Methods: We reviewed the prevalence and distribution of TP53 pathogenic variants(PVs) detected in 11,277 advanced cancer patients who underwent clinical testing with a clinical NGS pan-cancer panel. Potential somatic PVs were defined as variants with low VAF from 10% to 35%. The VAF were evaluated in matched tumor tissue samples if available. Results: TP53 pathogenic variants were detected in 36 (0.32%) patients from blood or saliva samples, VAF between 10% and 35% were identified in 8(22.22%) patients and 7 of them were performed NGS sequencing in matched tumor tissue samples. The average VAF of tissue samples were 9.31times lower than blood or saliva samples(21.69% vs 3.88%). Conclusions: TP53 pathogenic variants with low allele fraction in blood or saliva samples indicate the possibility of somatic variant, a reduced VAF in matched tumor tissue samples may contribute to confirmation for suspicion of somatic origin.
Questioning a Li-Fraumeni Syndrome diagnosis: Characterization of a commonly observed germline TP53 variant, p.Arg156His.
Authors: Nehoray Bita , Schwartz Alison , Hyman Sophie , Stokes Samantha , Cervantes Aleck , Amos Christopher , Gruber Stephen B. , Garber Judy Ellen
Published: June 2022

10612

Background: Germline pathogenic variants (PV) in the TP53 gene are associated with Li-Fraumeni syndrome (LFS). Increased use of multi-gene panel testing has identified TP53 variants suspected to have reduced penetrance, a departure from the significantly increased cancer risks expected with LFS, posing challenges in variant classification and clinical management. TP53 c.467G>A (p.Arg156His), R156H, is a variant with over 250 observations across multiple laboratories with prior discordant classification. R156H was recently downgraded by laboratories from likely pathogenic (VLP) to variant of uncertain significance (VUS). Characterization of R156H to clarify clinical significance has the potential to impact care for many. Methods: R156H carriers were identified through the Li-Fraumeni & TP53: Understanding & Progress (LiFT UP) study ( https://liftupstudy.org ) from 2019-2022. Clinical data were collected and reviewed for phenotypic characterization and to determine whether LFS Classic and/or Chompret criteria were met, and to assign Li-Fraumeni spectrum classification (Kratz et al.). Results: Proband/family characteristics are in the Table. Twenty R156H carriers were identified in 11 families. Seventeen carriers had a personal history of cancer; 8 had a LFS core cancer. All core cancers were breast except for an astrocytoma and a pediatric sarcoma. Two breast cancer cases also carried a BRCA2 PV. The average age at first cancer diagnosis was 40.5 years (range 6-71). No families met Classic LFS criteria. One proband met Chompret criteria due to breast cancer <31 years (who also carried a BRCA2 PV). Ten families were classified as attenuated LFS per Kratz et al. Conclusions: Most families in our case series did not meet LFS criteria, raising the question of appropriate clinical management and the willingness to de-escalate LFS surveillance. Our series supports the downgrade to VUS, but the presence of a few non-breast LFS core cancers warrants work to determine if R156H is a reduced penetrance PV. Recruitment of these families is ongoing through the LiFT UP study to perform segregation analyses and cancer risk estimations. This work may guide evaluation of other variants presenting similar challenges. [Table: see text]
Survival outcomes in metastatic HR-positive, HER2-negative invasive ductal carcinoma compared to invasive lobular carcinoma and mixed ductal/lobular treated with endocrine therapy in combination with CDK4/6 inhibitors, mTOR inhibitor, or PI3K inhibitor.
Authors: Mouabbi Jason A , Raghavendra Akshara Singareeka , Bassett Roland L. , Hassan Amy Aida , Tripathy Debu , Layman Rachel M.
Published: June 2022

