bluuebunny/crossref_metadata_2025 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]
Leukemia in hospitalized patients with inflammatory bowel disease: An analysis of the National Inpatient Sample (NIS) database.
Authors: Wikholm Colin , Vangimalla Shiva Shankar , Abaza Ehab , Ahmad Akram , Pothoulakis Ioannis , Patel Urvish , Dilawari Asma Ali , Cho Won Kyoo
Published: June 2021

10576

Background: Inflammatory bowel disease (IBD) and use of immunosuppressive therapy in IBD is linked with increased risk of leukemia. We studied the NIS database from 2003-2017 to analyze trends in any type of leukemia in IBD hospitalizations over time and examined the role of age, sex, and race. Methods: We analyzed NIS data of all adult hospitalizations for ulcerative colitis (UC) or Crohn’s disease (CD) with any type of leukemia as a primary or secondary diagnosis using validated ICD 9/10 codes. Age, sex, and racial demographics were collected. Trend analysis of leukemia was performed with Cochran-Armitage and Jonckheere-Terpstra tests. Results: Overall Trends: From 2003-2017, a total of 11,385 of 2,235,413 (0.51%) CD hospitalizations and 8,105 of 1,324,746 (0.61%) UC hospitalizations contained diagnosis of leukemia. An increase in leukemia was seen in both CD and UC group from 0.24% to 0.79% (pTrend < 0.0001) and 0.28% to 0.81% (pTrend < 0.0001) respectively. Sex: In both UC and CD patients, leukemia diagnoses were predominantly male in 2003 but approximated a near 1:1 ratio by 2017 (Table). In CD, the proportion of female (FEM) leukemia diagnoses grew from 31.33% to 45.05% from 2003 to 2017 (pTrend = 0.1898). In UC, the proportion of female leukemia diagnoses grew from 27.49% to 45.79% from 2003 to 2017 (pTrend = 0.0030). Age: Leukemia was more common with increasing age, with no significant changes in proportion of cases between age groups over time (pTrend >.05). Ethnicity: White patients composed 87.80% and 84.24% of leukemia diagnoses in CD and UC, respectively. In CD, an increasing proportion of leukemia diagnoses occurred in black (BK) patients, and a decreasing proportion occurred in white patients (pTrends <.0001; Table 1) during the study time. No trends in race were observed in the UC group (pTrend = 0.4229). Conclusions: Our study showed an increased prevalence of leukemia in CD and UC hospitalizations from 2003-2017 which may be related to increasing use of immunosuppressants such as anti-TNF medications. In both CD and UC, leukemia was male-predominant, but increasingly female by 2017. Rate of leukemia diagnosis increased with age. In the CD group but not the UC group, leukemia was increasingly prevalent in black patients.[Table: see text]
Subsequent primary cancers among survivors of adolescent and young adult onset cancers in the United States.
Authors: Sung Hyuna , Siegel Rebecca , Miller Kimberly , Jemal Ahmedin
Published: June 2021

10604

Background: Adolescent and young adult (AYA) cancer survivors are at increased risk of subsequent primary cancer (SPC); however, a comprehensive examination of risk patterns across cancer types is lacking in the U.S. Methods: SPC incidence and mortality was calculated among >1-year cancer survivors aged 15 to 39 years at first primary cancer (FPC) diagnosis during 1992-2016 in 12 Surveillance, Epidemiology, and End Results registries. Rates were expressed as number of cases/deaths per 10,000 person-years and compared with those expected in the general population using standardized incidence (SIR) and standardized mortality ratios (SMR). Results: Among 202,440 survivors of AYA-onset cancers (mean age at FPC diagnosis, 31.8 years; 60.7% women), 6,675 SPC cases (34.3 per 10,000) and 3,786 SPC deaths (19.4 per 10,000) occurred during 1,955,119 person-years of follow-up (mean, 9.7 years), corresponding to an SIR of 1.58 (95%CI = 1.54-1.62) and SMR of 4.19 (95%CI = 4.06-4.33. In men, overall incidence and mortality SPC rates were statistically significantly higher for each of 21 FPC types compared with risks in the general population, except for thyroid cancer mortality. In women, risk was statistically significantly higher for 14/23 FPC types for incidence and 19/23 FPC types for mortality. SIRs were highest in survivors of pancreatic cancer (SIR = 5.68, 95% CI = 2.94-9.93; 84 per 10,000), Kaposi sarcoma (SIR = 5.15, 95%CI = 4.62-5.73; 116 per 10,000) and liver cancer (SIR = 4.97, 95%CI = 2.57-8.68; 68.4 per 10,000) in men, and acute lymphoid leukemia (SIR, 3.27, 95% CI = 2.22-4.64; 49.5 per 10,000), Hodgkin lymphoma (SIR = 2.47, 95% CI = 2.22-2.73; 51.6 per 10,000), and bone sarcoma (SIR = 2.41, 95%CI = 1.80-3.16; 47.6 per 10,000) in women. SMRs were highest in survivors of pancreatic cancer, acute lymphoid leukemia, and stomach cancer in men, and liver cancer, acute lymphoid leukemia, and soft tissue sarcoma in women. Conclusions: Overall and type-specific risk patterns of SPCs among AYA cancer survivors differ considerably across FPC type, highlighting the need for targeted approaches for cancer prevention and surveillance in survivorship care planning.
Efficacy of AI and palbociclib in ER+ HER2- advanced breast cancer patients relapsing during adjuvant tamoxifen: An exploratory analysis of the PADA-1 trial.
Authors: Bidard François-Clément , Dalenc Florence , De La Motte Rouge Thibault , Pistilli Barbara , Cheneau Caroline , Delbaldo Catherine , Derbel Olfa , Garnier Tixidre Claire , Marques Nathalie , Marques Sandrine , Moreau Lionel , Berger Frederique , Lemonnier J , Hardy-Bessard Anne-Claire , Delaloge Suzette , Bachelot Thomas
Published: June 2021

