bluuebunny/crossref_metadata_2025_split huggingface dataset:
The association of HER2 low expression with the efficacy of CDK4/6 inhibitor in hormone receptor positive HER2 negative metastatic breast cancer.
Authors: Bao Kelvin K H , Sutanto Leone , Tse Shirley S W , Cheung Ka Man , Chan Jeffrey C H 
Published: June 2021

1052 Background: Markers for the efficacy of CDK4/6 inhibitor in estrogen receptor (ER) positive, HER2 negative advanced breast cancer are limited. The bidirectional crosstalks that exist between ER and HER2 pathways contribute to endocrine resistance. We investigated the association between low levels of HER2 expression and the clinical outcome of patients with ER+ HER2- metastatic breast cancer (MBC) treated with CDK4/6 inhibitors. Methods: We identified consecutive patients with ER+ HER2- MBC who received CDK4/6 inhibitor plus either letrozole or fulvestrant between Mar 2017 - Jun 2020 from an institutional cancer registry. HER2-low expression was defined as IHC score 1+, or 2+ with a negative ISH. Progression-free survival (PFS) was defined as the time from the initiation of CDK4/6 inhibitor to the date of radiological or clinical progression, or death. The relationship between HER2 expression levels and PFS was evaluated using log-rank test and multivariable Cox regression modelling. Results: 106 women with MBC were eligible for analysis. Median age at treatment was 58 (23.0-91.4). The majority received palbociclib (84%) while the rest received ribociclib. CDK4/6 inhibitor was used as first-line treatment in 50.9% of cases. Most tumors were of ductal histology (83%) and progesterone receptor (PgR) positive (84.9%), and 22.6% of the patients had bone-only disease. 77.3% of cases were considered HER2-low expressing. HER2-low expression was associated with a significantly shorter PFS compared with HER2 IHC 0 counterpart (median, 8.9 vs 18.8 months, p= 0.014). In multivariate analysis, HER-2 low expression remained significantly associated with an inferior PFS (HR 1.96, 95%CI 1.03-3.75, p= 0.041) after adjusting for the line of treatment, PgR status and disease extent (bone only vs extra-osseous disease). Conclusions: In patients with ER+ HER2- MBC treated with CDK4/6 inhibitors, HER2-low expression was associated with an inferior PFS, and may serve as a potential marker candidate for CDK4/6 inhibitor efficacy. As novel anti-HER2 antibody-drug conjugates demonstrated efficacy in HER2-low expressing MBC, coupled with the emerging evidence for the combination of CDK4/6 inhibitors with anti-HER2 agents, this HER2-low expression subgroup warrants prospective evaluations in future trials.
Identifying individuals with primary central nervous system tumors at risk for hereditary cancer syndromes using the Utah Population Database.
Authors: Whipple Nicholas Shawn , Kohlmann Wendy , Cheshier Samuel , Yu Zhe , Curtin Karen , Schiffman Joshua David 
Published: June 2021

10532 Background: CNS tumors are the most common solid tumors and the deadliest cancers in children. Approximately 10% of children with a CNS tumor harbor a hereditary cancer syndrome (HCS), but many will not be tested for a HCS. The Utah Population Database (UPDB) contains comprehensive cancer registry data for Utah families and can determine multigenerational cancer pedigrees across an archive of 5.8 million individuals. Early identification of HCSs results in improved cancer surveillance and outcomes, reducing the impact of CNS tumors in children. We hypothesize that the UPDB can identify children and families with HCSs not previously identified. Methods: We queried the UPDB for individuals ages 0-39 diagnosed with a primary CNS tumor (malignant and benign) between 1966-2017 and generated cancer pedigrees of 3 generations or more for probands, extending to at least third-degree relatives. Specialized software calculated a familial standardized incidence ratio (FSIR) to determine families with excess clustering of CNS tumors. Clinical cancer genetics experts reviewed pedigrees to confirm patterns of HCS. Results: We identified 4,634 CNS tumors in 4,550 individuals, of whom 2,233 (49%) reside in high-quality pedigrees containing ≥2 grandparents, at least 1 from both maternal and paternal sides. To identify families with excess clustering of CNS tumors, we selected pedigrees with an FSIR P< 0.05 and ≥2 affected patients, resulting in 161 high-risk families with a mean of 170 (median 96) relatives per pedigree of 3-6 generations. Among these 161 families, there were 2,017 unique relatives (first-third degree) of CNS probands with 2,355 tumors (any site), for a per pedigree average of 14.7 tumors in 12.5 relatives. Review of the 10 highest risk pedigrees indicated that 4 meet HCS criteria, including Li-Fraumeni (n = 2), von Hippel-Lindau (n = 1), and rhabdoid tumor predisposition (n = 1). Conclusions: The UPDB can produce multigenerational cancer pedigrees that identify individuals and families at risk of harboring a HCS who warrant germline testing. These findings should encourage clinicians to perform thorough family history screening and to always consider workup for associated HCSs.
An ultrasensitive method for noninvasive pan-cancer early detection based on targeted methylation sequencing of cell-free DNA.
Authors: Han Tiancheng , Hong Yuanyuan , Zhihua Pei , Xiaofeng Song , Yu Jianing , Chen Geng , Chen Weizhi , He Ji 
Published: June 2021