1067

Background: The majority of invasive lobular breast cancers (ILC) are hormone receptor (HR)-positive, HER2-negative and are clinically treated similarly to HR+ HER2-negative invasive ductal cancers (IDC). However, ILC differs distinctly from IDC in its clinicopathologic characteristics and molecular alterations. ILC also differs in response to systemic therapy, with studies showing ILC as less sensitive to chemotherapy. It is currently unknown if patients with ILC or mixed ductal/lobular (MDL) histologies derive similar benefits as IDC from endocrine therapy (ET) in combination with cyclin-dependent kinase 4/6 inhibitors (CDK4/6is), mTOR inhibitor everolimus or PI3K inhibitor alpelisib. Methods: We retrospectively searched for patients treated at MD Anderson Cancer Center with a diagnosis of HR+, HER2-negative metastatic breast cancer (MBC) with ET in combination with CDK4/6is, everolimus or alpelisib. Patients were divided into 3 groups based on their histology: ILC, IDC and mixed. We obtained data on demographics, estrogen (ER) and progesterone (PR) receptor status, menopausal status, treatment duration and survival status. The Kaplan-Meier product-limit method was used to compare progression-free survival (PFS) and overall survival (OS) between the three different groups stratified by the treatment received. Results: We identified 2,971 patients (2,432 IDC [82%], 427 ILC [14%], 112 Mixed [4%]) with HR+ HER2-negative MBC treated with ET in combination with CDK4/6is, everolimus and/or alpelisib between 2010 and 2021. Median age was around 50 years in all groups. Around 80% of patients were white, 10% Hispanic and 5% black. Around 55% of patients were post-menopausal, 99% had ER+ and 88% PR+ tumors; 1,895 patients (81% IDC, 15% ILC, 4% mixed) received CDK4/6is, 1,027 (82% IDC, 14% ILC, 4% mixed) received everolimus and 49 (81% IDC, 19% ILC) received alpelisib. PFS and OS were not statistically different between the 3 groups (Table). Conclusions: HR+ HER2-negative MBC patients with IDC, ILC and MDL benefited from ET in combination with CDK4/6is, everolimus or alpelisib similarly with no significant differences in PFS and OS. [Table: see text]
Safety and clinical activity of MEDI5752, a PD-1/CTLA-4 bispecific checkpoint inhibitor, as monotherapy in patients (pts) with advanced renal cell carcinoma (RCC): Preliminary results from an FTIH trial.
Authors: Albiges Laurence , Medina Rodriguez Laura , Kim Sang-We , Im Seock-Ah , Carcereny Enric , Rha Sun Young , Tran Ben , Oliveira Julio , Maroto-Rey Pablo , Su Wu-Chou , Voskoboynik Mark , Rodriguez-Vida Alejo , Costa Luis , Ascierto Paolo Antonio , Insa Molla Maria Amelia , Wang Yi , Gainer Shelby D. , Subramaniam Deepa S , Voss Martin H
Published: June 2022

