bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between race and BMI with response to neoadjuvant endocrine therapy in postmenopausal women with large estrogen receptor-positive breast cancers.
Authors: Ambros T. , Sujoy V. , Fernandez C. G. , Reis I. , Wright J. L. , Jorda M. , Saigal K. , Hurley J.
Published: February 2017

132

Background: Neoadjuvant endocrine therapy is increasingly used in the treatment of breast cancer. There is a need to define which patients will benefit the most from this form of therapy.

Methods: Retrospective review of medical records from University of Miami/Jackson Memorial Hospital from 1998 to 2011. Response to neoadjuvant endocrine therapy was evaluated through comparison of palpable breast mass size at presentation with pathological tumor size in surgical specimens. Response was stratified as “No Response” (NR), indicating no change or increase in size, “Moderate Response” (MR) as up to 50% decrease in size, and “Good Response” (GR) > 50% decrease in size. Data was analyzed by body mass index (BMI), type of endocrine therapy, race and histology.

Results: Data from 62 postmenopausal, estrogen receptor-positive women who received neoadjuvant hormonal therapy was analyzed. Median age was 62 (range 50-91). Clinical stage: II 24.2%, IIIA 25.8%, IIIB 35.5%, IIIC 6.5%. Endocrine therapy used was tamoxifen (14.5%) or aromatase inhibitor (AI) (85.5%). Response rate was NR in 22.6%, MR in 43.5% and GR in 33.9%. Fifty two patients had available height and weight information. In patients receiving AI, BMI was significantly higher in the NR group vs. GR group (mean BMI 38.68 vs. 27.56, p=0.041). Mean BMI in MR was 32.18, not statistically different from either group. Analysis of both AI and tamoxifen treated patients yielded similar results (results not included). The rate of GR was higher in the Caucasian vs. African American population (40.4% vs. 14.3%, p=0.017). Inversely, the rate of NR was higher in African Americans (50.0% vs. 14.9%, p=0.017). There was a trend towards more favorable tumor size change in Caucasian vs. African American women (mean 36.19% reduction vs. 11.69% increase in tumor size, p=0.058). The mean tumor size change was more favorable in ductal vs. lobular carcinomas (34.75% decrease vs 8.69% increase, p=0.184).

Conclusions: Lower BMI and Caucasian ethnicity were associated with higher frequency of GR (> 50% decrease in tumor size) to neoadjuvant endocrine therapy. No association was found between response and stage, PR status or HER2 expression.
Relative dose intensity (RDI) assessment in an academic center.
Authors: Arnaout A. , Leblebjian H. , Bartel S. , Hassett M. J.
Published: February 2017

139

Background: Patients with early breast cancer treated in the adjuvant setting realize maximum benefit as to disease- free and overall survival when they receive their full planned dose of chemotherapy. Due to the aggressive treatment regimens, patients are at increased risk of dose delays and reductions, which result in reduced RDI. Studies have shown that at RDI < 85%, treatment outcomes are compromised. We sought to calculate the RDI attained in our breast cancer clinic and identify factors contributing to decreased RDI.

Methods: We retrospectively reviewed records of 383 patients treated between January 2008 and December 2009. Treatment blocks were reviewed separately to better identify contributing factors to decreased RDI. Regimens were dose-dense doxorubicin and cyclophosphamide (ddAC), dd-paclitaxel (ddT), paclitaxel and trastuzumab (TH), and TH post ddAC. G-CSF support was noted when present. Dose reductions and dose delays (in days) with reason(s) were recorded for patients with RDI < 85%. Patients who switched care or regimen were excluded from this study.

Results: Of the 383 patients, 150 received ddAC; 101 ddT; 67 TH and 65 TH post ddAC. Of these, the percentage of patients with RDI < 85% was 10.4%. RDI was <85% in 8.7%, 6.9%, 14.9%, and 15.4% in the ddAC, ddT, TH, and TH post ddAC regimens, respectively. The major impediments were neutropenia in the anthracycline containing regimen, neuropathy with taxanes, and cardiotoxicity with trastuzumab. No dose delays were seen for administrative issues.

Conclusions: Our results show that 10.4% of treated patients had RDI < 85%. These results were superior when compared to historic data for same regimens. Major reasons for decreased RDI were neutropenia, neuropathy, and cardiotoxicity. Improving risk assessment of neutropenia before initiating treatment could improve RDI in this patient population. Prophylaxis with vitamin B6 may help reduce incidence of neuropathy. Efforts to assure on-schedule treatments should be maintained. This includes comprehensive paramedical support to overcome any hurdles to on-time treatment. Proper education of patients on the importance of RDI can increase awareness of the value of cooperating with the provider and encourage them to persevere with the treatment.
Risk of having BRCA mutations in women with triple-negative breast cancer: A systematic review and meta-analysis.
Authors: Tun N. M. , Villani G. M. , Ong K.
Published: February 2017

160

Background: Increased prevalence of BRCA1 mutations (BRCA1) has been associated with the occurrence of triple-negative breast cancer (TNBC) (estrogen receptor [ER]- and progesterone receptor [PR]-negative, HER2-negative) in independent clinical studies. However, BRCA2 mutation (BRCA2) has not been found to overrepresent in women with TNBC. We have performed a meta-analysis of these studies to provide further statistical evidence of the association between BRCA positivity and TNBC.

