bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcriptome-wide analysis of matched biopsy and prostatectomy to measure genomic classifiers of prostate cancer progression and field effect.
Authors: Knudsen Beatrice , Simko Jeffry P. , Lam Lucia L.C. , Erho Nicholas , Sierocinski Thomas , Tenggara-Hunter Imelda , Wellman Hugh , Davicioni Elai , Chan June M. , Carroll Peter , Kim Hyung Lae , Cooperberg Matthew R.
Published: February 2017

85

Background: Active surveillance (AS) allows patients with localized prostate cancer to delay and even avoid treatments that carry risk of significant side-effects. However, biomarkers are needed to more accurately risk-stratify patients and enhance acceptance of AS. Challenges with biomarkers measured from needle biopsy specimen that need to be address include limited material, tumor and specimen heterogeneity and fragmentation of RNA. Methods: A total of 23 patients with matched formalin-fixed paraffin-embedded (FFPE) biopsy and radical prostatectomy (RP) specimens were identified at University of California, San Francisco and Cedar Sinai. For each patient, samples were taken from tumor, non-neoplastic tissue adjacent to tumor (NAT) and non-neoplastic tissue contralateral to tumor (NCT) from both biopsy and RP specimens. RNA expression was measured in 130 samples using the 1.4 million feature Affymetrix Human Exon 1.0 ST arrays. Results: From 1 mm cylindrical cores punched from FFPE blocks, sufficient RNA was extracted for the assay from 63 out of 69 (91%) biopsy specimens and 69 out of 69 (100%) RP specimens. Median RNA yield from biopsies was lower than RP specimens but a similar quantity and quality of cDNA was amplified from the 100 ng RNA required for the assay. RNA from 62/63 (98%) of the biopsy specimens and 68/69 (99%) of the RP specimens generated expression data that passed quality control. Genomic classifiers (GC) predicting metastasis (GC1) and presence of high Gleason grade tumor (GC2) were highly correlated between matched biopsy and RP specimens with R=0.74 (p=0.0003) and R=0.63 (p=0.004), respectively. For GC2, matched tumor and NAT from RP had a higher correlation (R=0.57, p=0.0045) than matched tumor and NCT (R=0.10, p=0.67). There was no relationship between percentage of stromal contamination in the biopsy and the GC scores for either classifier, R=0.02 (p=0.91) and R=-0.16 (p=0.28) respectively. Conclusions: RNA expression levels can be measured in FFPE needle biopsy on a genome-wide scale with similar data quality compared to RP specimens. GC scores from biopsies and RP samples correlate well, are robust to stromal contamination, and are present in adjacent non-neoplastic tissue.
Stereotactic body radiosurgery versus intensity modulated radiotherapy for prostate cancer: Comparison of toxicity.
Authors: Yu James B. , Cramer Laura D. , Herrin Jeph , Soulos Pamela R. , Potosky Arnold L. , Gross Cary
Published: February 2017

89

Background: Stereotactic body radiosurgery (SBRT) is a recent innovation in the treatment of prostate cancer that has begun to disseminate into national practice. Comparative studies have yet to be performed and little is known about the cost to Medicare or difference in toxicity between SBRT and intensity modulated radiation therapy (IMRT). Methods: We performed a retrospective study using a national sample of all Medicare beneficiaries age 66 or older who received SBRT or IMRT as primary treatment for prostate cancer during 2008 through 2011. Each SBRT patient was matched to two IMRT patients with similar follow-up (6, 12, or 24 months) and clinical and demographic characteristics. Cost of treatment was calculated for matched patients with six months of follow-up. We assessed toxicity by searching Medicare claims for procedure or diagnosis codes indicative of treatment related toxicity. We used a random effects model to compare the likelihood of genitourinary (GU), gastrointestinal (GI), and other toxicity from 0 to 6, 0 to 12, and 0 to 24 months after the initiation of SBRT or IMRT treatment. Results: The study sample consisted of 1,335 SBRT patients matched to 2,670 IMRT patients. The mean cost of SBRT was $11,668 compared to $15,838 for IMRT. At all follow-up points, SBRT patients were significantly more likely to experience GU toxicity. In the first six months after treatment initiation, 15.6% of SBRT versus 12.6% of IMRT patients had claim indicative of a GU complication (p=.009). In the first 12 months, 27.1% of SBRT versus 23.2% of IMRT had a GU complication (p=.014). Finally, from 0-24 months, 43.9% of SBRT versus 36.3% of IMRT had a GU complication (p=.001). The higher rate of GU toxicity after SBRT was largely due to an increase in urethral strictures and bladder outlet obstructions and urinary incontinence or obstruction. Conclusions: In this retrospective observational study, while SBRT was associated with lower costs, there was a greater rate of urinary obstructive toxicity for patients undergoing SBRT compared to IMRT at all time points studied. Whether this increased rate of complication is offset by a higher cure rate or lower cost should be the subject of further study.
Clinical activity of abiraterone acetate in patients with castration-resistant prostate cancer who received prior ketoconazole therapy.
Authors: Zhao Bo , Garcia Jorge A. , Gilligan Timothy D. , Rini Brian I. , Dreicer Robert
Published: February 2017

