bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of a subpopulation of metastatic breast cancer patients with very high HER2 expression levels and possible resistance to trastuzumab
Authors: Sperinde J. , Ali S. , Leitzel K. , Fuchs E. , Köstler W. J. , Paquet A. , Weidler J. , Huang W. , Bates M. , Lipton A.
Published: August 2020

1059

Background: Many HER2-positive patients with metastatic breast cancer (MBC) fail to respond to trastuzumab. We previously reported that precise quantitation of HER2 expression (H2T) by the HERmark assay identified a sub-population of IHC 3+, FISH(+) (positive) patients with low H2T levels that responded poorly to trastuzumab (Lipton, San Antonio Breast Cancer Symposium 2008, abs #32). Here we identify a sub-population of FISH(+) patients with very high H2T levels, that experience clinical outcomes that are indistinguishable from those of FISH(-) (negative) patients with low H2T levels. Methods: The HERmark assay was used to measure H2T in formalin-fixed, paraffin-embedded (FFPE) primary breast tumor specimens from 99 women treated with trastuzumab for MBC. Specimens were also tested by central FISH. A sub-population treatment effect pattern plot (STEPP) was generated to examine the progression-free survival (PFS) rate at 12 months after treatment with trastuzumab across the distribution of H2T. Kaplan-Meier (KM) analyses were performed comparing the PFS of FISH(-), H2T low (log10H2T < 1.25) patients with those of FISH(+), H2T high (log10H2T ≥ 1.95) and FISH(+), H2T intermediate (1.25 < log10H2T < 1.95) groups. Cutoffs were identified by lowest p-value in a positional scanning analysis. Results: The PFS rate improved gradually with increasing H2T in STEPP analyses. At the highest levels of H2T, an abrupt decrease in the PFS rate was observed, consistent with a reduction in susceptibility to trastuzumab. KM analyses demonstrated that patients who were FISH(+), H2T intermediate had a significantly longer PFS than patients who were FISH(-), H2T low (median PFS 12.6 vs. 4.5 mos; HR = 0.34; p < 0.0001). Patients that were FISH(+), H2T high experienced a PFS that was no better than patients that were FISH(-), H2T low (median PFS 4.6 vs. 4.5 mos; HR = 0.87; p = 0.68). Conclusions: Precise quantitation of HER2 expression levels allows the identification of multiple sub-populations of HER2(+) patients that have different clinical outcomes on trastuzumab. MBC patients with very high levels of H2T could represent a sub-group with de novo resistance to trastuzumab who may benefit from combined therapy.

[Table: see text]
Patterns of HER2/neu, hormonal receptor expression, and proliferative activity in primary and metastatic breast cancer
Authors: Giotta F. , Simone G. , Fazio V. , Longo S. , Petroni S. , Rubini V. , Liuzzi M. , Addati T. , Colucci G.
Published: August 2020

1071

Background: The modification of biological features of metastatic sites (MS) in breast cancer patients arise some debatable questions regarding clinically usefull information and safe/efficient methods to detect them. Fine needle aspiration (FNA) of visceral MS is an available tool to characterize tumoral lesion and liquid based citology technique provides usefull cell samples for immunocytochemical and/or molecular assays. Methods: The aim of this study was to compare prognostic and predictive factors obtained from primary tumors (PT) and corresponding MS. Fluorescent in situ hybridization (FISH) was performed for HER2/Neu determination, while ER, PgR, and MIB-1 were detected by immunochemistry using specific monoclonal antibodies on monolayered cell sample and in the corresponding cytoinclusion. FNA with a 21–23 G needle was performed in 20 consecutive breast cancer patients with distant metacronous MS. Results: In 8/20 patients, both ER and PgR were absent in PT and in MS, in 7 were both present, in 4 cases only ER was detected, and only 1 case was ER negative with a low PgR. About the proliferative activity (MIB-1 index: cut off value >20%) only 3 MS presented an higher value. With regard to HER2/Neu, 4/20 cases were amplified and no discrepancies were found between cytological and cytoinclusion specimens. No substantial changes were found about kinetic activity. HER2/Neu status as assessed in PT was confirmed in MS in 10/12 cases; a lung mestastasis showed amplification while primary was not amplified and a liver lesion lost the amplification which was detected in the PT. Conclusions: Our study strongly suggest the opportunity in using FNA for detection of prognostic and predictive factors in MS. Pectasides et al. (Anticancer Res. 2006) found in patients with altered or conserved HER2/Neu in PT and in MS different response rates between the two groups and a significant poorer prognosis in patients with altered Neu. We think that liquid-based cytology applied on FNA of distant metastases could help us to understand some more in this issue.