Methods: A Medline search of the MeSH terms “BRCA”, “triple”, and “negative” yielded 37 articles. A search of ASCO abstracts yielded 18 relevant articles. Random effects model was used for analysis due to heterogeneity among the proportions of included studies (Cochran’s Q = 18.52 and 15.18, tau2 = 0.61 and 1.29, I2 = 73% and 80% for BRCA1 and BRCA2 respectively). Mantel-Haenszel method was applied to calculate the pooled event-based odds ratio (OR) with 95% confidence interval (CI).

Results: 6 studies including 1,602 BC patients were eligible for analysis of BRCA1 and 4 studies including 1297 BC patients for BRCA2. 172 patients with BRCA1 mutations and 79 patients with BRCA2 mutations were analyzed. Among these 6 studies, 1 included Ashkenazi Jewish women exclusively and 1 included only women of Chinese descent. The overall prevalence of BRCA1 was 10.05% (172 out of 1,602), and for TNBC patients 21.94% (95 out of 433) with an odds ratio of 5.90 (CI: 2.75, 12.66, p < 0.00001). TNBC was not a risk for BRCA2 (OR = 0.67, CI: 0.19, 2.39, p = 0.53). Chinese women with TNBC did not have an elevated risk of BRCA1 (OR = 0.94, CI: 0.24, 3.66) in contrast to Jewish women with TNBC who had the highest risk of BRCA1 among the populations studied (OR = 21.79, CI: 9.03, 52.55).

Conclusions: Women with TNBC carry a significantly high risk of having BRCA1 but not BRCA2 mutations. We recommend genetic testing for BRCA1 mutations in women with TNBC especially in Ashkenazi Jewish population. Further studies on Chinese population are needed to further establish the relationship between TNBC and BRCA1 mutations in this cohort.
Assessing the added value of breast tumor markers in breast cancer genetic risk prediction model BRCAPRO.
Authors: Arun B. , Biswas S. , Tankhiwale N. , Blackford A. L. , Gutierrez-Barrera A. M. , Litton J. K. , Hortobagyi G. N. , Amos C. I. , Parmigiani G.
Published: February 2017

164

Background: BRCAPRO is a widely used genetic risk prediction model for estimating the carrier probabilities of mutations in BRCA1/2 genes. BRCAPRO has been enhanced to utilize information on molecular markers ER, PR, CK5/6, and CK14. However, no independent validation study on the utility of these markers in risk prediction exists to support using these in actual clinical settings. Further, an important predictive and prognostic marker for breast cancer, Her-2/neu (Her2) is not utilized in BRCAPRO. Therefore, the aim of our study was to: 1) incorporate Her2 in BRCAPRO; 2) conduct a validation study of the markers.

Methods: Patients with breast cancer at the UT M. D. Anderson Cancer Center’s breast clinic who were referred for genetic evaluation were included. Separate sets of cohort were used for model building with Her2 and validation to avoid bias. This study was approved by the IRB. For the model building, we estimated the joint probabilities of ER and Her2 status for carriers and non-carriers of BRCA1/2 mutations. For the validation, BRCAPRO was run at two settings: 1) no marker data used and 2) ER/PR used. We calculated the Area Under the receiving operator characteristic Curve (AUC) using the probabilities of carrying any of BRCA1 or BRCA2 and conditional probabilities of carrying BRCA1 (CondBRCA1) and BRCA2 (CondBRCA2) given a proband is carrier.

Results: The model-building set for Her2 was based on 409 probands and validation set on 796 probands wherein 23% of the probands were carriers. In the model-building step, we found that joint consideration of Her2 and ER/PR is useful in discriminating between carriers and non-carriers in some subgroups, e.g., a proband with ER-, Her2+ is much more likely to be a non-carrier than a carrier. In the validation step, the AUC for CondBRCA1 and CondBRCA2 improved substantially when ER/PR was used. We are in the process of coding Her2 in BRCAPRO and then validating its utility.

Conclusions: Breast tumor markers are useful for prediction of BRCA1/2 mutation status in the BRCAPRO model. ER/PR helps discriminate between BRCA1 and BRCA2 mutation carriers. In our ongoing validation study Her2 is expected to improve discrimination between carriers and non-carriers in certain sub-groups.
Is obesity associated with increased recurrence risk in estrogen receptor (ER)-positive breast cancer?
Authors: Yap K. K. L. , Efiom-Ekaha D. N.
Published: February 2017

171

Background: Oncotype DX Score is a 21-gene expression analysis that has been validated clinically as a reliable predictor of breast cancer recurrence for ER-positive, node-negative breast cancers. Obesity is recognized as a risk factor for many cancers, including breast cancer. Additionally obesity has been shown to be an independent prognostic factor in breast cancer. The primary objective of this study is to determine the correlation between obesity and Oncotype DX score, hence the relationship between obesity and breast cancer recurrence in ER-positive breast cancer. The secondary objective is to investigate the association between weight gain after diagnosis and breast cancer recurrence.

Methods: An IRB-exempted retrospective chart review of female patients at Wellspan Group with ER-positive breast cancer who had Oncotype DX analysis in 2008 and 2009. Data collected included Oncotype DX score and BMI (at diagnosis, 6 months and 12 months). Data were analyzed to determine the correlation between Oncotype DX score and BMI at diagnosis, at 6 months and at 12 months. The correlation between Oncotype DX score and BMI changes at 12 months also was determined.

Results: A total of 125 patients were identified; 103 had BMI recorded at diagnosis, 88 had BMI recorded at 6 months and 87 had BMI recorded at 12 months. Of these, we were able to determine the BMI changes at 12 months for 82 patients. The Pearson correlation scores were 0.091 (p = 0.361), 0.074 (p = 0.492), and 0.047 (p = 0.669) for BMI at diagnosis, at 6 months and at 12 months respectively. The Pearson correlation score was 0.007 (p = 0.948) for BMI changes at 12 months.