99

Background: Studies have shown activity of Abiraterone acetate (AA) in patients (pts) with castration-resistant prostate cancer (CRPC) who have received prior ketoconazole. Prostate-specific antigen (PSA) response to AA in relation to previous PSA response to ketoconazole was investigated. Methods: A retrospective analysis was conducted to determine the clinical activity of AA in men with CRPC who have received prior ketoconazole therapy at our institution. Time to PSA progression (PSA TTP) was defined by PCWG2 criteria, a PSA reduction of 50% or more was considered as PSA response. Results: Thirty four pts were identified. Nineteen pts (56%) had previous PSA responses on ketoconazole, with a median PSA TTP of 11 months (95% confidence interval [CI] 6.8-19.9). Subsequently, 11 of 34 (33%) of pts achieved a PSA response on AA, with a median PSA TTP of 6 months (95% CI 4.9-9.5). Among the 19 pts having a PSA response on ketoconazole, only four (21%) pts subsequently had PSA response to AA. Two of these pts had transient PSA response with PSA TTP less than 3 months on kKetoconazole, one patient discontinued Ketoconazole due to side effects, one patient had intermittent non-castrate testosterone levels. In contrast, 7 of 15 (46.7%) pts without prior PSA response to ketoconazole subsequently achieved PSA response on AA (p=0.11). Of note, PSA reduction of less than 50% on AA was observed in 9 of 34 pts (26%), which was associated with a longer median PSA TTP compared to pts who had PSA-progressive disease (5.9 months [95% CI 3.5-7.3] vs.1.5 months [95% CI 1.0-3.5], p=0.028). Five of these nine patients had a prior PSA response to ketoconazole but required drug discontinuation for reasons other than disease progression. Conclusions: PSA response to prior ketoconazole therapy is associated with lower PSA response rate to subsequent AA. The observation suggests that there is a biologically distinct subset of patients who are ketoconazole-resistant but abiraterone-sensitive, the underlying mechanism needs to be further investigated.
Phase III, randomized trial (CheckMate 057) of nivolumab (NIVO) versus docetaxel (DOC) in advanced non-squamous cell (non-SQ) non-small cell lung cancer (NSCLC).
Authors: Paz-Ares Luis , Horn Leora , Borghaei Hossein , Spigel David R. , Steins Martin , Ready Neal , Chow Laura Quan Man , Vokes Everett E. , Felip Enriqueta , Holgado Esther , Barlesi Fabrice , Kohlhaeufl Martin , Rodriguez Oscar , Burgio Marco Angelo , Fayette Jerome , Gettinger Scott N. , Harbison Christopher , Dorange Cécile , Finckenstein Friedrich Graf , Brahmer Julie R.
Published: February 2017

LBA109

Background: Options for advanced non-SQ NSCLC patients (pts) who progress after platinum-based doublet chemotherapy (PT-DC) are limited, with minimal improvement in overall survival (OS). We report results from a randomized, global phase III study of NIVO, a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor antibody, vs DOC in pts with advanced non-SQ NSCLC after failure of PT-DC and tyrosine kinase inhibitor, if eligible. Methods: Pts were randomized to NIVO 3 mg/kg Q2W (n=292) or DOC 75 mg/m2 Q3W (n=290) until progression or discontinuation due to toxicity/other reasons. Primary objective was OS; Secondary objectives were investigator-assessed objective response rate (ORR; per RECIST v1.1), progression-free survival (PFS), efficacy by PD-L1 expression, quality of life, and safety. Results: NIVO demonstrated superior OS (HR=0.73; 96% CI: 0.59, 0.89; P=0.00155) and improved ORR (19.2% vs 12.4%; P=0.0235). HR for PFS was 0.92 (95% CI: 0.77, 1.11; P=0.393). PD-L1 expression was associated with benefit from NIVO (Table). In PD-L1+ pts, NIVO showed improved efficacy across all endpoints at predefined 1%, 5%, and 10% cut- points. Grade 3–5 drug-related AEs occurred in 10.5% (30/287) of NIVO and 53.7% (144/268) of DOC pts. No deaths were related to NIVO vs 1 DOC-related death. After discontinuation, 42.1% of NIVO and 49.7% of DOC pts received subsequent systemic therapy. Conclusions: NIVO demonstrated superior OS vs DOC in pts with advanced non-SQ NSCLC after failure of PT-DC. The safety profile of NIVO 3 mg/kg Q2W was favorable vs DOC. NIVO demonstrated survival benefit across histologies in two randomized phase III trials. Clinical trial information: NCT01673867. [Table: see text]
Survival of SLNB-positive melanoma patients with and without complete lymph node dissection: A multicenter, randomized DECOG trial.
Authors: Leiter Ulrike , Stadler Rudolf , Mauch Cornelia , Hohenberger Werner , Brockmeyer Norbert , Berking Carola , Sunderkötter Cord , Kaatz Martin , Schulte Klaus-Werner , Lehmann Percy , Vogt Thomas , Ulrich Jens , Herbst Rudolf , Gehring Wolfgang , Simon Jan-Christoph , Keim Ulrike , Garbe Claus
Published: February 2017

