bluuebunny/crossref_metadata_2025_split huggingface dataset:
PIK3CA mutation analysis in recurrent breast cancer
Authors: Ma C. X. , Lin L. , Gao F. , Giuntoli T. , Chia Y. H. , Guo Z. , McDowell R. , Naughton M. , Watson M. , Ellis M. 
Published: August 2020

11041 Background: Mutations in PIK3CA (encoding p110α catalytic subunit of phosphatidylinositol-3-kinase) are among the most common genetic events identified in breast cancer but the role of these mutations in determining the clinical course of the disease is uncertain. Furthermore the frequency of PIK3CA mutation in metastatic breast cancer samples has not been adequately studied but is an important concern in the design of studies with novel agents designed to inhibit mutant PIK3CA. Methods: We have established a tumor banking protocol for patients (pts) with metastatic breast cancer. In this study, we performed a mutational analysis of exons 9 (HD) and 20 (KD) of the PIK3CA using tumor DNA obtained from pts with recurrent disease and correlated mutational status with clinicopathological features and prognosis. Results: Biopsies were obtained from sites of recurrence in 51 pts with stage 4 disease. The median F/U was 44 (range: 0.9–239) months and death has occurred in 66%. Mutations in PIK3CA were identified in 24.5% (11.3% in HD and 13.2% in KD). PIK3CA mutation was significantly correlated with lower tumor grade (47% in grade 1/2 vs 8% in grade 3, p=0.004), positive ER (35% in ER+ vs 5% in ER-, p=0.017), and PR (37% in PR+ vs 5% in PR-, p=0.011). Overall survival (OS) was 139.5 and 53.7 months for mutation- and non-mutation- carriers respectively (p=0.014). Conclusions: About one quarter of pts with recurrent/advanced breast cancer carry PIK3CA mutations in samples of recurrent disease, which correlated with positive ER/PR status and a more indolent clinical course. These patients are good candidates for experimental protocols that combine endocrine agents with PI3 kinase inhibitors but the slower kinetics of disease progression in PIK3CA mutation carriers may have to be taken into account for statistical designs and power size calculations. No significant financial relationships to disclose.
Prevalence of CDH1 germline mutations in subjects with early onset or familial lobular breast cancer, a multicenter collaboration
Authors: Masciari S. , Schrader K. A. , Senz J. , Tung N. , Balmana J. , Razzak A. R. , Miron P. , Huntsman D. G. , Garber J. E. 
Published: August 2020

11042 Background: Invasive lobular breast carcinoma (LBC) is part of the hereditary diffuse gastric cancer (HDGC) syndrome, associated with germline mutations in the E-cadherin (CDH1) gene. CDH1 mutations can be identified in 80% of families ascertained by DGC. The risk of DGC in CDH1 mutation carriers is 67% in males, and 83% in females; the estimated risk of LBC in women is 39–50% to age 80. Management of HDGC includes prophylactic gastrectomy. In this study, we estimated the prevalence of germline CDH1mutations among women with LBC who were either diagnosed at young age or had family history of breast cancer (BC). Methods: Germline DNA was collected from 383 women with LBC or mixed, lobular/ductal, BC from breast cancer programs, familial cancer clinics, and population-based cohorts. Germline BRCA1or BRCA2mutations carriers were excluded. Eligible women had (1) LBC before age 45 or (2) LBC at any age with at least two 1st or 2nd degree relatives with BC of any type. Denaturing high pressure liquid chromatography was undertaken, followed by direct sequencing of exons displaying changes. Results: At the time of submission 310 of 383 samples have been fully sequenced. One previously characterized missense mutation and four novel non-synonymous variants (1.6%) were found. Three of these women had LBC before 45 years and no family history of BC; two had BC family history. No gastric cancers were reported in these families. Functional assays to assess the pathogenicity of the variants are in process. Conclusions: These results confirm that CDH1 is responsible for a small proportion of familial and early onset LBC. Given the difficulty of identifying CDH1 mutations from BC history alone and the importance of managing the gastric cancer risk in CDH1carriers, these findings should underscore the need to obtain an accurate abdominal cancer family history from women with LBC. No significant financial relationships to disclose.
Cancer aggressiveness and mortality in men of exceptional age
Authors: Yung R. L. , Kurth T. , Gaziano J. M. , Driver J. A. 
Published: August 2020