10544 Background: Screening the biomarkers from the cell-free DNA (cfDNA) of peripheral blood is a non-invasive and promising method for cancer diagnosis. Among diverse types of biomarkers, epigenetic biomarkers have been reported to be one of the most promising ones. Epigenetic modifications are widespread on the human genome and generally have strong signals due to the similar methylation patterns shared by adjacent CpG sites. Although some epigenetic diagnostic methods have been developed based on cfDNAs, few of them could be applied to pan-cancer and their sensitivities are barely satisfactory for early cancer detection. Methods: Targeted methylation sequencing was performed using our in-house-designed panel targeting regions with abundant cancer-specific methylation CpGs. The cfDNA samples from 80 healthy individuals and 549 cancer patients of 14 cancer types were separately sequenced. The dataset was randomly split into one discovery dataset and one validation dataset. Moreover, cfDNA samples from four cancer patients were diluted with the healthy cfDNAs to generate 12 in vitro simulated samples with low circulating tumor DNA (ctDNA) fraction. Additionally, DNAs extracted from 130 unmatched tumor formalin fixation and paraffin embedding (FFPE) samples of 10 cancer types were sequenced to screen the diagnostic biomarkers. Adjacent CpG sites were first merged into methylation-correlated blocks (MCB) according to their correlations of methylation levels in tumor DNAs. The MCBs with higher methylation levels in tumor DNAs than that of healthy cfDNAs (from the discovery dataset) were defined as our hypermethylation biomarkers. For each cfDNA sample, a hypermethylation score (HM-score) was computed to measure the overall methylation level difference of selected biomarkers. The performance of our method was evaluated with the real-world dataset, while the limit of detection was estimated using the simulated low-ctDNA samples. Results: Our model based on 37 hypermethylation MCB biomarkers achieved an area under the curve (AUC) of 0.89 and 0.86 in the real-world pan-cancer discovery and validation cfDNA datasets, respectively. Furthermore, the overall specificity and sensitivity are 100% and 76.19% in the discovery dataset, and 96.67% and 72.86% in the validation dataset. In the validation dataset, 28/40 (70%) of early-stage colorectal cancer patients and 10/20 (50%) of non-small-cell lung cancer patients were successfully diagnosed. Additionally, all the simulated samples with theoretical ctDNA factions over 0.5% were predicted as diseased, demonstrating the ability of our method to detect tumor signals at early stages. Conclusions: Our cfDNA-based epigenetic method outperforms currently available methods in various cancer types, and is promising to be applied to early-stage cancer detection and samples with low ctDNA fractions.
Contribution of family history of melanoma to associated risk factors: Analysis of an Internet-based risk assessment tool.
Authors: O'Keefe Ryan M , LaRiviere Michael Joseph , Vachani Carolyn , Hampshire Margaret K. , Bach Christina , Arnold-Korzeniowski Karen , Healy Marisa , Metz James M. , Hill-Kayser Christine E. 
Published: June 2021