LBA9002

Background: Complete lymph node dissection (CLND) following positive sentinel node biopsy (SLNB) was evaluated in a randomized phase III trial. Methods: 1,258 patients with cutaneous melanoma of the trunk and extremities and with positive SLNB were evaluated. Of these, 483 (39%) agreed to randomization into the clinical trial. 241 patients underwent observation only, 242 received CLND. Both groups had a subsequent 3-years follow-up. Recurrence-free (RFS), distant metastases free (DMFS) and melanoma specific (MSS) survival were analyzed as endpoints. Results: Patient enrolment was performedfrom January 2006 to December 2014. In the intent to treat analysis, both groups did not differ significantly in distribution of age, gender, localization, ulceration, tumor thickness (median 2,4 mm in both groups), number of positive nodes, or tumor burden in the SN. The mean follow-up time was 34 months (SD ± 22.1). No significant treatment-related difference was seen in the 5-years RFS (P = 0.72), DMFS (P= 0 .76) and MSS (P = 0.86) in the overall study population. Conclusions: In this early analysis of trial results, no survival benefit was achieved by CLND in melanoma patients with positive SLNB. A subsequent analysis three years after inclusion of the last patient is planned.
Breast MRI screening of women at average risk of breast cancer: An observational cohort study.
Authors: Kuhl Christiane K. , Bieling Heribert , Strobel Kevin , Leutner Claudia , Schild Hans H , Schrading Simone
Published: February 2017

1

Background: Breast-MRI is currently recommended for screening women at high-risk of breast-cancer only. However, despite decades of mammographic-screening, breast-cancer continues to represent a major cause of cancer-death also for women at average-risk – suggesting a need for improved methods for early diagnosis also for these women. Therefore, we investigated the utility of supplemental MRI-screening of women who carry an average-risk of breast-cancer. Methods: Prospective observational cohort-study conducted in two academic breast-centers on asymptomatic women at average-risk in the usual age range for screening-mammography (40 to 70). Women underwent DCE-breast-MRI in addition to mammography every 12, 24, or 36 months, plus follow-up of 2 years to establish a standard-of-reference. We report on the supplemental-cancer-yield, interval-cancer-rate, diagnostic accuracy of screening-MRI, and biologic profiles of additional, MRI-detected breast-cancers. Results: 2120 women underwent a total 3861 MRI-studies covering 7007 women-years. Breast-cancer was diagnosed in 61/2120 women (DCIS: 20, invasive: 41), and ADH/LIN in another 21. Interval-cancer-rate was 0%, irrespective of screening interval. Forty-eight women were diagnosed with breast-cancer at prevalence-screening by MRI alone (supplemental cancer-detection-rate: 22.6 per 1000); 13 women were diagnosed with breast-cancer in 1741 incidence-screening-rounds collected over 4887 women-years. A total 12 of these 13 incident cancers were diagnosed by screening-MRI alone (supplemental-cancer-detection-rate: 6.9 per 1000), one by MRI and mammography, none by mammography alone. Supplemental-cancer-detection-rate was independent of mammographic breast-density. Invasive cancers were small (mean size: 8mm), node-negative in 93.4%, ER/PR-negative in 32.8%, and de-differentiated in 41.7% at prevalence, and 46.0% at incidence-screening. Specificity of MRI-screening was 97.1%, False-Positive-Rate 2.9%. Conclusions: MRI-screening improves detection of biologically relevant breast-cancer in women at average-risk, and reduces the interval-cancer-rate down to 0%, at a low false-positive rate.
The relationship of magnetic resonance (MR) imaging characteristics with race.
Authors: Chun Jennifer , Schnabel Freya Ruth , Schwartz Shira , Marin Chelsea , Guth Amber Azniv , Axelrod Deborah M. , Shapiro Richard L. , Roses Daniel F. , Moy Linda
Published: February 2017

10

Background: Research has shown that women of different race have differences in tumor biology. Previous studies have shown that mammographic breast density (BD) and background parenchymal enhancement (BPE) are associated with breast cancer risk. There is data on the relationship of race and BD, but a dearth of information on the relationship of race and MR imaging characteristics such as fibroglandular tissue (FGT) and BPE. The purpose of this study was to evaluate the relationship of race with BD, BPE, and FGT in women with breast cancer. Methods: The institutional Breast Cancer Database was queried for all women with newly diagnosed breast cancer from 2010-2015. Variables included age, race, body mass index (BMI), imaging and tumor characteristics. Statistical analyses included Pearson’s Chi Square Tests. Results: A total of 2,092 women were included in this analysis. The median age was 59 years (range 22-95). Majority of patients had invasive ductal carcinoma (62%), early stage (0, I) tumors (71%), ER-positive (84%), PR-positive (71%), and HER2-negative (86%). However, there was a higher proportion of later stage (p < 0.0001) and triple negative (p = 0.002) disease among blacks. Compared to whites, blacks had higher BMI, lower BD and lower BPE, while Asians had lower BMI <, higher BD, higher FGT and higher BPE (see table). Conclusions: As previously described, we found differences among races with respect to tumor histology. However, the differences in imaging characteristics between races are likely accounted for by differences in BMI and may not be directly related to breast carcinogenesis. [Table: see text]
Factors influencing treatment of inflammatory breast cancer in the United States.
Authors: Lin Heather Y. , Babiera Gildy , Bedrosian Isabelle , Shaitelman Simona Flora , Kuerer Henry Mark , Woodward Wendy A. , Ueno Naoto T. , Shen Yu
Published: February 2017