11051 Background: Information on the characteristics of cancer in people ≥ 85 is limited, particularly in men. Methods: We evaluated the type, grade and extent of cancer among the 22,071 men in the Physicians’ Health Study by age at diagnosis (dx) (<65, 65–74, 75–84 and ≥85). All cases of cancer, deaths and cause of death were confirmed by medical record review. To investigate the relationship between age at dx and risk of cancer death, we matched newly diagnosed cancer patients to reference subjects by age and a modified Charlson comorbidity score. Participants were followed for all cause mortality. We estimated hazard ratios (HR) for death by age at dx using Cox proportional hazards models and adjusted for potential confounders. Results: Over a mean follow-up of 20.5 years, 5,623 incident cancers were confirmed. Prostate cancer remained the most common cancer across all age groups. Melanoma and lung cancer became less common with age, while unknown cancers and gastrointestinal cancers other than colorectal (other GI) became more common. There was no linear trend toward higher or lower grade across the four age groups for individual cancer types. For men ≥ 85 the frequency of metastatic cancer at dx increased for prostate (5.8% vs 14.6% p=0.01) and decreased for other GI tumors (63.8% vs 43.5% p=0.05). Cancer as a cause of death decreased among the entire cohort from 44.1% in men aged 55–64 to 20.5% in men ≥ 85, and among those with cancer it decreased from 93.6% to 52.8%. In the matched cohort analysis, the HR for death from all cancers combined declined markedly across categories of increasing age at cancer dx from 10.9 (95%CI:6.0–19.9) in men < 55 to 1.9 (95%CI:1.5–2.4) in men ≥ 85. There was a similar decline in the HR with increasing age for cancer death from lymphoma, melanoma, prostate and colorectal cancers, whereas the HR of lung, other GI and urinary tumors remained stable. Conclusions: In this prospective cohort of apparently healthy U.S. male physicians, characteristics of cancer in men ≥ 85 varied considerably with tumor type and may reflect changes in cancer detection or biology with age. Cancer specific mortality decreased markedly with increasing age of diagnosis for most cancers. This is likely explained by competing risks of death which outpace that of cancer, but may also suggest decreased cancer aggressiveness in advanced age. No significant financial relationships to disclose.
Prognostic factors by histologic subtype in stage IV non-small cell lung cancer (NSCLC): A population-based survival analysis of data from the Surveillance, Epidemiology, and End Results (SEER) Program (1988–2003)
Authors: Cetin K. , Ettinger D. S. , Hei Y. , O'Malley C. D. 
Published: August 2020

11053 Background: Representing roughly 85% of all lung cancers, NSCLC is frequently diagnosed at an advanced stage and has a poor prognosis. To better understand the prognostic importance of select patient and tumor characteristics in late-stage disease, we examined survival in patients diagnosed with stage IV NSCLC. Methods: Data from SEER were used to study 53,319 patients with stage IV NSCLC diagnosed between 1988 and 2003, with follow-up through 2005. The distribution of cases according to time period of diagnosis and select patient and tumor characteristics was described for each histologic subtype (squamous; adenocarcinoma (bronchioloalveolar adenocarcinoma (BAC), non-BAC); large cell; and other/unknown). Kaplan-Meier and multivariate Cox proportional hazard models were used to examine the influence of these variables on overall survival by histologic subtype. Results: Most recent period of diagnosis (1998–2003 versus 1988–1992) conferred a survival advantage across histologic subtypes, independent of gender, age, ethnicity/race, tumor grade, and uptake of surgery/radiation. This was especially pronounced for those diagnosed with large cell tumors (adjusted hazard ratio (aHR): 0.76, 95% confidence interval (CI): 0.71–0.82). Similarly, females survived longer than males across histologic groups, particularly for those with BAC tumors (aHR: 0.77, 95% CI: 0.66–0.89). Increasing age was associated with reduced survival in all histologic subtypes except BAC, where prognosis was poorest in the youngest age group. The influence of ethnicity/race also varied with histology: compared to Whites, American Indians/Alaskan Natives with squamous tumors and Blacks with large cell tumors had a poorer prognosis, whereas Asians/Pacific Islanders with either non-BAC or large cell tumors demonstrated superior survival. Conclusions: Survival among stage IV NSCLC patients improved over the study period, which may reflect the use of third generation chemotherapy as well as better supportive care. Nonetheless, lung cancer remains a deadly disease, and the prognostic effect of demographic factors varies with histologic subtype. [Table: see text]
Gemcitabine-oxaliplatin combination (SEGEMOX) in anthracycline (A) and taxanes (T) pretreated metastatic breast cancer (MBC): Results from the GERCOR-SEGEMOX phase II trial
Authors: Gligorov J. , Cals L. , Tournigand C. , Merad Z. , Dutel J. , Selle F. , Zeghib N. , Chibaudel B. , Cvitkovic F. 
Published: August 2020