1070

Background: In PADA-1 (NCT03079011), a phase III trial testing the clinical utility of ESR1mut detection, ER+ HER2- advanced breast patients (ABC pts) received Aromatase Inhibitor (AI) and Palbociclib (Pal) +/- LHRH agonist as first line therapy. PADA-1 was open to “AI-sensitive” pts, including those with de novo stage IV disease or metastatic relapse after adjuvant endocrine therapy but also pts with metastatic relapses during adjuvant tamoxifen (TAM). In this subsidiary analysis, we report the efficacy of AI+PAL as first line therapy in patients relapsing on adjuvant TAM. Methods: Main inclusion criteria in PADA-1 are: pre- or post-menopausal pts with ER+ HER2- ABC, who did not receive any prior therapy for ABC and who had no adjuvant AI or completed adjuvant AI for > 12 months or who had disease recurrence while on adjuvant TAM. Results: From 04/2017 to 01/2019, 1017 ABC pts have been included in PADA-1, of which 115 (11.3%) had a metastatic relapse while on adjuvant TAM (TAM only (N = 112) or TAM+GnRH agonist (N = 3)). Median age at inclusion was 46 years (range 25-81), and 58 (50.4%) patients had visceral disease. The median PFS under AI+PAL was 20.4 months (95%CI16.1;27.8) in patients relapsing during adjuvant TAM. In contrast, median PFS in patients with de novo metastatic disease and metastatic relapses after the completion of adjuvant endocrine therapy were 30.6 months (95%CI26.7;Not reached) and 27.8 months (95%CI24.1;30.)], respectively. A subgroup analysis among patients relapsing on adjuvant TAM showed that those relapsing during the first two years of adjuvant TAM had a shorter PFS (11.4 months 95%CI[8.7;20.7]) than those relapsing after 2 years of adjuvant TAM (23.8 months 95%CI[20.2;Not reached]). Conclusions: To our knowledge, these are the first data on first line AI+CDK4/6 inhibitor in patients relapsing on adjuvant TAM. While PFS on AI + PAL appears primarily driven by endocrine resistance status, our data show that AI+PAL is a valuable option also in patients relapsing during adjuvant TAM. Clinical trial information: NCT03079011 .
Clinical and pathological characteristics of breast cancer with resected brain metastasis.
Authors: Liu Shiyuan Anabeth , Luo Jingqin , Tao Yu , Dahiya Sonika , Ma Cynthia X.
Published: June 2021