107

Background: MEDI5752 is a monovalent bispecific antibody targeting PD-1 and CTLA-4. A phase I, open-label study (NCT03530397) of MEDI5752 monotherapy 2.25–2500 mg IV Q3W showed encouraging antitumor activity in advanced solid tumors. Maximum tolerated dose was not reached; doses <1500 mg were better tolerated than doses ≥1500 mg. Here we present preliminary results in pts with advanced RCC in the escalation (ESC) and expansion (EXP) cohorts. Methods: Eligible pts were ≥18 yrs old (ECOG PS 0–1). In ESC and EXP, pts could be treatment-naïve (1L) or refractory. Eligible EXP pts had clear cell component (ccRCC), were immunotherapy-naïve (IO-naïve) and limited to ≤2 prior lines of therapy. Pts were treated until progression or unacceptable toxicity. Primary objectives were safety and tolerability (ESC), and antitumor activity by objective response per RECIST v1.1 (EXP). Results: Overall, 46 RCC pts were treated: 19 ESC, 27 EXP. In ESC, pts (all IO-naïve, 73.7% prior nephrectomy, 26.3% 1L, 89.5% clear cell histology) were treated across 3 dose levels: 750 mg (n=1), 2000 mg (n=16) and 2500 mg (n=2). Seven pts (36.8%) had objective responses (all PRs); 4 of these were 1L, including 1 each with papillary and sarcomatoid histology. In EXP, pts (all IO-naïve, 63.0% prior nephrectomy, 48.1% 1L [of whom 69.2% had IMDC intermediate/poor risk], 96.3% clear cell histology) received MEDI5752 1500 mg IV Q3W. Ten (38.5%) had objective responses (2 CRs, 8 PRs). In 1L EXP pts, 58.3% had objective responses (1 CR and 6 PRs); disease control rate (DCR) was 91.7% (Table). Grade 3/4 treatment-related adverse events (TRAEs) were seen in 68.4% of ESC and 74.1% of EXP pts. In EXP, treatment-emergent AEs (TEAEs), particularly hepatotoxicity, were the most common cause of treatment discontinuation (D/C). At a median duration of follow-up of 14.6 mo, median duration of response (DOR; including in those who discontinued MEDI5752 due to AEs), median PFS and OS were NR in 1L EXP pts. Conclusions: MEDI5752 monotherapy showed deep and durable antitumor activity in pts with advanced RCC, despite high rates of treatment D/C, particularly in the 1L setting. To better characterize the risk-benefit profile, MEDI5752 is now being explored at doses <1500 mg in 1L ccRCC expansion cohorts. Clinical trial information: NCT03530397. [Table: see text]
The safety, tolerability, and preliminary antitumor activity of sitravatinib plus tislelizumab in patients with locally recurrent or metastatic triple-negative breast cancer.
Authors: Fan Lei , Liu Xiyu , Jin Xi , Yang Yunsong , Chen Li , Hu Xin , Wang Zhonghua , Jiang Yizhou , Shao Zhimin
Published: June 2022

1070

Background: Anti-PD-1 antibody plus chemotherapy has been demonstrated promising anti-tumor activity in patients with locally recurrent or metastatic triple negative breast cancer (TNBC). However, this regime only limited to TNBC patients with PD-L1 positive. As antiangiogenic agents could enhance the response to immune checkpoint inhibitors, we conducted this phase 2 study to assess the efficacy and safety of novel chemotherapy-free regimen of sitravatinib (targets receptor TKI against TYRO3, AXL, MERTK and VEGF family of receptors) in combination with tislelizumab (anti-PD-1 antibody) in patients with locally recurrent or metastatic TNBC regardless of PD-L1 status. Methods: Patients with locally recurrent or metastatic TNBC were included and divided into two cohorts. Patients received 70 mg (cohort A) or 100 mg (cohort B) sitravatinib QD PO and 200 mg tislelizumab IV Q3W until disease progression or intolerable toxicity. The primary endpoints included overall response rate (ORR) (cohort A and B) and rate of grade ≥3 treatment-related adverse events (AEs) (cohort B). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), 1-year overall survival rate and safety/tolerability. In cohort A, the first statistical analysis would be performed when 12 patients were enrolled; if ≥1 of 12 patients were with confirmed response during the first stage, additional 9 patients would be enrolled to the second stage based on Simon's two-stage design. We would deem cohort A to be statistically superior to a historical control of 8% under the settings if > 3 of 21 patients responded (one-sided a = 0.1 and power of 80%). Patients’ recruitment in cohort B would begin after completing the recruitment in cohort A. Results: Herein we reported the preliminary results in cohort A. Four patients were with confirmed response during the first stage, and additional nine patients were enrolled to the second stage. A total of 21 patients with 0-3 lines of prior chemotherapy were included from April 2021 to September 2021. The median age was 51 (32-66) years and 20 (95%) patients had ECOG PS 0. At data cut off 13 Jan 2022, 19 patients were alive, 11 are still on treatment. The confirmed ORR was 38.1% (95% CI, 18.1%-61.6%) based on current 21 efficacy evaluable patients. DCR was 95.2% (95% CI, 76.2%-99.9%), and median PFS was 7.0 (95% CI, 3.7 - not reached) months. 4/21 (19%) of patients experienced grade 3 treatment-related AEs. Grade 3 AEs reported in ≥5% of patients were aspartate aminotransferase increased (9.5%) and palmar-plantar erythrodysaesthesia syndrome (9.5%). No patients experienced grade 4 AEs. Conclusions: Sitravatinib combined with tislelizumab demonstrated clinically meaningful anti-tumor activity and had a manageable safety profile. Clinical trial information: NCT04734262.
Apatinib combined with chemotherapy versus single chemotherapy in HER-2 negative advanced breast cancer: A randomized, controlled, open-label phase II study.
Authors: Chen Zhanhong , Wang Xiaojia , Huang Jian , Zheng Yabing , Shao Xiying , Cao Wenming , Chen Junqing , Ye Weiwu , Ping Huang , Li Guangliang , Lei Lei , Shi Lei , Huang Yuan , Zou Weibin , Wang Rong , Shen Xia-Bo , Lou Caijin
Published: June 2022