1108 Objectives: To evaluate efficacy and safety of SEGEMOX regimen for previously A and T pre-treated MBC patients. Methods: Forty-five women with MBC not eligible for A and/or T chemotherapy were enrolled on SEGEMOX study. SEGEMOX was delivered as follows: Gemcitabine was given at 1000 mg/m2/100min on day 1, followed by oxaliplatin at 100 mg/m2/120min iv on day 2 every 2 weeks. Efficacy results were analyzed and are presented in an intention to treat analysis and toxicity according to the total number of cycles regimen. Results: Forty-four of the 45 patients received at least 1 cycle of SEGEMOX. Fifty-eight perccent of the patients have received previous adjuvant chemo, 36% 1st line and 42% 2nd line for MBC before the protocol inclusion. Visceral metastases were dominant site of disease (44% liver; 36% lung; 44% bone). Median age of the population was 55.8 years (36–73). After a median of 7.7 cycles (3.5 months of treatment); the overall response rate (ORR) is 38% [95%CI; 23%-51%] [1 CR (2.2%) and 16 PR (35.6%)]; 33% of stable disease [95%CI; 17%-43%], 24.4% progressive disease with a clinical benefit (CB) of 71% [95%CI; 57%-85%]. The median progression free survival (PFS) is 7.1 months for responders and 4.8 months for patients with stable disease. The all population median overall survival (OS) is 21.4 months with 22.7 months MOS for responders. Concerning toxicity analysis: 339 cycles of gemcitabine and 312 of oxaliplatinum were delivered. Respectively, grade 3–4 neutropenia occurred in 43% of patients (febrile neutropenia in 7%), grade 3–4 thrombocytopenia in 41%, and anemia in 2.3%. The most frequent non hematologic toxicities were represented by grade 3 peripheral neuropathy (Levi Scale) in 11.4% of the patients and grade 2 alopecia in 11.4%. For the subgroup of hormone receptor negative MBC (n = 12) the ORR is 33% [95%CI; 2%-64%], CB 50% [95%CI; 16%-73%], PFS of 2.8 months and MOS of 12 months. Conclusions: The SEGEMOX combination has relevant activity in A and T not eligible MBC patients, with a manageable toxicity profile. In the limited number of patients with HRN MBC even if the response rate is close to the overall population the prognosis seems still worse. No significant financial relationships to disclose.
Correlation of primary tumor engraftment in immune deficient mice and relapse rate in patients with early-stage non-small cell lung carcinoma (NSCLC)
Authors: John T. , Li M. , Panchal D. , Hui F. , Meng F. , Bandarchi-Chamkhaleh B. , Kohler D. , Zhu C. , Shepherd F. A. , Tsao M. 
Published: August 2020

11082 Background: Compared to cell lines, primary tumor xenografts potentially are more clinically relevant cancer models as they more closely reflect the phenotype and genotype of the original cancer. However, only a minority of tumors engraft successfully in severe combined immune deficient (scid) mice and can be passaged serially. Although xenograft models are used extensively, few studies have investigated whether tumors that engraft represent a distinct clinical subset. We hypothesized that NSCLC tumors with more aggressive clinical and histological features have greater engraftment capacity than those with a less aggressive phenotype. Methods: Fresh primary tumors were harvested from NSCLC patients who underwent curative resection. Tumor fragments were implanted into the subcutaneous tissue of non-obese diabetic-scid mice within 24 hrs of excision. Patient characteristics for tumors that engrafted (XG) and did not engraft (No-XG) were compared. Only tumors from patients with >1-yr follow-up were evaluated for time to progression (TTP) and to correlate clinicopathological features with engraftment. Results: Between March 2005 and October 2008, 110 tumors were implanted. Of these, 45 (41%) engrafted and were passaged serially in vivo. The histological features of the primary were retained in 93% of XG tumors. Squamous cell carcinomas engrafted significantly more than adenocarcinomas (57% versus 26%, p=0.03). There were no significant differences in differentiation grade or clinical stage between the XG and No-XG groups. XG patients had significantly shorter TTP than the No-XG group (10.19 versus 18.64 months, p=0.003). In multivariate analysis the ability to form a xenograft was an independent predictor of relapse (HR 4.15 95% CI 1.152–14.94, p=0.03). Conclusions: Xenograft models can be established from the histological spectra of NSCLC encountered in the clinical setting and mimic closely the features of their primary tumors. The capacity of these tumors to engraft may be predictive of a more aggressive phenotype and poorer clinical outcome. No significant financial relationships to disclose.
Survival of a cohort of 25 breast cancer patients with neoplastic meningitis treated with intrathecal liposomal cytarabine
Authors: Le Rhun E. , Zairi F. , Baranzelli M. , Faivre-Pierret M. , Devos P. , Bonneterre J. 
Published: August 2020