No significant financial relationships to disclose.
Randomized, phase II trial comparing continuous versus intermittent capecitabine monotherapy for metastatic breast cancer (MBC)
Authors: Martín M. , Calvo L. , Martínez N. , Ramos M. , Muñoz M. , Zamora P. , Hernando B. , Casado A. , García-Saenz J. A. , Puente J.
Published: August 2020

1086

Background: The approved capecitabine (X) regimen in MBC is 1,250 mg/m2 bid, d1–14 q21d (Xint). However, dose modifications are often required primarily for hand-foot syndrome and diarrhea. Therefore we designed an alternative regimen aimed to reduce the severity of these side effects while maintaining the total cumulative dose and efficacy of X. Methods: The primary objective was to show non-inferiority of X 800 mg/m2 bid, d1–21 q21d (Xcont) to Xint in terms of 1-year PFS rate. Secondary endpoints included response rate (RECIST), PFS, duration of response, OS, and safety (NCI CTCAE v2.0). Assuming median PFS of 5 months and 2-sided α=0.05, 176 evaluable patients (pts) will be needed to give 80% power. Pts are ineligible if they have received >2 chemotherapy regimens for MBC or prior X, or if they have HER2-positive MBC or symptomatic CNS metastases. Treatment is continued until progression, unacceptable toxicity, or refusal. Dose interruption/reduction is implemented if pts experience grade 2–4 clinically relevant adverse events. Results: The current interim analysis includes the first 60 pts, with median age 55 years (range 33–79) in the Xcont arm and 67 years (range 34–88) in the Xint arm. 26% and 14%, respectively, were hormone receptor negative. Prior chemotherapy included a taxane in 48% vs 52% and an anthracycline in 65% vs 76%, respectively. X was given as first-line chemotherapy in 48% and 38% of pts, respectively. Median duration of treatment was 7 cycles for Xcont vs 6 cycles for Xint. Dose reduction was required in 10% of cycles in each arm. Toxicity led to treatment discontinuation in 1 vs 8 pts, respectively. Activity and safety results at interim analysis are summarized below (Table). Conclusions: Xcont and Xint seem similarly active in MBC in this interim analysis. Xcont appeared slightly better tolerated. The study will continue recruiting additional pts.

[Table: see text]

No significant financial relationships to disclose.
Predicting response to second-line trastuzumab-based therapy in patients (pts) with HER2-positive advanced breast cancer (ABC)
Authors: Bartsch R. , Wenzel C. , Pluschnig U. , Dubsky P. , Gampenrieder S. P. , Rudas M. , Mader R. , Gnant M. , Zielinski C. C. , Steger G. G.
Published: August 2020

1090

Background: In HER2-positive ABC, the upfront use of trastuzumab (T) is well established. Following progression upon first-line therapy, pts may be switched to lapatinib. Others however may be candidates for continued antibody therapy. Finding the optimal treatment approach therefore is pertinent. Here, we aimed to identify factors predicting response to second-line T-based therapy. Methods: 80 pts (median age 50.5 years) with ABC treated with >1 line of T-containing therapy were identified from a breast cancer database. HER-2-status was determined by immunohistochemistry (HercepTest) and re-analyzed by FISH if a score of 2+ was gained. Response rate (RR; CR+PR), clinical benefit rate (CBR; CR+PR+SD >6 months), time to progression (TTP), overall survival (OS), and cardiac toxicity were recorded. Response was evaluated every three months (m) using UICC criteria. TTP and OS were estimated using the Kaplan-Meier product limit method. In order to identify factors associated with TTP, the following variables were included in a Cox regression model: age (≤65 y/>65 y), initial tumor stage (<IV/IV), grading, ductal/lobular carcinoma, endocrine receptor status, prior non T-containing palliative chemotherapy, metastatic sites (visceral/non-visceral only), and clinical benefit (CB) from T-based first-line therapy. The same variables were used in a multinomial logistic regression model to evaluate their influence on treatment response. P values <0.05 were considered to indicate statistical significance. Results: Median time of observation was 28 m. TTP was median 9.3 m (95% CI 7.73–10.96) in the first-line and 7.5 m (95% CI 6.14–8.82) in the second-line setting (n.s.). First-line treatment yielded an 83% CBR, as compared to 54% in second-line. None of the factors included in the multivariate model independently predicted outcome. A significant deterioration of cardiac function was observed in a single patient; 22.5% developed brain metastases. Conclusions: T in multiple lines showed considerable activity. None of the variables investigated could independently predict response to second-line therapy. In order to reliably predict activity of second-line T-based therapy evaluation of other factors such as truncated HER2 or PTEN-loss appears necessary.