10546 Background: Risk factors for melanoma (ML) include UV exposure, sunburns, multiple nevi, and fair skin. Smoking and alcohol use may also play a role. Demographics associated with increased UV exposure include male gender, white race, age 18-29, and high-income. Those with family history (FH) of ML have increased risk of developing ML themselves yet are often unaware or do not engage in preventive behaviors. We sought to understand the association between FH of ML and other personal risk factors for cancer. Methods: Since 2009, voluntary participants could receive personalized information regarding their cancer risk via the OncoLink.org Reduce My Risk tool. Survey data was collected on demographics, FH, risk-factors, and risk-associated behaviors. Use of data was IRB approved. Differences between respondents with v. without FH of ML were analyzed using chi-square test and adjusted via logistic regression. Results: 25255 responses were analyzed; 1928 (7.6%) had FH of ML. Of these, median age was 26 (range 18-75), 73.1% were female, 88.6% from North America, 91.4% White, 78.2% had at least some college, and 62.0% household income > $45,000. Comparing those with FH of ML to those without, no significant differences were observed in education, income, or home setting. Those with a FH of ML were less likely to be “light” smokers ( < 1 pack per day) but were more likely to be both “light” drinkers and “heavy” drinkers (Table). There were no significant differences in BMI or exercise habits. Those with FH of ML were more likely to sunbathe, to have had “blistering” sunburns, have 50+ moles, show signs of sun damage on their skin, and have dysplastic nevi (Table). There were no differences in use of indoor tanning beds (Table). Conclusions: Those with a FH of ML were more likely to sunbathe and to report skin damage and history of blistering sunburns; they were more likely to use tanning beds, though not statistically significant. These behaviors are modifiable and may suggest parental influence on sun-protective behaviors. Those with FH also reported increased non-modifiable risks. Future work should continue to explore targeted intervention for those with a FH of ML to educate on risk and promote sun-protective behaviors.[Table: see text]
Risk-reducing salpingo-oophorectomy and breast cancer incidence among BRCA-mutation carriers.
Authors: Perri Tamar , Naor-Ravel Shani , Eliassi-Revivo Perry , Lifshitz Dror , Friedman Eitan , Korach Jacob 
Published: June 2021

10548 Background: Uncertainty exists with regard to the role of bilateral salpingo-oophorectomy in altering the risk of breast cancer in BRCA-mutation carriers. Methods: Included were 1645 healthy Jewish Israeli BRCA1/2 -mutation carriers from a single center without prophylactic mastectomy. Carriers with and without risk-reducing bilateral salpingo-oophorectomy (RRBSO) were matched according to BRCA-mutation type (BRCA1 vs. BRCA2) and year of birth (±1 year). Hormonal and reproductive variables were compared and incidence of breast cancer recorded. Association between RRBSO and breast cancer was studied. Results: Seventy-seven and 50 matched-pairs had BRCA1 and BRCA2 mutation respectively. Fifty-two carriers had breast cancer, 21 in RRBSO-group and 31 in no- RRBSO group, with no statistically significant difference. When analysing each mutation group separately, stratified by age at surgery, no association between RRBSO and breast cancer incidence was found among BRCA1-mutation carriers. However, in BRCA2 mutation carriers, RRBSO was associated with a statistically significant decreased overall incidence of breast cancer, HR = 0.2 (confidence interval 0.44-0.913, p = 0.038). Breast cancer incidence was lower after 5, 10,15 and 20 years in BRCA2-mutation carriers with RRBSO compared to no-RRBSO. Age at menarche, age at surgery, parity and oral contraceptive use were not significant risk factors for breast cancer. Hormone replacement therapy was used by 62 mutation carriers, 52 in the RRBSO group and 10 in the no-RRBSO group, and its use did not alter breast cancer risk (p = 0.463). Conclusions: According to our findings, RRBSO is associated with a reduced risk of breast cancer only in BRCA2 mutation carriers, regardless of HRT use.
Overall survival in patients with breast cancer treated with a CDK 4/6 inhibitor plus fulvestrant: A U.S. Food and Drug Administration pooled analysis.
Authors: Gao Jennifer J , Cheng Joyce , Prowell Tatiana Michelle , Bloomquist Erik , Tang Shenghui , Wedam Suparna B. , Royce Melanie E , Krol Danielle , Osgood Christy , Ison Gwynn , Sridhara Rajeshwari , Pazdur Richard , Beaver Julia A. , Amiri-Kordestani Laleh 
Published: June 2021