118

Background: Guidelines for treating inflammatory breast cancer (IBC) using trimodality (chemotherapy, surgery and radiation) therapy (TT) remain largely unchanged since 2000. However, many such patients did not receive TT. It is unknown how patient-level (PL) and facility-level (FL) factors contribute to TT utilization. Methods: Using the National Cancer Data Base (NCDB), patients who underwent surgical treatment of locoregional IBC from 2003-2011 were identified. We correlated patient, tumor, and treatment data with TT. An observed to expected (O/E) ratio of number of patients treated with TT was calculated for each hospital by adjusting for PL factors. Hierarchical mixed effects models were used to assess the proportion of variation in the use of TT attributable to PL and FL factors, respectively. Results: Among 5,537 patients who met the study criteria, the use of TT fluctuated annually (67.3%-75.7%) and was less likely for patients who were over 70, had a lower income or had an N0 tumor (all p < 0.05). By insurance type, TT use was lowest among Medicare patients. Of the 542 hospitals examined, 55 (10.1%) and 24 (4.4%) were identified as significantly low and high outliers for the use of TT (p < 0.05), respectively. While comprehensive cancer centers represented the majority of high outliers, the TT use by facility type overall was not significantly different demonstrating variability within comprehensive cancer center practice. The percentage of the total variance in the use of TT attributable to facility (11%) was almost triple the variance attributable to the measured PL factors (3.4%). Conclusions: The use of standard of care TT varied widely across facilities with some high volume centers clearly underutilizing TT. To improve clinical outcomes for this rare and aggressive malignancy, it is critical to identify facility level factors impacting the use of TT to ensure the guideline adherence of IBC treatment.
TOX3 as a novel biomarker in luminal B breast cancer.
Authors: Hong Jenny Jimmy , Seksenyan Akop , Yuan Xiaopu , Knudsen Beatrice , Audeh William , Kaye Jonathan
Published: February 2017

130

Background: A breast cancer (BC)-associated SNP is found in an enhancer region of the TOX3 gene, which encodes a nuclear protein expressed in ER+ mammary epithelial cells but with unknown biological function. As the disease-risk allele reduces TOX3 expression, we proposed that a decrease in TOX3 might favor a progenitor cell state that is more susceptible to tumorigenesis. However, in the context of BC, our data has implicated TOX3 as a tumor promoter. Indeed, high TOX3 gene expression is significantly associated with poor outcome among patients with luminal B (LumB) disease. The Oncotype DX assay predicts likelihood of distant recurrence in ER+ early stage BC, improving patient selection for adjuvant chemotherapy. However, LumB subtypes often have an intermediate recurrence score (RS), where the absolute benefit of chemotherapy is unclear. Thus, we investigated whether TOX3 expression might provide additional discriminatory power. Methods: Tumor specimens were obtained from Cedars-Sinai Medical Center in a retrospective study. Tissue microarrays of 200 histologically-defined LumB breast tumors (ER+Her2-/+ Ki67 > 14%), half of which with associated Oncotype DX data, were stained with an anti-TOX3 monoclonal antibody, to correlate with RS and clinicopathologic outcomes. Results: TOX3 protein was expressed in a significant subset of LumB tumors. Using image analysis to create a histoscore, we found no correlation between TOX3 expression and RS. TOX3 expression was also not associated with frequency of Ki67+ cells, patient age, or tumor size. Further in-depth clinico-pathologic evaluation and prognosis data will be reported. Conclusions: Despite overall efficacy of adjuvant chemotherapy in early stage BC, many patients are exposed to the associated risks without deriving significant benefit. A number of lines of evidence suggest that TOX3 renders tumors more aggressive and metastatic. The lack of correlation of TOX3 expression and RS may suggest a facet of the biology of ER+ aggressive cancers that may not be addressed by the Oncotype DX assay. Thus, prospective studies examining recurrence risk and chemotherapy benefit may need to be expanded to integrate TOX3 expression as an adjunct novel biomarker to guide optimal personalized therapy for BC.
Caveolin-1: Oncogenic role in breast cancer? Clues from molecular profiling.
Authors: Feldman Rebecca , Gatalica Zoran , Reddy Sandeep K. , Castro Michael , Sachdev Jasgit C.
Published: February 2017