[Table: see text]
Use of multiplex mutation genotyping to identify novel and protective mutations in breast cancer
Authors: Kalinsky K. , Jacks L. M. , Hedvat C. , Bhanot U. , Patil S. , Heguy A. , Asher M. , Drobnjak M. , Hudis C. , Moynahan M. E.
Published: August 2020

11004

Background: We recently analyzed 590 primary invasive breast tumors for PIK3CA mutations by multiplex massARRAY genotyping. We identified a 32.5% PIK3CA mutation rate (manuscript submitted). Associations between PIK3CA mutation status and favorable pathology, such as lower grade tumors, lymph node negativity and hormone receptor (HR) positivity, were observed. Multiplex analysis allows the rapid assessment of mutations not commonly described in breast cancer. To identify activated pathways that may serve as predictive biomarkers, tissue microarrays (TMA) underwent immunohistochemical (IHC) analysis. Methods: 590 archival formalin-fixed paraffin embedded (FFPE) tumors > 1 cm were used to ensure adequate tissue procurement for mutation detection and TMA construction. MassARRAY (Sequenom) genotyping was performed on native DNA to identify PIK3CA, RAS, RET, and other known mutations. IHC staining of the TMAs included assessment of steroid nuclear receptors, HER2 expression, Akt pathway activation (including pAKT, p70S6K, eIF4E), and PTEN. Stained TMAs underwent digital quantitative image analysis and scoring (Aperio, Vista, CA). The Kaplan-Meier method and Cox models were used in univariate and multivariate analysis for associations of mutation status and clinicopathologic features on overall survival (OS) and breast cancer-specific survival (BCSS). Results: Compared to wild-type, PIK3CA mutated tumors (median f/u: 12.8 years) demonstrate a significant improvement in OS (p=0.03) and BCSS (p=0.004). For patients with any PIK3CA mutation, the improvement in BCSS is maintained in HR positive and ER negative subgroups. In addition to PIK3CA mutations, RAS and RET mutations are identified in a small proportion of breast tumors. Additional analysis to evaluate the association of mutation status and biomarker data derived from the TMA analysis will be performed for meeting presentation. Conclusions: We have recently defined the positive prognostic significance of PIK3CA mutations in breast cancer. RAS mutations are confirmed to occur rarely in breast cancer. The finding of RET mutations in breast cancer is novel. Future tumor biomarker identification directed towards predictive measurement will assist in tailoring therapy to appropriate patient populations.

No significant financial relationships to disclose.
Performance of a blood-based gene-expression test, BCtect, for early breast cancer detection
Authors: Tobin D. , Bårdsen K. , Kauczynska M. , Kumar Y. , Shroff C. , Punia D. , Srinivasan V. , Børresen Dale A. , Sharma P. , Hollingsworth A.
Published: August 2020

11012

Background: We report the development of a gene expression based blood test to detect breast cancer (BC). Validation of the test has been performed in multiethnic populations (European/US and Indian). Here we report findings from a multi-centre validation study. Methods: In a multicentre-study, blood samples were collected from women recruited in 4 groups 1) early stage BC, 2) late stage BC, 3) benign breast lesions, 4) without abnormal mammographic findings. Samples were collected in PAXgene tubes and shipped to a central laboratory where RNA extraction and quality control were performed. Gene expression analysis was performed using TaqMan low density arrays containing a BC-specific gene signature in a 96-gene assay format. The overall gene expression pattern was converted to a test score which was used to classify the subject as positive or negative for BC. A total of 442 samples were used to develop an India specific algorithm and estimate its prediction efficacy. Samples were divided into a training cohort (N=292) and a test cohort (N=150). The performance of the test was determined from the class of the independent test cohort. Results: The model correctly predicted the class of 110/150 test samples, resulting in an overall accuracy of 73%. Performance was similar for early and late stage cancer and for benign and healthy (no mammographic findings). No significant difference in diagnostic performance was seen between pre- (57/75 correctly predicted) and post-menopausal (53/75 correctly predicted) women indicating the clinical value of our test in younger women. No statistical correlation between correct/false test score and body mass index was noted. Lesion size varied from 8mm diameter to 120mm. No statistical correlation of the test score was seen with lesion size in this cohort. Conclusions: The blood based gene expression test showed similar diagnostic performance between women with early and late stage BC, and the test was independent of the subject's BMI and menopausal status suggesting broad applicability of the test and indicating its clinical potential in younger women where mammography is of less value due to dense breast tissue. No correlation with lesion size was seen suggesting the lower limit of detection is below 8mm.