1055 JJG, JC, TMP contributed equally. JAB, LAK contributed equally. Background: Cyclin dependent kinase 4/6 inhibitors (CDKIs) are oral targeted agents approved for use in combination with endocrine therapy as first or secondline treatment of hormone-receptor positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. We previously reported the pooled analyses of progression-free survival of patients in certain clinicopathologic subgroups, and results showed a consistent benefit from the addition of a CDKI to endocrine therapy. Here, we report the pooled overall survival (OS) results in patients treated with a CDKI plus fulvestrant. Methods: We pooled individual patient data (n=1948) from three phase III randomized breast cancer trials of a CDKI plus fulvestrant submitted to the FDA in support of marketing applications. All analyzed patients received at least one dose of a CDKI or placebo, plus fulvestrant. The median OS was estimated using Kaplan-Meier (KM) methods, and hazard ratios (HR) with corresponding 95% confidence intervals (CIs) were estimated using Cox regression models. Results: Results of OS analyses, including all pooled patients, patients treated in the first-line setting, and patients treated in the second line and later settings, are summarized in the table below. Additional subgroup analyses of OS by progesterone receptor status, site of metastases, breast cancer histology, ECOG performance status, race, and de novo metastatic presentation all favored adding a CDKI to fulvestrant. In patients age < 40, the estimated OS HR favored fulvestrant alone, but this subgroup had a small sample size (n=89), so this result must be interpreted with caution. All results are considered exploratory and hypothesis-generating. Conclusions: Addition of CDKIs to fulvestrant appears to confer a consistent survival benefit across all pooled patients and within most clinicopathological subgroups of interest.[Table: see text]
Sociodemographics, lifestyle determinants, and viral infections in patients with head and neck cancer undergoing radiotherapy in Taiwan: A prospective cohort study.
Authors: Ma Kevin Sheng-Kai , Tan Jasmine , Velarde Lopez Angel Alfonso 
Published: June 2021

10553 Background: Human papillomavirus (HPV) screening has been implemented to monitor both cervical cancer and head and neck cancer. In this prospective cohort study, we determined sociodemographic, behavioral, and infectious etiology for head and neck squamous cell carcinoma (HNSCC) in Taiwan using data collected from an anonymous sexually transmitted infections screening program. Methods: An anonymous sexually transmitted infections screening program was conducted at a medical center during 2016, in which sociodemographic characteristics including gender, age, marital status, education level, and occupation; medical history regarding underlying comorbidities and history of receiving HPV and other vaccines; lifestyle determinants including betel quid chewing, drug using, and sexual behaviors, were inquired. Blood, anal swab, and penile swab samples were collected to determine viral infections using polymerase chain reaction (PCR). With PCR, 37 HPV genotypes were detected. Regular follow-ups were made for patients enrolled in the screening program until end of 2020, during which all suspected malignancies were recorded upon referrals to oncologists. From this prospective cohort, odds ratios (ORs) of HNSCC for sociodemographic, lifestyle, and infectious variables were derived with logistic regression (R version 4.0.1). P < 0.05 was considered statistically significant. Results: A total of 376 patients were enrolled. Most patients were men (n = 372), with a median age of 27 years. There were 124 (32.98%) HPV-positive patients and 78 (20.74%) HIV-positive patients. Among HPV-positive patients, 20 (25.64%) were of high-risk genotypes. During the follow-up, 44 patients developed HNSCC and all received radiotherapy. Multivariate analysis revealed that patients who were single (OR = 1.43, 95% CI = 1.12-1.83, P = 0.01) or widowed (OR = 2.47, 95% CI = 1.88-3.25, P < 0.001) had higher risk of HNSCC than patients who were married. Patients aged 51-60 (OR = 2.93, 95% CI = 2.10-4.09, P < 0.001) and over 60 (OR = 1.89, 95% CI = 1.45-2.47, P < 0.001) presented higher risks of HNSCC, compared with those aged below 20. Patients addicted to betel quid chewing had high HNSCC risk (OR = 1.29, 95% CI = 1.11 – 1.50, P < 0.001). However, patients with HPV infections did not present with higher HNSCC risks (OR = 0.925, 95% CI = 0.852 – 1.003, P = 0.058). Conclusions: In this prospective cohort study, the elderly, unmarried patients, and patients addicted to betel quid chewing, presented with high HNSCC incidence. On the contrary, the association between HPV infection and HNSCC was insignificant. As both betel nut-chewing and HPV infection could be prevented, we advocate for comprehensive screening and patient education for HNSCC prevention.
One-stop-shop for cancer screening: A model for the future.
Authors: Bernstein Ezra , Shapira Shiran , Lev-Ari Shahar , Leshno Ari , Sommer Udi A. , Galazan Lior , Al-Shamsi Humaid O. , Wolf Ido , Shaked Meital , Hay Levy Mori , Sror Miri , Moshkowitz Menachem , Segal Ori A. , Gur Eyal , Neugut Alfred I. , Arber Nadir 
Published: June 2021