134

Background: Caveolin-1 (CAV1) is the structural component of caveolae, compartments within the plasma membrane that sequester signaling molecules, thus facilitating molecular “hot spots”. The role of CAV1 in breast cancer is an active area of investigation. We sought to understand the clinical and pathological characteristics of CAV1 positive tumors (CAV 1+) through a retrospective analysis of molecularly-profiled breast cancer patients. Methods: 2,728 breast cancer patients molecularly profiled with a commercial assay (Caris Life Sciences) were evaluated retrospectively for expression of various biomarkers by immunohistochemistry (IHC) and in situ hybridization. JMP statistical analysis tool was used to ascertain distributional differences. Results: Using a threshold of 2+ and 30%, 121/2728 (4%) of patients exhibited CAV1 over-expression by IHC. To observe clinicopathologic differences in the CAV1 + and CAV1- tumors, distribution by age, metastatic disease, and triple negative histology (TNBC) were analyzed. Average age for both groups was 55. 39% vs. 54% were metastatic and 74% vs. 26% were TNBC (p = 0.0001) among CAV1+ and CAV1- groups, respectively. To evaluate the potential oncogenic associations of CAV1, we evaluated the relationship between CAV1+ and various oncogenic pathways. Positive EGFR protein expression and presence of EGFR gene amplification, as well as cKIT over-expression associated with CAV1+ (all p-values < 0.001), whereas HER2 expression and amplification were associated with CAV1- (p = 0.001 for both). In addition, higher Ki67, p53 and TOP2A expression by IHC were observed in CAV1+ patients compared to the CAV1- subgroup (90% vs. 66%, 50% vs. 36%, 84% vs. 65% ; all p-values < 0.0001). Biomarker expression differences that did not meet statistical significance: ERCC1, MGMT, PDGFRA, RRM1, SPARC, TS and TOPO1. Conclusions: The majority of CAV1+ breast cancers are comprised of triple negative, higher proliferative tumors, with aberrant p53 expression as well as expression of other growth factor signaling proteins. This data supports the potential role of CAV1 in fostering molecular hubs for signaling and CAV-1 being a potential target for future therapeutic investigation in TNBC.
Primary analysis of a randomized phase II, multicenter trial: Neoadjuvant weekly nab-paclitaxel 100mg/m2 followed by FE100C compared with docetaxel 75mg/m2 followed by FE100C for early breast cancer in Japan.
Authors: Kuwayama Takashi , Yamauchi Hideko , Takano Toshimi , Tsugawa Koichiro , Sato Takanobu , Kitani Akira , Hayashi Naoki , Okuyama Hiromi , Nakamura Seigo
Published: February 2017

136

Background: Nanoparticle Albumin-Bound Paclitaxel (nab-PTX) is a new solvent free taxane-based anticancer drug. According to CA024 trial, nab-PTX 100mg/m2 demonstrated superior response to docetaxel (DTX) in patients with metastatic breast cancer. Besides, nab-PTX 100mg/m2 was less toxicity. In operable breast cancer, GeparSepto study was reported that the pCR rate were significantly higher with nab-PTX 125/150 mg/m2 compared to paclitaxel. We planned the randomized parallel design phase II trial to evaluate nab-PTX 100mg/m2in early breast cancer. Methods: Stage II-III HER2-negative breast cancer patients were included in this trial and received either 4 cycles of DTX (75 mg/m2 day1) q 3 w or 4 cycles of nab-PTX (100 mg/m2 day1/8/15) q4w followed by 4 cycles of FE100C. The primary end point is pCR (ypT0/is ypN0) rate, and the secondary end points are response rate, histological effect of treatment, breast conservation rate, and toxicity. Results: Between March 2011 to March 2014, 152 eligible patients were enrolled at 6 centers (75 pts were allocated for nab-PTX). Baseline characteristics were well balanced; median age was 51/49 years (DTX/nab-PTX), 61/61% of the patients with ER positive, 38/36% triple negative breast cancer, 57/65% Ki67 > 20%. Clinically response rate was similar to each drug. (53/57%) The pCR rate was 12/17% (p = 0.323). In TNBC group, the pCR rate was 28/30% (p = 0.866). In Ki67 > 20% group, the pCR rate was significantly higher, 16/48% (p = 0.021) with nab-PTX arm. The most common grade3-4 adverse event was neutropenia, which was observed in 40/36% of cases. Non-hematological adverse events of any grade were; 34/32% myalgia (DTX/nab-PTX), 42/35% arthralgia, 55/65% peripheral sensory neuropathy. No Grade3-4 peripheral sensory neuropathy was observed in nab-PTX arm. Infusion reaction of DTX occurred in 1 patient. Conclusions: In this initial effectively analysis, neoadjuvant weekly nab-paclitaxel 100mg/m2 were promising drug in HER2-negative operable breast cancer patients. Larger studies will be needed to evaluate neoadjuvant weekly nab-paclitaxel compared with DTX. Clinical trial information: 000005388.
Safety and efficacy of gemcitabine and trastuzumab in HER2-directed therapy pretreated patients with HER2-positive metastatic breast cancer: SBP-01 study.
Authors: Yoshitomi Seiji , Tsuji Hisashi , Ikeda Masahiko , Ito Mitsuya , Ohtani Shoichiro , Higaki Kenji , Sagawa Teiri , Matsuoka Kinya , Kawai Hiroshi , Takabatake Daisuke , Doihara Hiroyoshi , Shien Tadahiko , Taira Naruto , Ohtawa Yasuyuki , Maruyama Shuichiro , Hikino Hajime , Fujii Sayaka , Yamamoto Yutaka , Ohsumi Shozo , Hara Fumikata
Published: February 2017