[Table: see text]
Semi-quantitative protein analysis of HER2 and ER levels in human breast cancer reveals broad expression ranges within HER2+ and ER+ phenotypes
Authors: Liotta L. , Pierobon M. , Wulfkuhle J. , Laird J. , Livasy C. , Espina V. , Esserman L. , Petricoin E.
Published: August 2020

11014

Background: ER and HER2 measurements underpin a majority of breast cancer clinical testing, yet determination of ER and HER2 protein levels are routinely performed using subjective approaches. We have developed a semi-quantitative calibrated protein microarray, the Reverse Phase Protein Microarray (RPMA), to more adequately determine accurate and precise protein expression levels in clinical tissue specimens. We utilized this method to determine HER2 and ER expression levels and compared the results to those values reported from the clinical laboratory. Methods: Pure tumor epithelium from 149 frozen pre-treatment human breast cancer tissue specimens (from the I-SPY TRIAL: CALGB 150007/150012, ACRIN 6657) were procured via Laser Capture Microdissection and protein pathway mapping was performed whereby the ER (N=112) and HER2 (N= 118) levels were directly measured and compared with reported IHC values. Results: Overall, RPMA measurements of HER2 had excellent correlation with IHC and FISH HER2 determination with no IHC or FISH false positives (88/88). 7 out of 30 of the FISH/IHC+ cases were found by RPMA to have HER2 values as low or lower than the FISH/IHC- cases with the HER2+ population having RPMA expression levels that varied by as much as 10-fold. There was less concordance between RPMA ER values and IHC ER values. Detailed analysis of a more homogeneous ER+ population (Allred =8) revealed a large dynamic range of expression of ER (10–20 fold) by RPMA. The HER2 and ER RPMA results were independently validated by Western Blot using a separate biopsy. Conclusions: Discreet protein expression values obtained by RPMA for ER and HER2 reveal distinctly broad expression values, with as much as 10–20 fold dynamic range in expression, even in a homogeneous (e.g. Allred score of 8) population. Such dynamic differences in protein expression may produce dramatic effects in therapeutic response rate. These findings, if found to be clinically useful, point to a potential need for more fine-tuned protein expression determination by quantitative high-throughput technologies for patient stratification even for standard-of-care FDA approved therapies.

[Table: see text]
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]
The Egyptian National Breast Screening Program: Priorities, challenges, and results of the pilot phase
Authors: Salem D. S. , Kamal R. , Said N. H. , Adel I. , Talaat S. , Adel L. , Abdel Razek N. , Helal M. , Selim A.
Published: August 2020

1523

Background: According to the World Health Organization,the number of breast cancercases in developing countries will increase dramatically by the year 2050. Egypt is likely to see an increase in this disease burden unless effective programs for early detection and control are implemented. Many women, especially those who are medically underserved, still do not understand the importance of regular mammograms, or how and where to get one. Methods: Four mobile mammography vans were launched in October 2007, to screen women over 45 years old in the underserved areas of Cairo. Each van was equipped with a full field digital mammography (FFDM) machine, dedicated computer system linked to the National Breast Screening Center via video SAT & ADSL, sphygmomanometer, blood glucose measuring kit, and spring scale and meter to measure weight and height. Based on positive findings, patients were directed to Cairo University Hospital to receive appropriate treatment. Mobile units continued to operate through October, 2008. Results: From October 2007 through October 2008, 11,414 women were screened for breast cancer, hypertension, diabetes, and obesity. Two hundred forty four (2.13%) women were radiologically positive for cancer; of these, only 112 (45.9%) women agreed to be recalled for assessment; of these, 49.1% were confirmed to be true positive with BI-RADS 4,5 (61% cases were mass, with 27.9 % 1–2 cm in size; 16.4% cases were microcalcifications alone; multicentricity in 6.6 %; bilaterality in 2.5% of cases). 36.6% were false positive, and 14.2% are under further investigation. Conclusions: Although Cairo is the most developed city in Egypt, there is lack of breast cancer awareness, especially in the underserved areas. Breast cancer is now a priority for the Ministry of Health, with four more vans and 10 fixed FFDM units to be implemented during the next year. A 5-year plan has been established to cover all 29 Egyptian Governorates.