1072

Background: Apatinib is an oral, highly potent tyrosine-kinase inhibitor targeting VEGFR2. A series of clinical studies have shown that anti-angiogenic drugs combined with chemotherapy enable to improve the efficacy of HER2-negative advanced/metastatic breast cancer(MBC). Methods: Patients with HER2-negative MBC with less than two lines of systemic therapy were enrolled in this open-label, controlled, phase II trial. Patients with measurable disease were randomly assigned, in a 1:1 ratio, to receive oral apatinib (250 mg once daily) combined with chemotherapy(A+CT) or chemotherapy(CT) alone (the physician’s choice) until disease progression or intolerable toxicity. The primary end point was progression-free survival(PFS), which was assessed by investigator and was analyzed on an intention-to-treat basis. Results: Between August 2017 and January 2021, of the 80 patients who underwent randomization, 40 were assigned to receive apatinib plus chemotherapy(A+CT) and 40 were assigned to receive standard therapy(CT). As of January 2022, 10 patient had not undergone response evaluation or dropout, 70 patients(36 patients in A+CT, 34 patients in CT were finally included with PFS events and 72 patients were included in safety set. Median PFS was significantly longer in A+CT than in CT (182 days vs 63 days; P = 0.043);The median PFS of TNBC subgroup (11 in A+CT group, 14 in CT) was longer in the aptinib group than in CT group (167 days vs 63 days; P = 0.637);The median PFS of HR+ subgroup(25 in apatinib group, 20 in chemotherapy group) was longer in the aptinib group than in CT group (259 days vs 56 days; P = 0.054);The median PFS of patients with liver metastases(19 in apatinib group, 17 in chemotherapy group) was longer in the aptinib group than in the CT group (151 days vs 54 days; P = 0.191); The severe adverse reactions (grade 3/4) were neutropenia(22.2% vs 13.9%), hypertension(11.1% vs 0.0%), leukopenia(8.3% vs 8,3%), hypokalemia(8.3% vs 2.8%), anemia(5.6% vs 11.1%), ALT(2.8% vs 8.3%), AST(0.0% vs 5.6%) in the apatinib group and the CT, respectively. Proteinuria did not occur in both groups. Treatment delay or dose reduction owing to adverse event was 16.7% and 11.1%, respectively. Treatment discontinuation owing to adverse event was 23.5% and 8.8%, respectively. Conclusions: Apatinib combined with chemotherapy showed a significant improvements in PFS and a manageable safety profile in HER2 negative MBC.
Leveraging patient engagement to optimize a phase 3 clinical trial design, study participation and recruitment for women diagnosed with triple-negative breast cancer (TNBC).
Authors: Elmer Mary E. , Karantza Vassiliki , Vichnin Michelle , Aktan Gursel , Powell Valerie J.
Published: June 2022