Conclusions: Obesity and weight gain are not independent predictors of recurrence in patients with ER-positive breast cancer. The reported adverse prognostic associations may be more prominent in ER-negative breast cancers. This is consistent with the reports suggesting a higher rate of ER-negative, high-grade cancers in obese women as well as a greater magnitude of benefit from dietary and weight reduction interventions seen in women with ER-negative cancers.
Mammography screening and surgical breast cancer treatment in Norway.
Authors: Suhrke P. , Mæhlen J. , Schlichting E. , Zahl P. H.
Published: February 2017

177

Background: We have investigated whether the introduction of organized mammography screening in Norway led to less aggressive breast cancer surgery in the invited age group.

Methods: We obtained aggregate incidence and surgical treatment data for women treated for ductal carcinoma in situ or invasive breast cancer from the Norwegian Cancer Registry. Rates of breast operations (mastectomy plus breast conserving therapy) and rates of mastectomy only for three age groups; women aged 40-49, 50-69 and 70-79 years were calculated. Changes in rates from a pre-screening period (1993-95) to a screening introduction phase (1996-2004) and then to a screening period (2005-08) are presented as hazard ratios comparing invited and non-invited women.

Results: From the pre-screening period (1993-95) to the screening period (2005-08) the annual breast operation rate increased by 70% (HR=1.70 95% CI 1.62 to 1.78), from 180 to 305 per 100 000 women in the invited age group (50-69 years). In contrast, the increase was only 8% (HR=1.08 95% CI 1.00 to 1.16), from 133 to 144 per 100 000 women per year in the younger, non-invited age group (40-49 years) while an 8% decline (HR=0.92 95% CI 0.86 to 1.00), from 227 to 214 per 100 000 women per year occurred in the older, non-invited age group (70-79 years). In the screening period (2005-08) mastectomy rates fell similarly in invited and non-invited women. However, during the screening introduction phase (1996-2004) the mastectomy rate was 31% (HR=1.31 95% CI 1.20 to 1.43) higher in screened compared to non-screened younger age group. Annual mastectomy rates increased in invited from the pre-screening period to the screening introduction period from 156 to 167 per 100,000 women compared to a decline from 109 to 91 per 100,000 women in younger non-invited.

Conclusions: Mammography service screening is associated with a marked increase in breast operation rates in the invited age group and also an increase in mastectomy rates. While overdiagnosis likely caused the initial increase in mastectomy rates and the overall increase in use of surgery in the age group subjected to screening, the more recent decline in mastectomy rates has affected all age groups and is likely to have been caused by changes in surgical policy.
What has changed in the management of breast cancer in the past 25 years at the Istanbul University Hospital?
Authors: Aydogan F. , Gazioglu E. , Canbay E. , Aydin I. , Aydogan T. , Uras C. , Celik V. , Cengiz A. , Ferahman M. , Unal H.
Published: February 2017

184

Background: There have been important changes in diagnosis and treatment of the breast cancer during the last century. Diagnosing the cancer in early stages brought the new approaches such as breast conserving surgery instead of mastectomy and sentinel lymph node biopsy instead of direct axillary disection. In this study our purpose is to compare the operations which were performed in 1983 and 2008 on breast cancer patients of our clinic and to search the differences in their ages and tumor characteristics.

Methods: In each group the files of 100 patients, who were operated in 1983 and 2008, were compared with each other including the variabilities such as size of the tumor, age of the patient and operation technique.

Results: There were 100 patients in both of the groups. Six of the patients (6%), who were operated on in 1983, were found to be between the ages of 20-39 and this percentage was found to be much higher as 19% (19 patients) in 2008. In 1983, there wasn't any patient at stage 0 and the number of patients at stage 1 was 15 (15%), in 2008 the number of stage 0 patient was 9 (9%) and stage 1 patient was 25 (25%). Breast conserving surgery rate was found to be 9% in 1983 and 41% in 2008.

Conclusions: According to the data of this study, breast cancer is now being seen at younger ages when compared to 25 years ago. Currently the patients have diagnosis at earlier stages and the breast conserving surgery is much more prevalent. Earlier-stage diagnosis can be explained by widespread use of screening mamographies and increasing consciousness of the patients.
Risk of breast cancer among Japanese women with a positive family history.
Authors: Suzuki J. , Hojo T. , Jimbo K. , Asaga S. , Kinoshita T.
Published: February 2017

191

Background: Most breast cancer cases are sporadic, rather than associated with inherited gene mutations, such as BRCA1 and BRCA2. However, women with a family history of breast cancer are at increased risk of developing breast cancer compared to those women without any family history, even if they lack these gene mutations.

Methods: We analyzed 10892 patients including bilateral breast cancer cases (total of 11398 breast cancers) who underwent surgery at our hospital between 1962 and 2009. We excluded 295 cases whose family history data were not available. Clinical and pathological differences between following patient groups were tested; 9528 patients or 9955 cancers (88%) with negative family history (FH-), 896 patients or 951 cancers (8%) who had at least one first-degree relative with breast cancer (1FH+), 468 patients or 492 cancers (4%) who had second-degree relative with breast cancer (2FH+), and 1364 patients or 1443 cancers (12%) with family history regardless of first- or second-degree relative (FH+). Significance was established at a p-value of < 0.05.