142

Background: Prognosis of HER2-positive metastatic breast cancer (MBC) has been dramatically improved by trastuzumab (Tmab). More recently, newer anti-HER2 agents such as lapatinib, pertuzumab and T-DM1 have prolonged survival. Despite the efficacy of these drugs, most patients develop progressive disease during or after treatment, and alternative anti-HER2 agents plus chemotherapies are required in subsequent lines of treatment. However, there are few evidence on efficacy of Tmab-containing regimens after disease progression. Gemcitabine (GEM) is non-cross resistant to anthracycline and taxane. Preclinical studies have shown that the combination of Tmab and GEM has synergistic effect against HER2-positive breast cancer cell lines. SBP-01 study assessed the efficacy and safety of the combination of Tamb and GEM in patients with HER2-positive MBC previously treated with anti-HER2 therapy. Methods: SBP-01 study included patients treated with one or more anti-HER2 directed regimens for MBC. Patients were administered with GEM 1250 mg/m2 on days 1 and 8 of each 21-day cycle and Tmab 4mg/kg loading dose and then 2mg/kg weekly. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression free survival (PFS), overall survival, and safety. Results: Between June 2011 and June 2014, 35 patients were enrolled. Patients had ER positive tumor (37.1%), a median of 2 metastatic organ sites, visceral metastasis (80.0%), prior (neo) adjuvant Tmab (22.9%) and a median of 2 prior chemotherapy regimens for MBC. Previous HER2-directed drugs included Tmab (94.3%), lapatinib (37.1%), T-DM1 (8.6%) and pertuzumab (2.9%). ORR was 22.9% (95% CI, 8.6%-36.8%). Median PFS was 146 days. Patients with stable disease response received a median of 7 cycles (6-28 cycles) of treatment. Grade3/4 leukopenia (20.0%) and neutropenia (48.6%) were observed. All non-hematological toxicities were less than grade3. Conclusions: The Combination Tmab and GEM is effective and well-tolerated regimen for patients previously treated with HER2-directed therapy, and appears to make disease stable for long time period. Clinical trial information: UMIN000005881.
Review of trends in adjuvant chemotherapy regimens in breast cancer over 10 year period at Yale New Haven Hospital (YNHH).
Authors: Gnanajothy Rosana , Chung Gina G. , DiGiovanna Michael , Abu-Khalaf Maysa M. , Lannin Donald R. , Harris Lyndsay
Published: February 2017

144

Background: Adjuvant chemotherapy for breast cancer has undergone many changes over the past 10 yrs. The objective of the study was to review prescribing trends in adjuvant chemotherapy regimens for early stage breast cancer in a single institution, over a decade. Methods: A retrospective chart review was conducted of patients (pts) with early stage breast cancer treated at YNHH from 2002 to 2011.Total charts analyzed was 1097 and 308 pts had complete data. Results: The HER 2 positive group accounted for 64 pts. The most commonly used regimen was ACTH (doxorubicin and cyclophosphamide 4-14 d cycles, paclitaxel and trastuzumab weekly for 12 weeks, and trastuzumab for 1 yr). This regimen was utilized in 35% of pts and was most likely to be used in node positive (N+ve) pts compared to node negative (N-ve) pts (OR 2.9 (95 % CI 0.97-9.1)).TCH (docetaxel, carboplatin, trastuzumab,6-21 d cycles and trastuzumab for 1 year) was the second most common regimen used in 21% of pts and predominantly in N-ve pts(OR 12.4 (95% CI 02.45-63.2)). Majority of the study group (184 pts) were ER+PR+ and HER 2- .The predominant chemo regimen was DD AC T (dose dense AC followed by paclitaxel in 4 -14d cycles each) in 50% of pts, and TC (Docetaxel, cyclophosphamide4-21d cycles) utilized in 48 pts (26.09 %). Majority of the N-ve pts were treated with TC (OR 12.4(95% CI 2.4-63.27) whereas N+ve pts were predominately treated with DDACT (OR 2.98(95% CI 0.97-9.16). The Triple negative group included a total of 57 pts .The most frequent chemo regimen through the years was DDACT (54.39% of pts) followed by TC (21.05% of pts). N+ve pts were more likely to be treated with DDACT (OR 8.91(95% CI (2.65-29.94)) whereas N-ve pts mostly received TC (OR 8.75(95% CI (1.70-45.00)) The methotrexate and 5 fluorouracil based regimens were utilized more frequently in earlier years of study and less frequently in later years. Conclusions: Anthracycline and taxane based regimens have gained precedence over older regimens. HER 2 +ve pts were most commonly treated with ACTH, and TCH. N+ve HER 2+ pts were most likely to be treated with ACTH and N-ve HER2+ pts with TCH. In Her 2 negative and triple negative pts, DDACT was more utilized in N+ve pts whereas, TC regimen in the N-ve pts.
IO-125: A novel supramolecular platinum chemotherapy for triple negative breast cancer.
Authors: Sengupta Aniruddha , Mylavarapu Sanghamitra , Kumari Smita , Hossain Samad , B Heeralal , Gupta Nimish , Sarkar Arindam , Ansari Aasif , Velpandian Thirumurthy , Roy Monideepa , Sengupta Shiladitya
Published: February 2017