1109 Background: Neoplastic meningitis (NM) occurs in 5% of the patients with breast cancer; if untreated the median duration of survival is 5 weeks. Combination of intrathecal (IT), systemic chemotherapy, and supportive care may increase overall survival (OS) to 5 months (Chamberlain, 2005). Methods: 30 consecutive female breast cancer patients diagnosed with NM, on the basis of cerebrospinal fluid (CSF) cytology and/or cerebrospinal MRI with clinical symptoms, have been prospectively treated for 19 months. Three patients did not receive any treatment because of a poor neurological status at diagnosis; 2 patients stopped treatment because of the lack of improvement after 1.5 months. The aim was to report clinico-pathological characteristics and OS in patients treated with IT liposomal cytarabine and supportive care with or without systemic chemotherapy. Statistical analyses were performed in the 25 treated patients. Correlations between tumor characteristics and OS were analyzed using usual statistical methods (Kaplan Meier, Log-rank, Cox). Results: Median age at NM diagnosis was 56 years. Median Karnofsky Performance Status (KPS) was 75. Breast cancers were invasive ductal carcinoma in 75%. Estrogen and progesterone receptors were detected in respectively 64 and 40%. HER-2 hyperexpression was observed in 33.5%. Tumors were triple negative in 17%. At the time of NM diagnosis CSF cytology and cerebrospinal MRI were positive in respectively 64% and 87.5%. Brain metastases were present in 64% of the patients, 36% had whole brain radiotherapy. Median delay between first symptoms and diagnosis was 16 days. Median delay between NM diagnosis and first IT was 17 days. Systemic chemotherapy was given in 56.5% at the discretion of the referring oncologist. All patients had supportive care. After 5 IT a clinical stabilization or improvement was observed in 56.5%. A CSF response was observed in 36%. Median OS of treated patients was 7 months. KPS at diagnosis (≥80), neurological status after 5 IT were significantly correlated with OS. A trend was also observed between association with systemic chemotherapy and OS. Conclusions: Our results confirm that the association of IT, systemic treatment and supportive care treatment may be useful in treating this cancer complication. No significant financial relationships to disclose.
GRB7 and HER2 protein overexpression and breast cancer outcome
Authors: Luoh S. , Ramsey E. E. , Bai T. , Keenan E. J. 
Published: August 2020

11102 Background: The growth factor receptor-bound protein-7 gene (GRB7) encodes a multi-domain signal transduction molecule and is located in close proximity to human epidermal growth factor receptor 2 (HER2) on chromosome 17q11–12. This study examines the roles of GRB7 protein in human breast cancer. Methods: We performed western blotting analysis of protein extracts from 563 annotated frozen breast tumors, collected from 1988 - 1998. GRB7 and HER2 bands were assigned low or high values compared to specific protein controls, and tubulin bands. Chi-square tests were used to test the hypothesis that there was no association between expression status of GRB7 or HER2 with clinical covariates and outcomes. Univariate Cox regression was performed to identify risk factors and Cox proportional hazards backward step model for variable selection to identify independent predictors of progression free survival. All P values were two sided. P values less than 0.05 were considered statistically significant. HER 2 gene amplification status was determined by fluorescence in situ hybridization (FISH). Results: GRB7 protein over-expression was associated with negative estrogen (< 5 fmole/mg protein) and progesterone receptor (< 10fmole/mg protein) status, higher grade (1, 2, or 3), larger primary tumor size (< 2.0 vs. > 2.0 cm), (more) axillary lymph node involvement (continuous), higher clinical stage (1, 2, 3, or 4) and shortened progression free survival (months). We found a discrepancy in HER2 and GRB7 protein over-expression. Isolated GRB7 protein over-expression correlated with inferior progression free survival, while HER2 protein over-expression without GRB7 protein over-expression did not. Multivariate analysis revealed that GRB7 over-expression was an independent predictor of progression free survival (hazard ratio 1.69: 95% confidence interval, 1.073 - 2.672; P = 0.0236). All 18 tumors submitted to FISH analysis that over-expressed both HER2 and GRB7 proteins and no tumors (0 / 10) with HER2 but no GRB7 protein over-expression demonstrated HER2 gene amplification. Conclusions: GRB7 protein over-expression is an independent adverse prognostic factor in breast cancer. No significant financial relationships to disclose.
Analysis of cell surface erythropoietin receptor (EpoR) expression and function in human epithelial tumor tissues
Authors: Rossi J. , McCaffery I. , Paweletz K. , Tudor Y. , Elliott S. , Fitzpatrick V. D. , Patterson S. D. 
Published: August 2020