Results: Among the family members, sisters were more likely to have treated for breast cancer (38% in FH+ group), followed by mothers (27%), aunts (26%), grandmothers (7%), and daughters (2%). The incidence of developing contralateral breast cancer was significantly higher in 1FH+ group, compared to patients in FH- and 2FH+ groups. No other factors showed any significant difference, including the incidence of cancer in other organs, pathological characteristics, and age of onset, although BRCA1 and BRCA2 mutation may be associated with increased risk of developing breast cancer at younger age. Outcome studies with available data did not show any significant difference in overall survival between FH+ and FH- patients.

Conclusions: A Japanese woman with a positive family history has a higher risk of developing breast cancer than women without any close relatives with breast cancer, similar to the results reported in Western countries where prevalence of breast cancer is higher. Regular checkup of contralateral breast is important for those patients whose first-degree relatives have also been diagnosed with breast cancer.
The effect of combined therapy with 5-aza-2’-deoxycytidine, sodium butyrate, and tamoxifen on apoptosis of breast cancer cell lines.
Authors: Kim S. J. , Kim J. S.
Published: February 2017

197

Background: DNA methytransferase inhibitors and histone deacetylase inhibitors have been extensively studied in recent years as another novel and specific target therapy for cancer treatment. In this study, we investigate the effect of combined therapy of 5-aza-2’-deoxycytidine (5-aza-CdR), sodium butyrate (SB) and tamoxifen on tumor suppression and expression of anti- or proapoptic proteins in breast cancer cell lines.

Methods: Water-soluble tetrazolium salt-1 was used to study the proliferation rate of the cells in MDA-MB-231 and MCF-7 breast cell lines treated with the different concentration of variable combinations of these agents. Western blot was used to explore the change of expression of proapaptic regulator proteins according to variable combined therapy. Methylation specific transcriptase-polymerase chain reaction and immunofluorescence staining were used to analyze the ER re-expression in the MDA-MB-231 and MCF-7 cell lines treated with 5-aza-CdR.

Results: We observed that the survival fraction of MCF-7 and MDA-MB-231 cells treated with 2um, 4um, 8um 5-aza-CdR and 0.5mM, 1mM and 2mM SB respectively was decreased in inverse proportion to the concentration. The survival fraction of MCF-7 cells as ER positive cell lines treated with 2.5um, 5um and 10um tamoxifen was slightly decreased in inverse proportion to the concentration, but that of MDA-MB-231 cells as ER negative cell lines was slightly increased regardless the concentration. ER re-expression was detected in ER negative cell line, MDA-MB-231 treated with 5-aza-CdR. In cases of being treated with variable combination of agents in MCF-7 and MDA-MB-231 cell lines, the survival fraction treated with the combination of all 5-aza-CdR, SB and tamoxifen was the lowest. We also observed that the expression of proapoptic regulator protein were slightly decreased in MCF-7 and MDA-MB-231 cells treated with combined 5-aza-CdR with SB and combined with all agents.

Conclusions: Our data indicate that combined therapy with 5-aza-CdR, SB and tamoxifen was the most effective in apoptosis of breast cancer cells and changed expression of the proapoptic regulator proteins.
Accuracy and upgrade rates of stereotactic vacuum-assisted breast biopsy: Impact of number of core samples taken on malignancy underestimation rates.
Authors: Vossen J. A. , Edwards S. D. , Pronovost M. , Reeser P.
Published: February 2017

20

Background: There are multiple options for the diagnostic evaluation of mammographic suspicious breast abnormalities. The therapeutic strategy is often based on lesion histopathological information obtained from stereotactic vacuum-assisted biopsy (VAB). Therefore, accurate information obtained by VAB is very important. This study was performed to evaluate the impact of the number of core samples obtain during VAB on malignancy underestimation rates for mammographically detected breast lesions.

Methods: The pathologic results of 128 consecutive stereotactic biopsies (January 2010-December 2010) were retrospectively reviewed. All biopsies were performed using a 9-gauge needle. Pathologic results of core biopsies and surgical excision were compared. Underestimation rates of malignancy were calculated and correlation was made with the number of core samples obtained.

Results: Surgical excision was performed on 41% (52/128) lesions; 4 benign, 19 indeterminate and 29 malignant. Overall malignancy underestimation rate was 19%. There were 8 cases of ductal carcinoma in situ (DCIS) on core biopsy that were proven to be invasive ductal carcinoma (IDC) on surgical excision. There was one case of benign microcalcifications that was proven to be lobular neoplasia (LN). There was one case of an atypical papillary lesion that was proven to be DCIS. There was a significant difference (p=0.02) between the mean number of core samples taken in the underdiagnosed lesions (8, range 6-12) and the concordant lesions (10, range 6-20).

Conclusions: In the case of stereotactic VAB diagnosis of breast lesions, the underestimation rate of malignancy is more likely with a lower number of core samples obtained.
Preliminary results from a comparative effectiveness study of breast cancer survivorship care: A University of California (UC) ATHENA Breast Health Network project.
Authors: Hahn E. E. , Ganz P. A. , Melisko M. E. , Pierce J. P. , Von Friederichs-Fitzwater M. M. , Lane K. , Hiatt R. A.
Published: February 2017

212

Background: The ATHENA Breast Health Network collaboration is a large scale, UC system-wide project initiated with the intent to drive innovation in breast cancer prevention, screening and treatment. An IRB approved research protocol was developed to examine survivorship care across Network sites, which includes key informant interviews at each site and patient/survivor surveys. This abstract presents preliminary analyses from the key informant interviews.

Methods: Investigators at each site conducted semi-structured interviews with oncology specialists and primary care providers (PCPs). Interviews used case study examples and open and closed-ended questions on the delivery of post-treatment breast cancer care. Informant responses were manually recorded by the interviewer, compiled in a database, then coded and analyzed using NVIVO9 software.