No significant financial relationships to disclose.
Detection of human papillomavirus DNA from the breast carcinomas and the cervix: Are they correlated?
Authors: Choi J. , Lim H. , Kim W. , Lee S. , Kim S. , Kim S. , Kim D. , Cho E. , Lee J. , Nam S. , Yang J.
Published: August 2020

1544

Background: The association between human papillomavirus (HPV) and cervical cancer is well known. However, it remains unclear whether there is also a correlation between HPV infection and human breast cancer. The aim of this study is to investigate the hypothetic association between HPV infection and breast carcinoma through the comparison of the type of HPV infection in the breast and cervix. Methods: From April to December 2008, 106 patients who were diagnosed as breast cancer and underwent mastectomy were analyzed. Their breast tissue (tumor, normal parenchyme, and nipple-areolar complex) and cervix smear were analyzed for HPV infection with DNA chip microarray method. Results: 24 patients (23.1%) showed HPV infection in their cervix smear; high-risk type of HPV was found in 12 patients. But only six patients (5.8%) revealed the HPV infection in breast cancer; half of them were high-risk group (HPV-16, 31); the same types of HPV was found at the normal breast tissue in two patients of them. However, there were no patients with HPV infection in both breast and cervix concurrently. Conclusions: There were no positive results for HPV infection of cervix in HPV-infected breast cancer patients. Also, we cannot find that the presence of high-risk HPV in the breast might be related to the breast carcinogenesis. We concluded that HPV infection is not correlated to the carcinogenesis of breast.

No significant financial relationships to disclose.
Phase I/II study of sorafenib and temsirolimus for patients with recurrent glioblastoma (GBM) (NABTC 05–02)
Authors: Wen P. Y. , Cloughesy T. , Kuhn J. , Lamborn K. , Abrey L. E. , Lieberman F. , Robins H. I. , Wright J. , Prados M. D. , Gilbert M.
Published: August 2020

2006

Background: The activity of targeted molecular therapy with single agents has been disappointing in GBM. Combination therapy simultaneously targeting both the PI3k/Akt/mTOR and the MAP kinase pathway may be more effective. Methods: The North American Brain Tumor Consortium conducted a phase I/II study of sorafenib (VEGFR/PDGFR/Raf inhibitor) in combination with temsirolimus (mTOR inhibitor) in recurrent GBM. Eligibility criteria included histologically proven GBM, radiologic progression, > 18 years old, KPS > 60, adequate bone marrow reserve, and organ function. There was no limit on the number of prior relapses for phase I and no more than two prior relapses for phase II. No enzyme-inducing antiepileptic drugs were allowed. Dose-finding used a standard 3 + 3 design with the MTD defined as the dose with DLTs in 1/6 or fewer patients. The primary endpoint for the phase II component was PFS6 (p0 = 15%; p1 = 35%). A 2-stage design was used. If > 4 of the initial 19 patients achieved PFS6, an additional 14 patients would be accrued for a total of 33 patients. Results: In phase I, 13 patients were enrolled. Median age was 50 years (32–59); median prior chemotherapy 1 (1–3). The initial doses were sorafenib 200 mg bid and temsirolimus 25 mg intravenously once weekly. The MTD was 400 mg bid of sorafenib daily combined with 25 mg of temsirolimus weekly. At this dose 1/6 patients had a DLT (grade 3 thrombocytopenia). Other grade 3 or 4 toxicities included transaminitis, hypophosphatemia, fatigue, diarrhea, and hyperlipidemia. Pharmacokinetic data were similar to that for single agent sorafenib and temsirolimus suggesting that there were no significant interaction between the two drugs. In phase II, 19 patients were accrued to stage I. Median age 50 years (24–64); median prior relapses 1 (range 1–2). One patient was found not to have GBM on central review. No patient remained progression free at 6 months, although two patients stopped treatment prior to 26 weeks for other than progression (alternative therapy, cerebral ischemia). As result, the study was terminated and did not proceed to the second stage. Conclusions: The combination of sorafenib and temsirolimus was moderately well-tolerated but did not demonstrate sufficient efficacy in recurrent GBM to warrant further investigation.

No significant financial relationships to disclose.