11104 Background: EpoR mRNA and protein expression have been reported at low levels in human tumors implying EpoR may be functional in tumor cells with inferred implications for the use of erythropoiesis stimulating agents in the Oncology setting. However, mRNA studies use bulk tumor tissue which ignores contribution from the stroma and IHC studies have all used Abs that have since been shown to not be specific for EpoR. Therefore this important question remains unresolved. Methods: EpoR expression and function was investigated in viable, non-apoptotic primary human tumor cells (using tumor specific Abs) that were disaggregated from at least 30 patients from each of the following tumor types: breast (incl. metastases), NSC lung, colorectal, and ovarian. Additional tumor types included head and neck, GBM, pancreatic and gastric. Analysis was performed under conditions that were shown to preserve EpoR expression and function in positive control tissues (primary human erythroid progenitors from bone marrow and UT-7 cells). Cell surface EpoR expression was evaluated by flow cytometry using novel EpoR-specific Abs. EpoR function was investigated by analysis of EpoR signaling using phospho-specific Abs specific for STAT5, Erk, Akt etc following ex vivo Epo stimulation (0U- 300U/mL; for 5 and 30 min). Results: No expression of cell surface EpoR was detected in tumor cells in any of the over 130 tumors. In contrast, high levels of expression were observed in positive controls analyzed in parallel. No induction of EpoR signaling was observed in tumor cells at any [Epo], whereas activation was readily detected in tumor cells treated in parallel with a cocktail of known tumor growth factors. Positive controls treated in parallel, showed robust Epo concentration-dependent signaling. No evidence of EpoR expression or function was observed in tumor endothelial cells. Conclusions: These data demonstrate that epithelial tumor cells do not express functional cell surface EpoR and are not responsive to physiological, therapeutic or indeed very high levels of Epo (300U/mL). No significant financial relationships to disclose.
Interim safety analysis of the randomized phase III PELICAN trial evaluating pegylated liposomal doxorubicin (PLD) versus capecitabine as first-line therapy for metastatic breast cancer
Authors: Al-Batran S. , Saupe S. , Schmidt M. , Kreienberg R. , Otremba B. , Warm M. , Lerbs W. , Untch M. , Harbeck N. 
Published: August 2020

1118 Background: Treatment of metastatic breast cancer (MBC) focuses on relieving symptoms and extending life. Single-agent therapy is preferred in the first-line setting to reduce the risk of toxicity and maintain quality of life. The PELICAN trial was designed to evaluate efficacy and safety of first-line PLD vs capecitabine at standard approved dosages. Methods: PELICAN is an open-label, multinational, randomized, multicenter trial. MBC Patients (pts) were randomized to receive PLD (50 mg/m2 every 28 days) or capecitabine (1250 mg/m2 BID x 14 days every 21 days) until disease progression or unacceptable toxicity. The primary endpoint was to compare time to disease progression between treatment arms. Toxicity was evaluated continuously. Results: The study is still ongoing, but no longer recruiting. So far, 210 pts (PLD, 105; capecitabine, 105) were evaluated for safety, of whom 131 pts have already completed their treatment (83 for disease progression, 19 for toxicity, 5 died, 24 for other reasons). 90% of pts had ECOG performance status 1 or 2, and 79% were postmenopausal. Mean age was 61.5 years, and 34% received prior adjuvant anthracycline. Pts received a median of 4 cycles of PLD and a median of 5 cycles of capecitabine. Over 90% of pts in both groups experienced at least one adverse event (AE). Grade 3/4 AEs were reported in 99 patients (PLD, 44; capecitabine, 55). Hand foot syndrome (HFS) was the most common AE (grade 3: PLD 35%; capecitabine 19%), followed by diarrhea (grade 3/4: PLD, 0; capecitabine, 13%) and thromboembolic events (PLD, 0%; capecitabine, 9%). Other grade 3/4 AEs affected 1 week in 16%. Conclusions: Overall, first-line monotherapy with PLD or capecitabine at approved doses was maintainable for a median of about 4 months with manageable AEs. Interim safety results of the PELICAN trial show no unanticipated toxicity. Efficacy results will be available once all patients have completed their therapy. [Table: see text]