Results: There were 39 key informants across five participating UC sites: 14 medical oncologists, 7 radiation oncologists, 11 surgeons, 3 oncology nurses, and 4 PCPs. Care coordination is a major unprompted theme identified in the interviews. 85% of all participants reported using shared care coordination between PCP and oncology for post-treatment follow-up. 49% report the need for greater care coordination in general, and 28% report the need for greater care coordination within oncology, particularly to help avoid duplication of follow-up care and services. The responses demonstrate wide variability among provider types and institutions (Table). Additional analyses from this study will be updated in our presentation.

Conclusions: These preliminary results identify the need for focus on care coordination during the post-treatment phase of breast cancer care within the UC system.

[Table: see text]
Utilization of pegfilgrastim in adjuvant chemotherapy regimens for breast cancer in the community.
Authors: Patt D. A. , Espirito J. L. , Turnwald B. , Hoverman J. R. , Neubauer M. A. , Busby L. T. , Brooks B. D. , Kolodziej M. A. , Anderson R. W. , Beveridge R. A. ,   US Oncology Pathways Task Force and Clinical Content Development Team
Published: February 2017

213

Background: Selection of adjuvant breast cancer (BC) therapy varies based on patient risk factors. Choice of chemotherapy (CT), schedule, duration, and supportive care affects costs and toxicity. Because pegfilgrastim (PEG) is a large driver of cost in adjuvant therapy it is important to understand the utilization characteristics. We aimed to characterize PEG utilization during neoadjuvant/adjuvant (N/Ad) CT by age and regimen type.

Methods: Using the US Oncology iKnowMed EHR database, we retrospectively identified female BC patients (pts) diagnosed with stage I-III BC, between 7/2006 and 11/2010. Secondary diagnoses were excluded. Pts were characterized by age, ER and HER2 status, tumor size, grade, and nodes. CT utilization was determined by the number of pts assigned an N/Ad line of therapy (LOT) during the study period. Regimens were categorized by CT title and drugs. Clinical trial pts were included. PEG utilization was characterized if administered within 6 months of being assigned to an N/Ad CT regimen.

Results: During the time period, 40,881 newly diagnosed localized BC pts were identified. Of these, 15,328 pts (37%) were assigned an N/Ad CT regimen and 72% (11, 022 pts) received PEG at any time within 6 months of their N/Ad CT. When analyzed by regimen type, TC, TAC, TCH, and dose-dense AC-paclitaxel were the most highly utilized regimens accounting for 64% of all PEG use. PEG use with the TC regimen was 70% and represented 25% of all N/Ad PEG utilization. PEG utilization by age was characterized as 81% of pts <40 yrs, 74% of pts 40-49 yrs, 70% of pts 50-59 yrs, 71% of pts 60-69 yrs, 68% of pts 70-79 yrs, and 40% of pts ≥80 yrs.

Conclusions: While 37% of women treated in the N/Ad setting received CT, PEG was given to 72% of that subset. Utilization was high among all age groups. Dose-dense and docetaxel-containing regimens accounted for the majority of PEG use. With availability of generic docetaxel, commonly used drugs in adjuvant BC except trastuzumab will have generic equivalents and PEG will be the largest cost driver in women receiving adjuvant CT in the community. Since febrile neutropenia occurred in 5% of pts on the original TC trial, determination of appropriate level of use of PEG in the adjuvant setting needs further study.
Association of gene expression module biomarkers with clinical and therapeutic endpoints and their use with a universal companion diagnostic assay.
Authors: Tomlins S. A. , Williams P. , Sadis S. , Wyngaard P. , Oades K. , Lee B. , Chattopadhyay S. , Wang Y. , Monforte J. , Rhodes D.
Published: February 2017

228

Background: Gene expression patterns are increasingly capable of stratifying patients based on prognosis and response to therapy. Given the limited availability of sample tissue, however, it is not feasible to utilize every test for every patient, suggesting the need for a universal companion diagnostic assay that is informative with respect to multiple clinical and therapeutic endpoints. Key challenges are identification of appropriate gene expression biomarkers, translation of biomarkers to clinical assays, and development of reliable gene expression profiling of formalin-fixed clinical specimens. Here we describe a novel RT-PCR biomarker assay optimized for FFPE clinical samples that has broad prognostic and predictive potential.

Methods: A co-expression meta-analysis of 5,339 breast tumors from 56 microarray datasets identified highly co-expressed sets of genes (modules) across multiple datasets. Module biomarkers were tested for their ability to associate with prognostic and predictive targets in published datasets. In addition, each module was reduced from 10–1000 genes to 2-3 genes for use in companion diagnostic assays based on degree of co-expression across the meta-analysis, and validated against an independent panel of tumor samples.

Results: This study demonstrates that a single test utilizing multiple module biomarkers is informative with respect to standard parameters such as ER, PR and Her2, and in addition reproduces existing prognostic and predictive genomic signatures. Furthermore, we show that modules of 10-1000 genes can be represented by 2-3 genes for direct use in companion diagnostics development.

Conclusions: The molecular heterogeneity of breast cancer can be summarized by discrete gene expression modules that individually represent distinct biological programs, and that collectively can be represented by as few as 96 genes. Modules, together with outlier genes, allow for summation of the entire transcriptional program and provide a universal assay with broad application to companion diagnostics development.
Elective bilateral risk-reducing mastectomy (BRRM) in patients (pts) without breast cancer (BC): Experience at Mastologica Lomas Breast Center in Mexico City.
Authors: Sanchez-Forgach E. R. , Sanchez Basurto C.
Published: February 2017

235

Background: BRRM otherwise known as prophylactic or preventive mastectomy has increased in frequency due to patient (pt) and/or physician preference. Variables included indications, medical or pt initiative, efficacy, complications and degree of satisfaction.