1089

Background: Breast cancer brain metastasis (BCBM) has poor prognosis and limited therapeutic options. Studies have shown that BCBM may differ from their matched primary tumors in receptor subtypes and genomic characteristics. However, studies have been limited by the tissue availability of BCBM. Taking advantage of our institutional database of resected BCBM with matched primary breast samples, this study aimed to investigate the clinical and pathological characteristics of patients with resected BCBM. Methods: We performed retrospective chart review for all breast cancer patients who had resected BCBM samples at our institution over the last 20 years. Hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status of the primary breast and BCBM samples, location of BCBM, and extracranial metastases at time of BCBM diagnosis were categorized. Overall survival (OS) from time of BCBM diagnosis was calculated using the Kaplan-Meier method. Progression interval and receptor subtype switching from primary diagnosis to brain metastasis were computed and compared using Wilcoxon rank sum test and Fisher’s exact test, respectively. Results: Eighty-six patients were included in this study (median age at time of BCBM diagnosis 54.3 [range 28.3-84.0] years, median follow up 26.0 months). These included 47 HR+, 15 HER2+, 20 triple negative (TN), 4 unknown subtype breast samples, and 42 HR+, 18 HER2+, 17 TN and 9 unknown subtype brain samples. OS was significantly shorter in patients with TN compared to HR+ or HER2+ subtype, whether the TN status was in the primary breast tumor (median 20.5 vs 34.0 months, p = 0.04, thresholded at year 2) or in the brain metastasis (median 16.0 vs 34.0 months, p = 0.02, thresholded at year 2). No significant difference in OS was observed between HR+ and HER2+ groups. There was no significant difference in the progression interval from primary diagnosis to brain metastasis among receptor subtypes. From primary tumor to brain metastasis, receptor subtype switching occurred in 10 out of 73 patients (13.7%) for estrogen, 20 out of 70 (28.6%) for progesterone (PR), and 6 out of 72 (8.3%) for HER2. Receptor subtype switching did not significantly correlate with OS. Presence of extracranial metastases at time of BCBM diagnosis corresponded to significantly lower OS compared to no extracranial metastasis (16.5 vs 36.0 months, p = 0.01). No significant difference in OS was observed between patients with cerebral vs cerebellar brain metastases. Conclusions: These data indicate that patients with TN BCBM disease have the worst overall survival among all receptor subtypes. Metastases in extracranial sites at time of BCBM diagnosis significantly decreased survival. Location of the brain metastasis and receptor subtype switching from primary diagnosis to BCBM, which was relatively infrequent outside of the PR group, did not significantly correlate with OS in this limited data set.
Impact of the COVID-19 pandemic on the wellbeing of international fellows training in hematology/oncology at the Princess Margaret Cancer Centre (PMCC).
Authors: Stecca Carlos , Jiang Di Maria , Alt Marie , Elliott Mary , Fallah-Rad Nazanin , Michelis Glaucia , Sridhar Srikala S.
Published: June 2021

11038

Background: The COVID-19 pandemic has led to significant disruptions across all levels of medical training. International fellows in subspecialty training programs are essential members of the frontline physician workforce, who may be facing additional and unique challenges being far away from their home country. We aimed to understand the impact of the pandemic on the wellbeing of current international fellows in the Hematology/Oncology training program. Methods: We conducted an online survey of 52 international fellows at the PMCC from July 6-August 10, 2020. There were 60 questions divided into 4 sections: demographics, wellbeing assessment using the validated Short Warwick Edinburgh Mental Wellbeing Scale (SWEMWBS), fellowship specific questions (personal and professional) and coping strategies using the validated brief COPE scale. Results: Response rate was 46% (n = 24). Relevant demographics include: married (65%), male (54%), age between 31-35 years (48%), have children (48%), and home country from Asia (48%). Mean SWEMWBS score was 21, indicating lower overall wellbeing than the general population (23.6). Compared to pre-COVID-19, many reported a decline in their wellbeing (63%), sense of guilt for not being with their family (45%) or helping their country (41%), stress in personal relationships (26%), fatigue (50%), sleep disorders (38%) and loss of interest in daily activities (38%). Personal events were altered by almost 80% and 20% plans to extend their fellowship. According to the Brief-COPE scale, most fellows used more adaptive coping mechanisms (mean score 39.2) as opposed to maladaptive ones (mean score 21.8). Conclusions: The ongoing COVID-19 pandemic has negatively affected the overall wellbeing of international fellows. Understanding the specific challenges and coping mechanisms of international fellows may help Institutions develop better targeted strategies to promote their overall wellbeing, professional development and high-quality patient care during these unprecedented times.
Representation trends in radiation oncology training programs in the United States.
Authors: Garcia Emilie , Lang Jacob , Ukaegbu Oke Oluchi , Reddy Krishna , Ekwenna Obi
Published: June 2021