1073

Background: The importance of Patient Engagement (PE) on clinical trial design is well established. PE in oncology medicines development can serve many purposes including obtaining input on trial design/procedures, identifying recruitment challenges and barriers to participation, and understanding retention strategies. Designing a clinical trial with procedures that have been confirmed as acceptable to participants is also likely to improve patient adherence to treatments. Triple-Negative Breast Cancer (TNBC) is a virulent subtype associated with early onset and increased risk of early recurrence and accounts for 15% to 20% of breast cancers. In addition, a higher risk exists in premenopausal and Black women. Chemotherapy is the mainstay of curative therapy recommended by guidelines. The aim was to obtain insights from patients to inform key aspects of a clinical study design including choice of chemotherapy regimen, study feasibility and recruitment strategies. Methods: Two groups of US women (N = 20) ages 28-54; (race 55% Caucasian, 30% African American, 10% Hispanic, 5% Native American) diagnosed with Stage IIb-IV TNBC and in active or completed treatment were recruited to participate in two in person IRB approved sessions. Trained 3rd party facilitators used qualitative methods to elicit patient feedback. Preliminary research included interviews with key stakeholders, including TNBC advocacy group leaders and a review of online patient communities. Patients reviewed a study design with an investigational agent every 3 weeks plus chemotherapy (nab-paclitaxel; paclitaxel) or placebo plus chemotherapy. Results: Patient reaction to the choice of taxane chemotherapy in the standard of care arm was neutral to negative. Approximately 50% of the patients identified taxane treatment as a barrier to participation. All patients requested flexibility in treatment choices, clear information about required tests and visits, and more diversity in recruitment materials. Black and Hispanic women impacted by TNBC did not feel they had equal access to clinical trials due to race, rural location, and other factors. Patient insights reinforced the decision to add another standard-of-care option (carboplatin plus gemcitabine) as a treatment arm to the trial design and was confirmed with investigators. Patient feedback was incorporated into the trial along with additional strategies to support recruitment of diverse patients in the clinical study. Conclusions: On November 13, 2020 the FDA approved this regimen in the label for pembrolizumab in combination with chemotherapy, as the 1st line treatment in women with locally recurrent or metastatic TNBC. Both patients and physicians perceived that a flexible chemotherapy backbone was a benefit.
Genomic landscape and peripheral blood biomarkers of advanced triple-negative breast cancer treated with immune checkpoint blockade: An exploratory analysis of the TQB2450-Ib-07 trial.
Authors: Han Yiqun , Wang Jiayu , Sun Tao , Ouyang Quchang , Li Jianwen , Xu Binghe
Published: June 2022