Methods: Retrospective review of cases of BRRM from 2005-2010. Pts. were divided by indications including high risk factors, specimen pathology, breast reconstructions technique, complications, patient satisfaction index, and pt status.

Results: A total of 16 pts. had a BRRM either for medical recommendations due to high risk features (including history of first degree relatives with BC (2 pts were BRCA 1 positive) or premalignant pathology in previous biopsies) in 13 (81.25%) cases and 3 (18.75%) owing to personal issues i.e. cancerophobia.Reconstruction technique for BRRM included 12 (75%) subpectoralis implants, 1 (6.25%) tissue expanders and secondary implants, and one (6.25%) latissimus dorsi flap with implant. BRRM complications included diverse degrees of seroma , diverse degrees of nipple-areola complex necrosis, total breast necrosis in one pt. 3 (18.75%) pts. had atypical ductal hyperplasia, 1 of which was bilateral. No BC cases have been recorded to date. Satisfaction with procedure is good to excellent in 14 (87.5%).

Conclusions: BRRM is a safe procedure. Indications include medical evaluation (premalignant disease, high risk profile), or patient preference. Satisfaction with procedure is high.
Anticancer prescription appropriateness: The APA score—A new method to assess anticancer prescriptions in the clinical setting.
Authors: Launay-Vacher V. , Aujoulat O. , Brandely M. , Chevrier R. , Dumas L. , Favier B. , Pelloquin A. , Rioufol C. , Rey J.
Published: February 2017

261

Background: Innovation is crucial in cancer care and access to innovation cannot be—only—economically ruled. We need new drugs, more effective and/or better tolerated to improve the care of our patients. In this context, we need new tools to evaluate the appropriateness of anticancer drugs prescriptions. In fact, the better the appropriateness, the better is the patient care, and the overall balance, including economically.

Methods: A group of 9 pharmacists from university hospitals, general hospitals, and cancer centres joined under the umbrella of the European Fellowship for Pharmacists (EFP) association. The aim was to set up a common process in evaluating the appropriateness of anticancer drugs prescriptions (ADP), focusing on innovative drugs, but not only.

Results: The backbone of our work was to put back the patient at the centre and not to focus on the costs as themselves. We defined a composite criterium called “value of an ADP” which included the costs of course in addition to several factors such as the existence of alternatives for a particular patient, the level of evidence from literature data, the existence of other indications, and several other items. First, a decision tree was elaborated, which allows systematic and standardized screening of ADP leading to early identification of ADP which do not necessitate thorough evaluation: prescription within the terms of either a market authorisation or a Temporary Therapeutic Protocol, or a Temporary Utilization Authorization (ATU), and not on a clinical trial. For the other prescriptions, an evaluation grid coupled to a score was set up. This APA Score (Anticancer Prescription Appropriateness) will allow to decide whether or not a ADP, in a particular clinical context and patient, should be judged as appropriate or not.

Conclusions: At the time of this abstract: the evaluation grid has been discussed, modified, and validated with the participation of two clinical oncologists, specialized in Breast Cancer; the APA scoring is currently under testing by a team of methodologists and bio-mathematicians; and the grid and the APA Score will be tested in “real-life” within the departments of the people involved in the group by the end of 2011.
MEDI-573 as a novel approach to IGF-1R and IR-A signaling inhibition by blocking IGF ligands: Phase I PK/PD, safety data, and disease linkage studies in breast cancer.
Authors: Haluska P. , Huang J. , Lam B. , Liang M. , Huang W. , LoRusso P. , Menefee M. E. , LaVallee T. , Yao Y. , Viner J.
Published: February 2017

271

Background: MEDI-573 is a dual-targeting human antibody that neutralizes IGF-I/-II ligands and inhibits IGF-1R and insulin receptor-A (IR-A) signaling pathways, which play a role in breast and other epithelial cancers. By sparing IR-B and its hybrid receptors, MEDI-573 is expected to achieve antitumor activity without perturbing glucose homeostasis.

Methods: In a 3 + 3 dose-escalation trial ( NCT00816361 ), patients with advanced solid tumors, KPS ≥ 60, received MEDI-573 as a weekly 1-hr IV infusion at 0.5, 1.5, 5, 10, or 15 mg/kg every 21 days. Objectives included determination of MTD, safety profile, pharmacokinetics (PK), pharmacodynamics, and tumor response. In a separate biomarker study, mRNA expression of IR-A and IR-B was compared in HR+/HER- breast cancers.

Results: Patients included 13M/12F (17 evaluable for efficacy at data cutoff); median age 59 yrs (range 37-78). No DLTs, drug-related SAEs, or significant toxicity patterns were reported. Forty-five AEs were considered treatment-related (% of patients): decreased appetite (28%), fatigue (24%), nausea (20%), diarrhea (16%), and anemia (12%). Hyperglycemia occurred in 2 patients, 1 with evidence of prestudy insulin resistance. No other significant changes in plasma glucose levels occurred. MEDI-573 had dose-proportionality, with AUC of 415 ± 165, 597 ± 298, and 1940 ± 904 d*μg/mL at 5, 10, and 15 mg/kg, respectively. Suppression of free IGF-1 and -2 was fully achieved at doses ≥ 5 mg/kg. Stable disease spanning ≥ 12 wks (range 12-36+) was seen in 6/17 patients. No antidrug antibodies were reported. In a study to identify breast cancer subsets that are dependent on IGF signaling, the IR-A:IR-B ratio was significantly higher in HR+/HER2- breast cancer than matched adjacent normal tissues and in proliferative luminal B than in luminal A breast cancer.