10554 Background: Cancer is the second leading cause of death globally. Early detection will often greatly reduce mortality for many cancers, increase treatment effectiveness, and improve the quality of life for cancer patients, and, by implementing evidence-based prevention strategies, 30–50% of cancers can be prevented. Screening for different cancer types separately is inefficient. A solution is the Integrated Cancer Prevention Center (ICPC), a program with specialists in each discipline who test for multiple cancers during one visit. Methods: This is a prospective cohort study of 17,104 self-referred, asymptomatic patients who visited the Integrative Cancer Prevention Center (ICPC) between January 1, 2006, and December 31, 2019. Clinical, laboratory, and epidemiological data were recorded by multiple specialists. Patients were given follow-up recommendations and diagnoses when appropriate. The primary measure was the detection and staging of new malignant lesions. Secondary measures included cost-benefit and mortality benefit. Results: We screened 8618 men and 8486 women with an average age of 47.11 ± 11.71 years. Of 259 cancers detected through the ICPC, 49 (18.9%) were stage 0, 115 (44.4%) were stage I, 31 (12%) were stage II, 25 (9.7%) were stage III, and 32 (12.4%) were stage IV. Seventeen cancers were missed, only six of which were within the scope of the ICPC, and 189 cancers developed > one year after the last visit to the ICPC. Compared to the stage of detection for cancers in the US, all cancers except for colon were detected at an earlier stage at the ICPC. Lung was the most significant with 86.7% of cancers detected at stage 0, I, or II at the ICPC compared to only 49.3% caught at those stages in the US. Conclusions: This is a proof of concept for a one-stop-shop approach to asymptomatic cancer screening in a multidisciplinary outpatient clinic. It offers evidence that this screening framework can and should be replicated in other healthcare settings and on a national policy level as it saves lives and money. The encouraging results presented here should further the conversation about the utility of screening and add momentum to the movement for increased screening.[Table: see text]
A single-arm phase II trial of palbociclib in combination with tamoxifen as first-line therapy for metastatic hormone receptor-positive breast cancer.
Authors: Danciu Oana Cristina , Hoskins Kent , Truica Cristina I. , Blaes Anne Hudson , Tamkus Deimante , Rana Jatin , Tandra Pavankumar , Green Lauren , Yu Menggang , Zhao Qianqian , Toppmeyer Deborah , O'Regan Ruth , Wisinski Kari Braun 
Published: June 2021

1056 Background: Palbociclib is a CDK4/6 inhibitor used to treat metastatic hormone receptor-positive (HR+) breast cancer (MBC) in combination with endocrine therapy. Tamoxifen is an effective treatment for HR+ MBC, with different toxicity profile compared with aromatase inhibitors (AI) and fulvestrant. Preclinical data demonstrated synergy for the combination of tamoxifen and palbociclib, being effective in a model of acquired tamoxifen resistance. Methods: We conducted an open-label, single-arm, multicenter phase II trial of palbociclib in combination with tamoxifen in patients with HR+/HER2 - advanced BC, with no prior therapy for MBC. Ovarian suppression was recommended for pre-menopausal women, but not required. Primary objective was progression free survival. Secondary objectives: objective response rate (CR or PR) based on RECIST 1.1 or MDA Criteria (for patients with bone only disease); safety and tolerability (using CTCAE v4); clinical benefit rate (CR, PR or SD lasting min 24 weeks); 2-year overall survival. Correlative objectives: proteomic analysis of plasma exosomes to identify mechanisms of primary and secondary resistance to tamoxifen/palbociclib. Results: Between 6/30/2016 and 7/02/2019, we enrolled 49 patients (47 evaluable): 23 pts with de-novo metastatic disease and 24 pts with recurrent BC (12 pts were on adjuvant treatment with AI at time of recurrence and 12 pts on surveillance). As of 1/5/21 data cut-off, 7 pts were still on treatment. Median follow-up time was 24 months (range 8-42). Median age was 60 (range 39-82). The median PFS was 14.6 months with 95% CI (7-41) for pts with de-novo MBC and 6 months (2-12) for pts with recurrent BC. The ORR was 30% overall, 39% for pts with de novo MBC, 21% for pts with recurrent BC. CBR was 64% overall, 78% for pts with de novo MBC and 50% for pts with recurrent BC. CBR was 65% for white pts and 55% for African American pts. Best response per RECIST1.1: 14 pts (34%) had PR, 18 pts (44%) had SD, 9 pts (22%) had PD. All 6 pts with bone only disease had SD. The most common drug related grade ≥ 3 AE was neutropenia (51%), transient and manageable by dose modifications, no cases of febrile neutropenia. Four patients developed thromboembolic events (1 grade 2, 2 grade 3, 1 grade 4). One patient died while on treatment from PD. Conclusions: The combination of palbociclib and tamoxifen showed tolerable, expected safety profile. This may be an alternative approach for selected patients in first line treatment of HR+ MBC, especially those who are intolerant to AI, although this small study indicates a lower PFS. Clinical trial information: 02668666 .[Table: see text]