1080

Background: Immune checkpoint inhibitor (ICI) has emerged as a novel therapeutic option for advanced triple-negative breast cancer (aTNBC). However, no robust biomarker indicative of clinical outcomes has been identified. Herein, we portraited the genomic landscape and explored the biomarkers for patients with aTNBC receiving ICI-based therapy. Methods: This is a prospective, multicenter, phase 1b clinical trial (NCT03855358) to assess the efficacy and safety profiles of TQB2450, a humanized monoclonal PD-L1 antibody, plus anlotinib in pretreated TNBC. Eligible patients undergo liquid biopsy at baseline and the timepoint of disease progression. NGS-based assay was performed based on circulating tumor DNA (ctDNA) in the bloodstream. Meanwhile, results of laboratory blood tests were dynamically collected and blood markers, including neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), and platelet to lymphocyte ratio (PLR), were successively evaluated. The primary endpoints were progression-free survival (PFS) and clinical efficacy assigned via guidelines for response criteria for use in trials testing immunotherapies (iRECIST). Results: Between May 29, 2019, and December 31, 2020, 34 patients with aTNBC were enrolled. Gene alternations primarily comprised mutation, amplification, or deletion of TP53, MLL3, DNMT3A, PI3KCA, EP300, PTEN, LRP1B, MDM2, and NCOR1. The median maximum somatic allele frequency (MSAF) was 9.97% significantly indicative of PFS, which was 3.58 months for the MSAF-high group and 13.34 months for the MSAF-low group (P = 3e-04), respectively. Else, a strong association was also signified between MSAF and tumor shrinkage (CR/PR vs. SD/PD, P = 0.012). For blood tumor mutation burden (bTMB), the median was 6.72 muts/Mb, which the bTMB-low group was suggestive of a better PFS (11.09 months vs. 5.52 months, P = 0.007), yet no obvious association existing in terms of clinical response. Dynamic analysis revealed that a decline in MSAF was significantly associated with a better PFS (7.10 months vs. 2.74 months, P = 0.018), while no correlations were detected between bTMB and PFS. Based on NLR week 2/0 of 0.95, PFS was significantly worse in the NLR-low group (11.0 months vs. 3.5 months, P = 0.006) and likely distinguished the clinical response (CR/PR vs. SD vs. PD, P = 0.049; non-PD vs. PD, P = 0.022). Moreover, NLR week 2/0 could notably foretell the clinical response for patients with aTNBC with the AUC of 0.82 (0.61-1.00). No comparable utilities were identified regarding LMR and PLR. Conclusions: For aTNBC treated with ICI, MSAF tended to be a robust indicator for both PFS and clinical response. NLR week 2/0 presented a favorable profile indicative of PFS as well as a strong predictor for clinical responsiveness of patients with aTNBC receiving immune checkpoint blockade. Clinical trial information: NCT03855358.
Survival and prognostic factors in oligometastatic breast cancer.
Authors: Van Ommen - Nijhof Annemiek , Steenbruggen Tessa Gerjanne , Capel Laura C. , Vergouwen Michel J.P. , Vrancken Peeters Marie-Jeanne T.F.D , Wiersma Terry G. , Sonke Gabe S.
Published: June 2022

1089

Background: Clinical guidelines for the treatment of oligometastatic breast cancer (OMBC) propagate multimodality treatment including polychemotherapy and ablative local therapy for all detected disease. The aim of this aggressive approach is prolonged disease remission, or even cure, but randomized data to support this strategy lack and long-term outcomes are not well known. We report prognostic factors, and event-free survival (EFS) and overall survival (OS) in a real world, single center cohort of patients with OMBC with long-term follow-up. Methods: Patients with breast cancer and 1-3 distant metastatic lesions who underwent treatment in the Netherlands Cancer Institute were identified via text mining of medical files. We collected patient, tumor and treatment characteristics as well as recurrence and survival data from the medical records. The Kaplan-Meier method was used to calculate EFS and OS estimates, and Cox regression analyses to assess potential prognostic factors. Results: The cohort included 239 patients (of whom two males), diagnosed between 1997 and 2020. Median follow-up was 75.0 months. Fifty-one percent had hormone receptor (HR)-positive/ human epidermal growth factor receptor 2 (HER2)-negative disease, 20.1% had HER2-positive disease, and 19.2% had triple negative (TN) disease. Median age at OMBC diagnosis was 49.0 years and 47.3% of patients had synchronous disease (metastases ≤6 months of primary diagnosis). Most patients (81.2%) received chemotherapy and local therapy (surgery, radiotherapy and/or radiofrequency ablation) of all metastatic lesions (83.7%). Of 239 patients, 134 experienced disease recurrence with a median EFS of 40.0 months (95% confidence interval (CI): 28.6-51.4); 97/239 died and median OS was 93.0 months (95% CI 74.5-111.5). The table shows factors associated with favorable OS in multivariable analysis. Cox regression analysis for EFS showed similar results. Conclusions: In this large real world cohort of OMBC patients, EFS and OS compare favorably to survival in the general MBC population. HR-positive and/or HER2-positive subtypes, synchronous disease or long DFI, favorable response to first-line systemic therapy and local therapy of all distant lesions are independently associated with better survival. Future studies should be directed at optimizing patient selection and therapy choices in this population with the potential for cure. [Table: see text]
Quantitative proteomics landscape and association with BASP1 and breast cancer metastasis.
Authors: Kaur Jaspreet , Austdal Marie , Jung Sung Yun , Janssen Emiel , Søiland Håvard , Aneja Ritu
Published: June 2022