Conclusions: MEDI-573 showed acceptable safety and favorable PK profiles without significant changes in glucose levels. The IR-A:IR-B ratio supports a biomarker approach for MEDI-573 patient stratification. A biomarker-rich phase Ib/II study of MEDI-573 with an aromatase inhibitor in patients with advanced HR+/HER2- breast cancer opens in 2011.
Gemcitabine (G) and cisplatin (C) as first-line treatment of metastatic breast cancer (MBC): Results of phase II trial.
Authors: Karthaus M. , Poddubnaya I. , Churilova L. , Khasanov R. , Veremeychuk T. , Rumyantseva E. , Garin M. , Brichkova O. , Heinrich B. , Heinemann V.
Published: February 2017

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Background: G has been studied in combination with a variety of agents known to be active in cancer. G has a mild toxicity profile. GC is active in various advanced tumors. Splitting of C dose (D 1 + d8) is better tolerated and can be a good alternative to once a cycle in pts with advanced breast cancer. This phase II trial evaluates G (1000 mg/m2) C (35 mg/ m2) d1+8 repeated every 21 d in the 1st-line treatment of metastatic breast cancer (MBC). The primary objective of the study was to determine the objective tumor response rate (ORR) of 1st-line GC in patients with metastatic breast cancer.The one-stage design tested the null hypothesis that the true response rate for this population should be equal to 50% for efficacy. Overall survival (OS), time to progression (TTP) and toxicity were evaluated.

Methods: 70 female MBC pts with the median age of 49.8 ys (range 29.6-80.0) were enrolled. Tumor assessment was performed every other cycle by standard criteria including CT or MRI. 67 pts received a total of 310 cycles GC, out of these 54 pts were evaluable for efficacy.

Results: Complete and partial responses were observed in 7/54 (13.0%) and 19/54 (35.2%) evaluable pts, respectively with an overall response of 48.2%. Disease stabilization was noticed in 19/54 (35.2%) pts. Progression was observed in 5/54 (9.3%) pts. TTP was 33.9 weeks (95% CI, 23.9-48.0). OS was 84.0 weeks (95% CI, 58.6-119.3). 1-year overall survival rate was 68.4% (95% CI, 53.6-79.3%). Hematological toxicity G4 was neutropenia in 14.9% (10/67), and no G4 thrombocytopenia. Hypotension G4 (1.5%) was the only severe non-hematological toxicity.

Conclusions: GC in the first-line treatment of MBC, demonstrated a substantial overall response rate and had a good toxicity profile. GC is a suitable option for first-line MBC in selected pts.
Comparison of MammaPrint, BluePrint, and TargetPrint with clinical parameters in patients with breast cancer: Findings from a prospective United States cohort.
Authors: Nguyen B. , Deck K. B. , Sinha R. , Kerlin D. , Barone J. , Rivera E. , Garcia A. , Yao K. , Stork-Sloots L.
Published: February 2017

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Background: MammaPrint (MP) is a powerful predictor of disease outcome in early stage breast cancer. In addition, TargetPrint (TP), a microarray-based test that measures the mRNA expression level of ER, PR and HER2 and an 80 gene expression Molecular Subtyping profile BluePrint (BP) were developed. In the present study, MP, BP and TP were measured in a prospective U.S. breast cancer patient cohort.

Methods: MP results were evaluated in fresh tumor samples from 127 breast cancer patients (T1-4N0-2; median age 62 [39-97 yr]) collected by core needle biopsy or from a surgical specimen between July 2008 and January 2011. We compared treatment advice as recommended by NCCN guidelines and classification according to MP. In addition, we compared IHC/FISH ER, PR and HER2 assessments with TP. The MP and BP results were used to subtype the patients into molecular subgroups.

Results: For the group of patients (n=59) for which NCCN recommends the use of a multi-gene signature for determining chemotherapy treatment recommendations, 42 patients were classified as High Risk and 17 as Low Risk by MP. Comparison of TP with IHC/FISH indicated a concordance of 98% for ER, 94% for PR, and 98% for HER2. For a subgroup of 53 patients combined MP and BP results were available; 18 patients were Luminal-type/MP Low Risk, 27 patients were Luminal-type/MP High risk, 1 patient was Her2-type/MP Low Risk, 1 patient was Her2-type/MP High Risk and 6 patients were Basal-type/MP High Risk.

Conclusions: Adding the multi-gene signature MammaPrint, as well as BluePrint and TargetPrint provides additional information for treatment guidance. By combining MammaPrint with the BluePrint molecular subtyping profile, specific groups of patients can be recognized that are at high risk of recurrence and that would possibly benefit from specific treatment. This study shows that TargetPrint provides high quality second opinion for local IHC/FISH assessment.
Molecular profiling of metastatic breast cancer in body cavity fluids.
Authors: Ashfaq R. , Fong E.
Published: February 2017

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Background: The diagnosis of malignant effusion signifies disease progression and is associated with a worse prognosis regardless of tumor origin. The cancer cells in fluids have unique genotypic and phenotypic characteristics that are uniquely different from the primary tumor. Therapeutic guidance should be based on the evaluation of tumor cells in effusions. This study reports the feasibility of molecular profiling for breast cancer metastasis in pleural and peritoneal fluids.