11043

Background: The ASCO and American Society of Radiation Oncologists (ASTRO) have recently committed to initiatives on increasing URM representation in the radiation oncology workforce. This study aims to assess representation trends in radiation oncology training programs across five academic years in order to understand representation trends and better guide initiatives moving forward. Methods: Data on racial and ethnic representation from the ACGME Data Resource Books over a span of five academic years (2015-2020) was included. URM was defined as those who identified as Hispanic, Black, or Native American/Alaskan in concordance with AAMC definition. Chi square testing was used to compare the proportion of residency positions occupied by URM residents by self-identified race and ethnicity in radiation oncology to that of hematology and medical oncology, complex general surgical oncology, and all other specialties. Results: A total of 3,315 radiation oncology positions were identified over the study period, 2015 and 2020. 1,938 (58.5%) of radiation oncology residency positions were filled by residents who identified as White, 967 (29.2%) as Asian/ Pacific Islander, 126 (3.8%) as Hispanic, 120 (3.6%) as Black, 7 (0.2%) as Native American/ Alaskan, and 157 (4.7%) as Other. URM representation was 7.6% in total and was relatively stagnant, remaining between 7.3% and 8.0% across study years. Results of chi square comparative analysis demonstrated lower rates of representation in radiation oncology in comparison to hematology and medical oncology as well as all other specialties (Table). Conclusions: There is lack of racial and ethnic diversity in radiation-oncology residency training positions in the United States. Over the five-year study period, only 7.6% of trainees identified as URM. URMs have significantly lower rates of representation in radiation-oncology compared to hematology and medical oncology, and other specialties. Efforts to mitigate disparities require a multifaceted approach.[Table: see text]
Demographics, outcomes, and risk factors for patients (Pts) with sarcoma and COVID-19: A multi-institutional cohort analysis.
Authors: Wagner Michael J , Ingham Matthew , Painter Corrie , Chugh Rashmi , Trent Jonathan C. , Subbiah Vivek , Khaki Ali Raza , Tachiki Lisa May Ling , Loggers Elizabeth Trice , Labaki Chris , McKay Rana R. , Griffiths Elizabeth A. , Thornton Katherine Anne , Kasi Anup , Hwang Clara , Chen James Lin , Halfdanarson Thorvardur Ragnar , Reuben Daniel Y. , Park Cathleen , Davis Elizabeth J.
Published: June 2021

11523

Background: Sarcoma pts often receive aggressive, highly immunosuppressive therapy and may be at high risk for severe COVID-19. Demographics, outcomes and risk factors for pts with sarcoma and COVID-19 are unknown. We aimed to describe the course of COVID-19 in sarcoma pts and to identify factors associated with adverse outcomes. Methods: The COVID-19 and Cancer Consortium (NCT04354701) is an international registry of pts with cancer and COVID-19. Adult pts (≥18 years old) with a diagnosis of sarcoma and laboratory confirmed SARS-CoV-2 were included from 50 participating institutions. Data including demographics, sarcoma diagnosis and treatment, and course of COVID-19 infection were analyzed. Primary outcome was the composite rate of hospitalization or death at 30 days from COVID-19 diagnosis. Secondary outcomes were 30 day all-cause mortality, rate of hospitalization, O2 need, and ICU admission. Descriptive statistics and univariate Fisher tests are reported. Results: From March 17, 2020 to February 6, 2021, N=204 pts were included. Median follow up was 42 days. Median age was 58 years (IQR 43-67). 97 (48%) were male. 30 (15%) had ECOG performance status ≥2. 104 (51%) received cancer treatment, including surgery or radiation, within 3 months of COVID-19 diagnosis. 153 (75%) had active cancer, of whom 34 (22%) had lung metastases. 100 (49%) pts met the composite primary endpoint; 96 (47%) were hospitalized and 18 (9%) died within 30 days from COVID-19 diagnosis. 64 (31%) required oxygen, and 16 (8%) required ICU admission. Primary endpoint rates were similar for pts who received cytotoxic chemotherapy (38/58, 66%) or targeted therapy (16/28, 57%). Pts with higher rates of the primary endpoint included patients ≥60 years old (59% vs 40%, OR 2.04, 95% CI 1.12-3.74, p=0.016), pts with ECOG PS ≥2 vs 0-1 (90% vs 41%, OR 12.2, 95% CI 3.44-66.8, p<0.001), pts receiving any systemic therapy within 3 months of COVID-19 diagnosis (62% vs 39%, OR 2.65, 95% CI 1.43-4.97, p=0.001), and pts with lung metastases (68% vs 42%, OR 2.77, 95% CI 1.19-6.79, p=0.013). Primary endpoint rates were similar across sarcoma subtypes (Table). Conclusions: This is the largest cohort study of pts with sarcoma and COVID-19 to date. Sarcoma pts have high rates of complications from COVID-19. Older patients, those with poor performance status, those recently receiving systemic cancer therapy, and those with lung metastases appear to have worse outcomes.[Table: see text]
Whole-genome sequencing to improve sarcoma diagnosis and patient care.
Authors: Schipper Luuk J. , Monkhorst Kim , Samsom Kris , Snaebjornsson Petur , Van Boven Hester , Roepman Paul , Van Der Kolk Lizet , Bosch Linda J.W. , van Houdt Winan J. , Van Der Graaf Winette T.A. , Meijer Gerrit A. , Voest Emile E.
Published: June 2021