1090

Background: Tumor recurrence and metastatic progression remain the leading cause for breast cancer related mortalities. The study aimed to identify differences in proteomics landscape in serum between (i) healthy controls and breast cancer patients, (ii) baseline samples at time of diagnosis from patients that later developed metastases versus those that did not and, (iii) baseline samples presented after completed treatment versus the samples collected before patients developed metastasis. Methods: We performed mass spectrometery-based proteome profiling of 100 serum samples from 51 breast cancer patients and 27 healthy donors. Of the 51-breast cancer patients, 29 patients did not metastasize, and 22 patients had a metastatic recurrence. Each of the 22 breast cancer patients with metastasis had 2 samples-one collected within a year of diagnosis and second one collected within a year before the patient developed metastases. Intensity-based absolute quantification (iBAQ) method was employed to convert recovered peptide information to quantificational gene protein product and then normalized to final quantificational value using an in-housed software. Protein values were normalized using z-score before differential expression analyses. FDR < 0.1 and a p-value < 0.05 was used as the cutoff to identify differentially expressed proteins. Results: We identified 1177 proteins in total from 100 serum samples of healthy women and breast cancer patients. PCA analysis revealed a complete separation of the breast cancer and healthy control samples. However, we found overlapping but distinct groups of metastatic and non-metastatic samples. We found 179 proteins to be differentially expressed between normal healthy control samples and baseline breast cancer samples irrespective of their metastatic status. Upon comparing baseline breast cancer samples that metastasized with breast cancer samples that did not metastasize, we found BASP1 as the top-ranked gene that was significantly upregulated in metastatic samples. We did not find any significant differences between paired baseline samples collected at diagnosis and pre-metastatic samples collected before the patient developed metastasis. Conclusions: Our results show distinct proteomic profiles exist between breast cancer and normal healthy control samples. Further studies are required to confirm if serum BASP1 can be used as a putative biomarker for predicting metastatic risk in breast cancer patients.
A phase IB/II study of nivolumab in combination with eribulin in HER2-negative metastatic breast cancer (KCSG BR18-16).
Authors: Kim Se Hyun , Suh Koung Jin , Im Seock-Ah , Lee Kyung-Hun , Kim Min Hwan , Sohn Joohyuk , Park Yeon Hee , Kim Ji-Yeon , Jeong Jae Ho , Lee Kyoung Eun , Choi In Sil , Park Kyong Hwa , Kim Hee Jun , Cho Eun Kyung , Park So Yeon , Kim Milim , Kim Jee Hyun
Published: June 2022