Methods: A computer search was conducted to retrospectively identify malignant fluid samples or cell blocks for molecular profiling. A cell-block was either prepared or available for testing for all samples. An H&E slide was prepared from the cell- block and reviewed by a pathologist before any testing. Malignant cell percentages were determined for purpose of DNA microarray analysis and Sequencing. Appropriate clusters and malignant cells were marked for FISH. The results were reviewed and data compiled to calculate the yield of various molecular predictive tests.

Results: We studied 172 fluid of which 28 were metastatic breast cancer (16.2%). Of the 28 breast cases, 10 IHC biomarkers could be performed in 20 (71.4 %), 1-9 in 1 (3.5 %), while 7 (25%) were insufficient. DNA microarray analysis was done in 10 (35.7%), FISH for EGFR 7 (25%), Her2 Neu FISH 11(39%), cMYC FISH 5 (17.8%) and TOPO2a by FISH 3 (10.7%). Combined IHC/FISH/MA data was available in 10, IHC and FISH data in 11 and IHC and MA data in 10 cases. Combined results of predictive markers provided information on therapeutic guidance in 21 of 28 cases.

Conclusion: Molecular profiling of malignant fluids offers additional opportunities for testing those patients where other tissue samples such as needle core biopsy or resection samples are not available. Molecular profiling provides insight into the molecular characteristics of malignant cells in body cavity fluids and associated expression of unique therapeutic targets.
Evaluation of the performance of breast cancer cell line–derived multigene predictors of chemotherapy response in multiple clinical trials.
Authors: Song N. , Rice S. D. , Gingrich D. , Wang D. , Tian C. , Ding Z. , Brower S. L. , Ervin P. , Gabrin M. J. , Shen K.
Published: February 2017

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Background: While various multi-gene predictors (MGPs) of chemotherapy response have been developed based on cancer patient primary tissues or cancer cell-lines, the accuracy and consistency of these predictors remain a concern in clinical validation studies. In this study we developed four unique MGPs for chemotherapy response from breast cancer cell lines and performed a systematic evaluation of the performance of these MGPs using data from five distinct clinical trials.

Methods: Forty-six immortalized breast cancer cell-lines were exposed to various concentrations of drug combinations [paclitaxel, 5-fluorouracil, doxorubicin, cyclophosphamide (TFAC); 5-fluorouracil, doxorubicin, cyclophosphamide (FAC); 5-fluorouracil, epirubicin, cyclophosphamide (FEC) and epirubicin, cyclophosphamide (EC)] using an in vitro chemosensitivity assay. Utilizing publicly available breast cancer cell-line microarray data, genes highly associated with in vitro chemosensitivity were selected as candidate MGPs. Five independent and publicly available clinical trials were used for validation. In three of these clinical trials patients were treated by TFAC, while EC, FAC or FEC were used in the other two trials. All five studies involved neoadjuvant chemotherapy treatment, and pathologic complete response (pCR) was used as the endpoint. The association of MGPs with pCR was assessed using receiver-operator curve (ROC) analysis and area under the ROC (AUC) was used to evaluate the performance of prediction.

Results: In five independent clinical trials, the MGPs predicted patient pCR to EC, FAC/FEC and three TFAC treatments with an AUC of, 0.671, 0.632, 0.735, 0.738 and 0.647 respectively.

Conclusions: In the five independent clinical trials in which patients were treated by various chemotherapy agents, the performance of MGPs is promising. These results demonstrate the feasibility of using breast cancer cell-line derived MGPs to predict breast cancer patients’ chemotherapy responses.
Diffusion-weighted magnetic resonance imaging in patients with known or suspected breast malignancy: Correlation between apparent diffusion coefficient and histopathologic diagnoses.
Authors: Kim A. C. , Ying D. , Sheth P. , Park J. M.
Published: February 2017

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Background: Magnetic resonance imaging (MRI) is an important imaging modality for evaluating patients at high risk for breast malignancy. However, the role and utility of diffusion-weighted imaging (DWI) in breast MRI has not been fully elucidated. This study was designed to investigate the relationship between apparent diffusion coefficient (ADC) values and histopathologic diagnoses in benign and malignant breast pathologies as well as to assess the relative diagnostic value of this parameter.

Methods: We searched our database for patients who received breast MRI studies from February 2010 through March 2011. We then identified those patients who had either known or suspected breast malignancy and who had also undergone DWI. Breast abnormalities were identified through a review of the short tau inversion recovery (STIR) and T1-weighted pre- and post-contrast images. DWI images were evaluated and the corresponding ADC values were calculated. These lesions were correlated with histopathologic results when available.

Results: A total of 174 patient MRI studies were evaluated. Single dominant lesions were assessed and included biopsy-proven infiltrating ductal carcinoma (IDC), biopsy-proven ductal carcinoma in situ (DCIS), and benign lesions including cysts. The median ADC value for IDC was 118 x 10-5 mm2 s-1. The median ADC value for DCIS was 123 x 10-5 mm2 s-1. Finally, the median ADC value for breast cysts was 217 x 10-5 mm2 s-1.

Conclusions: As the role of MRI continues to evolve in the evaluation of breast pathology, the addition of DWI may increase diagnostic confidence for breast cancer, allowing for further differentiation from benign lesions. DWI is feasible to implement in many clinical practices and correlates with imaging features of breast cancer. The DWI images are acquired rapidly and without intravenous contrast. This method of imaging could be used in short intervals to assess treatment response to therapies such as biologic inhibitors or radiation therapy.