11540

Background: With more than 70 different histological subtypes, accurate classification sarcomas is challenging. Although pathognomonic genetic events aid accurate classification, large-scale molecular profiling is generally not incorporated in regular diagnostic workflows for sarcoma patients. We hypothesized that whole genome sequencing (WGS) optimizes clinical care of sarcoma patients by detection of pathognomonic and actionable variants, and of underlying hereditary conditions. Methods: WGS of tumor and germline DNA was incorporated in the diagnostic work-up of 83 patients with a (presumed) sarcoma as part of the WIDE (Whole genome sequencing Implementation in standard Diagnostics for Every cancer patient) study in a tertiary referral center. WGS results were reported back to the pathologist and treating clinician. Clinical follow-up data were collected prospectively to assess impact of WGS on clinical decision making. Results: WGS analysis had impact on multiple levels. First, in 14% of cases (12/83 patients), the genomic profile led to a revision of the diagnosis (table). All patients had undergone multiple diagnostic procedures (mean number: 4) and pathologist assessments (mean: 6) before WGS analysis was performed. Secondly, actionable biomarkers with therapeutic potential were detected for 36/83 patients and finally, 8 pathogenic germline variants were present. Taken together, WGS had implications for clinical decision making in 52% of patients with (presumed) sarcomas. Conclusions: WGS is an important extension of the diagnostic arsenal of pathologists and has contributed to change of care in 52% of patients with sarcomas. Given the diagnostic complexity and high unmet need for new treatment opportunities in sarcomas we advocate the use of WGS for sarcoma patients early in the disease course. Clinical trial information: NL68609.031.18. [Table: see text]
The sarcoma microbiome as a diagnostic and therapeutic target.
Authors: Tinoco Gabriel , Husain Marium , Hoyd Rebecca , Jagjit Singh Malvenderjit , Liu YunZhou , Mo Xiaokui , Chen James Lin , Liebner David A. , Spakowicz Daniel
Published: June 2021

11541

Background: Sarcoma is a heterogeneous group of malignant tumors that consist of distinct histological and molecular subtypes, each with unique features. Despite immunotherapy’s promise in many cancers, immunotherapeutic approaches for sarcoma have had variable response rates. Evaluating the tumor microbiome is a promising new approach that aims to improve our understanding of the immunogenicity of sarcoma subtypes, leading to improved treatment options and better clinical outcomes. Methods: We utilized The Cancer Genome Atlas (TCGA) and Genome Tissue Expression (GTEx) database to obtain RNA sequencing (RNAseq) data to identify microbes in sarcoma samples (all subtypes available). Due to the large number of sarcoma subtypes, we focused on three groups: dedifferentiated liposarcoma (DDLPS), leiomyosarcoma (LMS) and “other,” representing all other sarcoma subtypes. We utilized ExoTIC, “Exogenous sequences in Tumors and Immune cells,” a tool recently developed by Dr. Daniel Spakowicz and Dr. Xaiokui Mo. ExoTIC takes raw RNAseq reads and carefully aligns to both human and non-human reference genomes to identify low-abundance microbes. Models of association were analyzed based on each of the three groups as well as all the samples: “All” group. We performed Cox proportional hazards regression to identify the microbes associated with overall survival (OS). Results: We evaluated 97 LMS, 56 DDLPS and 100 “other” RNAseq samples (Table). ExoTIC identified 1304 microbes, of which 431 were statistically associated with OS in the “All” group. Of these, 50 microbes were statistically associated only with DDLPS, 54 only with LMS (e.g., Candida dubliniensis, Mycobacterium avium, Streptococcus sp. Z15), and 46 with “other.” The presence of no organism was associated with improved survival. Median hazard ratios were largest in DDLPS (2.3), followed by “other” (2.1) and LMS (1.9). Only 18 microbes were found in the DDLPS, LMS and “All” groups, including Bacillus sp., Streptococcus lutetiensis, Clostridium tetani, and Pseudomonas sp. LTJR-52. Each was negatively correlated with survival with a median hazard ratio of 2.5. Conclusions: We found a specific relationship between microbial presence and histological sarcoma subtype (DDLPS, LMS), which also statistically correlated with OS. Assessing individual characteristics of a sarcoma histological subtype with its particular microenvironment (e.g., microbes) can lead to personalized treatment insights and improvements in outcomes. Our future research will consist of validating and correlation of the microbial profile of sarcoma subtypes with clinical outcomes retrospectively and prospectively. [Table: see text]