1098

Background: Combining immune checkpoint inhibitors with chemotherapy has become a promising therapeutic strategy in metastatic breast cancer. Eribulin is a potent microtubule inhibitor and modulates the immune microenvironment of tumor cells. Therefore, combining eribulin to nivolumab may synergize antitumor efficacy in metastatic breast cancer. Methods: Adult patients with histologically confirmed recurrent/metastatic HER2- breast cancer were enrolled prospectively from 10 academic hospitals in Korea (ClinicalTrials.gov Identifier: NCT04061863). Key eligibility criteria included prior treatment with taxanes and/or anthracyclines, ≥1 measurable disease, and ≤2 prior cytotoxic chemotherapies in the metastatic setting. Patients received nivolumab 200 mg intravenously (IV) on day 1 plus eribulin 1.4 mg/m2 IV on day 1 and 8 of every 3 weeks until disease progression or intolerable toxicity. The dose level was determined from safety profile of three patients in run-in phase. The primary endpoint was investigator-assessed progression-free survival (PFS) rate at 6 months. Secondary endpoints included investigator-assessed objective response rate (ORR) per RECIST v1.1, disease control rate (DCR), overall survival (OS), and toxicity profile of the combination treatment. The association between PD-L1 expression by SP142 Ab and efficacy was analyzed. Results: From August 2019 to June 2021, 90 patients (HR+HER2- 45 pts/TNBC 45 pts), with a median age of 51 (range 31–71), were enrolled in the study. With a median study follow-up time of 16.3 months, 68 (75.6%) patients experienced progressive disease. PFS rate at 6-months was 49.6% and 24.1% in patients with HR+HER2- and TNBC group, respectively. Median PFS was 5.6 months (95% CI: 4.3-6.8) and 3.0 months (95% CI: 1.3-4.7) for HR+HER2- and TNBC group, respectively. ORRs were 53.3% (CR:0, PR: 24) for HR+HER2- and 21.8% (CR1, PR: 12) for TNBC. Patients with PD-L1+ tumors (PD-L1 expression ≥ 1% on TC or IC) had similar ORR compared to PD-L1- tumors (ORR 50% vs. 53.8% in HR+HER2-, 30.8% vs. 29.0% in TNBC). The most common grade 3/4 adverse event was neutropenia (15/90, 16.7%), and the most common immune-related adverse events were grade 1/2 hypothyroidism (19/90, 21.1%) and grade 1/2 pruritus (16/90, 17.8%). Five patients had discontinued study treatment due to immune-related adverse events (3 pneumonitis, 1 hepatitis, 1 skin rash). Conclusions: In this parallel phase II clinical trial, the addition of nivolumab to eribulin showed promising efficacy and tolerable safety profile in previously treated HER2- MBC. Further survival and exploratory analyses to find predictive markers will be followed. Clinical trial information: NCT04061863. [Table: see text]
The parent penalty: Parental leave and return to work in trainees and early-career faculty in oncology.
Authors: Malapati Sindhu Janarthanam , Singh Sunny R K , Idossa Dame , Jordan Bruno Ximena , Chino Fumiko , Patel Monica Arun , Wei Zihan , Duma Narjust
Published: June 2022

11005

Background: Prime childbearing years occur during medical training and early career, leaving physicians with tough choices between family planning and career growth. Restrictive parental leave (PL) policies can affect physician well-being and limit decisions about reproduction. We evaluated Medical and Radiation Oncology trainees and early career faculty to assess policies and practices regarding PL and return to work. Methods: An anonymous 48 question cross-sectional survey developed by researchers with expertise in gender equity was distributed via email and social media channels between May and June 2021 to oncology trainees and physicians within 5 years of terminal training. Descriptive statistics were used to compare study groups. Results: 255 physicians completed the survey- 54% female, 65% Medical Oncology and 35% Radiation Oncology, 71% trainees and 29% early career faculty. 46% (117) had no formal PL policy during training. PL impacted selection of first job for 37% (94) participants. Of all responders, 114 used PL, either in early career (18%), as a trainee (69%) or both (13%). Duration of PL during training was ≤4 weeks in 37%, 4-6 weeks in 19%, 6-8 weeks in 12% and ≥8 weeks in 24%. 27% of those who took PL as a trainee had to extend training to allow for this. Only 27%(31) of those who took PL had resources available at workplace to assist with transitioning back to work, primarily from informal mentoring by faculty/colleagues (65%, 20). Other important findings are summarized in the Table. Conclusions: In this study evaluating parental leave in oncology trainees and early faculty, almost half of the participants had no formal parental leave policy during training and majority of those who took parental leave during training had parental leave only for 6 weeks or less. Most participants experienced a parental leave penalty: guilt when seeking help and feeling overwhelmed at return to work. Policies and practices around parental leave need to be restructured to meet the needs of the evolving oncology workforce. [Table: see text]