153

Background: Triple-negative breast cancer (TNBC) accounts for 15-20% of breast cancer patients, with a median survival of 13 months and limited treatment options. Recent studies have indicated clinical benefits in TNBC with platinum agents. We designed a novel platinum chemotherapeutic (IO-125), with platinum (II) tethered to cholesterol-based leaving group via a novel coordination environment, conferring properties unique from current platinum-based chemotherapies. In this study, we investigated the anti-tumor activity of IO-125 in pre-clinical models of TNBC. Methods: Cellular viability of IO-125 was assessed in TNBC cell lines using MTT assay, while Pt levels in cells, plasma and tumors were quantified using atomic absorption spectroscopy. Antitumor activity was assessed in MDA-MB-231 xenograft model. Results: We reportthat IO-125 shows enhanced cellular cytotoxicity and higher intracellular uptake as compared to oxaliplatin in TNBC lines. In addition to uptake by organic cation transporters known for transporting current platinum chemotherapies, IO-125 is also internalized via caveolin-mediated endocytic pathway, resulting in 10-20 fold greater uptake into cells as compared to oxaliplatin. Studies have implicated caveolin in TNBC progression and drug resistance, and harnessing this mechanism could confer enhanced activity. In animals bearing MDA-MB-231 xenografts, three cycles of IO-125 at well-tolerated doses (35 mg Pt/kg) resulted in significant tumor growth inhibition as compared to reported tumor inhibitions seen with existing platinum chemotherapies. Pharmacokinetic studies conducted in mice and rabbits indicate markedly improved profile of IO-125 as compared to oxaliplatin, showing a significantly higher area-under-the-curve (AUC), a substantial reduction in clearance and volume of distribution, with an enhanced half-life. Conclusions: Collectively, our findings demonstrate that IO-125 exhibits superior pharmacokinetics profile and biodistribution to tumors, resulting in enhanced anti-tumor activity in a TNBC xenograft model. Based on these observations, we propose that IO-125 may emerge as a potentially effective platinum-based drug for TNBC patients.
Utilization of Oncotype DX testing in a community hospital system: How did this affect patient care?
Authors: Snow Jennifer , Halaharvi Deepa R. , Pastorino Alyssa , Wooster Meghan , Dusseau Brian , Cripe Mark H.
Published: February 2017

19

Background: The Oncotype DX Breast Cancer Assay is a multigene assay which quantifies risk of distant recurrence at 10 years and predicts benefit of chemotherapy in women with stage I/II, lymph node negative, estrogen receptor positive breast cancer. This retrospective study examines utilization of Oncotype DX for appropriate patients in a community hospital system. We hypothesize that chemotherapy administration follows the Oncotype DX score recommendation that patients with low recurrence scores not receive chemotherapy and patients with high recurrence scores receive chemotherapy and intermediate recurrence scores receive chemotherapy half of the time. Methods: In this retrospective study, 302 female patients from 1/1/12 – 1/1/14, were identified by breast cancer ICD9 codes from the system’s cancer registry. Data including imaging findings, pathology, and treatment information was then compared using chi square tests for categorical variables and two sample t tests or Wilcoxon rank sum tests for continuous variables. Results: Three hundred two female patients with stage I/II, lymph node negative, HR+, HER2/neu, breast cancer from a community hospital system were identified as appropriate candidates by NCCN guidelines, for Oncotype DX testing between 1/1/12 - 1/1/14. In patients receiving Oncotype DX, mass sizes were larger and were a higher proportion of stage 2 cancers (p < 0.001). Utilization of Oncotype DX in our CoC and NAPBC accredited hospital system was lower than hypothesized with only 73% of patients receiving testing. Following Oncotype DX testing, appropriate treatment ensued 94% of the time (low and high recurrence risk). Intermediate recurrence scores received treatment 36% of the time. Conclusions: In our CoC and NAPBC accredited hospital system, utilization of Onocotype DX testing was lower than hypothesized. For the patients who received testing, expected treatment was administered. Oncotype DX testing when performed influences patient care, however with 27% of patients not receiving testing and 25 % of the time this was due to patient preference, this observation supports that testing not be ordered reflexively, but rather with patient input and appropriate consent.
Germline mutations in early-onset or hereditary breast cancer from the Middle East.
Authors: Marafie Makia J , Al-Temaimi Rabea , Megarbane Andre , Al-Mulla Fahd
Published: February 2017

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Background: Breast cancer is the most common cancer affecting women of Middle Eastern origin. Epidemiologically, breast cancer in the Middle East clusters in families and usually affects women a decade younger than Western women. This dilemma is compounded by the lack of curated databases and ambitious studies that address the roles genetic or genomic may play in breast cancer. Methods: We have exome sequenced 60 Middle Eastern women with moderate and strong family history of cancer or young women without significant family history of cancer. DNA extracted from peripheral blood of patients and matching normal Middle Eastern women without history of familial or sporadic cancers, were subjected to whole-exome sequencing using the HiSeq 2500 Illumina platform and MLPA to map major breast cancer–activating genetic defects. Results: Several novel BRCA1/2 mutations were identified in the minority of these women. However, other complex mutations in non-BRCA1/2 genes appear to play a more subtle role in breast cancer in the Middle Eastern women. Germline mutations in TP-53, BARD1 and mismatch repair genes were more frequent than expected by chance. Conclusions: BRCA1/2 gene mutations are not a significant cause of heritable cancers in the Middle East. The region may benefit from a well-curated region-specific database accessible to clinicians and scientists where clinical and variants information can be deposited from all over the Middle East.
Breast surgeons' attitudes towards bilateral risk-reducing mastectomy: A National Survey of American Surgeons.
Authors: Basu Narendra Nath , Den Heijer Mariska , van Asperen Christi J , Harris Hilary , Nippert Irmgard , Schmidtke Joerg , Bouhnik Anne Deborah , Julian-Reynier Claire , Beitsch Peter D. , Tibben Aad , Hodson James , Evans D. Gareth
Published: February 2017

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Background: Bilateral risk-reducing mastectomy (BRRM) confers the greatest risk-reduction in women at high-risk of developing breast cancer. Uptake of BRRM is influenced by the attitudes of these women as well as the breast surgeons offering these procedures. We surveyed surgeon members of the American Society of Breast Surgeons to assess their attitudes and knowledge. Methods: An International Cancer Risk Communication Study (InCRisC) questionnaire, previously used to assess attitudes of European physicians and surgeons was sent to 2648 members. Personal and occupational characteristics were recorded and knowledge of cancer genetics and attitudes to BRRM were assessed using clinical vignettes. Results: 439 breast surgeons responded. 98% of surgeons actively took a family history of the father. Almost 100% of surgeons reported a positive attitude towards BRRM. Female surgeons and those treating greater than 100 breast cancers a year were predictors of knowledge of breast cancer genetics and a positive attitude towards BRRM. Conclusions: Multiple factors contribute to surgeons' attitudes towards BRRM. Gender of surgeon and workload contribute to theses observed variations.
Recurrence rates for ductal carcinoma in situ: Analysis of 2,996 patients treated with breast-conserving surgery over 30 years.
Authors: Van Zee Kimberly J. , Subhedar Preeti , Olcese Cristina , Patil Sujata , Morrow Monica
Published: February 2017

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Background: Randomized trials of radiation after breast-conserving surgery (BCS) for DCIS found substantial rates of recurrence, with half of recurrences invasive. Decreasing local recurrence rates for invasive breast carcinoma have been observed, and are largely attributed to systemic therapy improvements. Here we examine recurrence rates after BCS for DCIS over 3 decades at one institution. Methods: We retrospectively reviewed a prospectively maintained database of DCIS patients undergoing BCS from 1978–2010. Cox proportional hazard models were used to investigate the association between treatment period and recurrence, controlling for other variables. Results: 363 (12%) recurrences among 2996 cases were observed. Median follow-up for patients without recurrence was 75 months (range 0–30 years); 732 were followed for ≥ 10 years. The 5-year recurrence rate for 1978–1998 was 13.6% versus 6.6% for 1999–2010 (hazard ratio [HR] 0.62, p < 0.0001). After controlling for age, family history, presentation (radiologic vs clinical), nuclear grade (non-high vs. high grade), necrosis, number of excisions ( ≤ 2 vs ≥ 3), margin status (positive/close vs negative), radiation, and endocrine therapy, treatment period remained significantly associated with recurrence, with later years associated with a lower HR (0.74, p = 0.02) compared to earlier. After stratification by radiation use, and adjustment for 7 other factors, the decrease in recurrence rates was limited to those without radiation (HR 0.62, p = 0.003); there was no decline in recurrence rates among those receiving radiation (HR 1.13, p = 0.6). Conclusions: Recurrence rates for DCIS have fallen over time. Increases in screen-detection, negative margins, and use of adjuvant therapies only partially explain the decrease. The unexplained decline is limited to women not receiving radiation, suggesting it is not due to changes in radiation efficacy, but may be due to improvements in radiologic detection and pathologic assessment. The lower recurrence risk observed for DCIS patients treated in more recent years is important for patient education, especially in view of the widely reported recent increase in use of mastectomy.
Outcomes associated with adjuvant radiation after lumpectomy for elderly women with T1-2N0M0 triple-negative breast cancer: SEER analysis.
Authors: Szeja Sean , Hatch Sandra S.
Published: February 2017

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Background: Adjuvant Radiation (RT) may be omitted for elderly women with early stage breast cancer having favorable estrogen receptor status, however in the setting of triple negative breast cancer (TNBC), less evidence exists to guide decision making. As some findings thus far have shown TNBC to have an increased recurrence rate, this is an important subject to address. The purpose of this study is to use the Surveillance, Epidemiology, and End Result (SEER) database to evaluate how the addition of adjuvant radiation affects the survival of women ages 70 and above with T1-2, N0, M0 TNBC that undergo Lumpectomy (L). Methods: Cases diagnosed from 2010-2011 were downloaded from the SEER Database. Inclusion criteria were ages 70 and above, with T1-2N0M0 TNBC. Kaplan meier curves calculated overall survival (OS) and disease specific survival (DSS) in months (m). Log-Rank tests were performed to compare survival. Cox multivariate regression was performed to calculate Hazard Ratios (HR) and control for confounding variables including neoadjuvant chemotherapy, number of lymph nodes sampled, age, laterality, grade, T stage, extent of surgery, existence of other cancers. Results: From 2010-2011, SEER contained 109,559 cases of breast cancer with recorded results of Her-2-neu (H2N) status. Combining other receptor values, showed 12,620 triple-negative, which was 12% of cases. Of these, 6980 (55%) had stage T1-2, N0, M0. Lumpectomy was used in 4002 of these cases. There were 974 lumpectomy cases of women aged 70 and above. RT was given in 662 (68%) cases. After 23 months, L+ RT was associated with improved OS at 98.2% compared to 85.6% for L only (p=<0.001), as well as DSS at 99% for L+RT better than 94% for L only (p=0.003). Cox Regression showed radiation demonstrated improved OS (HR=0.14, p<0.001) and DSS (0.14, p=0.01). Conclusions: The use of adjuvant RT after lumpectomy for elderly women with early stage TNBC was associated with improved OS and DSS. Noting the potential for selection bias in this study, future prospective study is required to define the management of early stage triple negative breast cancer.
Prospective assessment of deep inspiration breath hold to prevent radiation-associated cardiac perfusion defects in patients with left-sided breast cancer.
Authors: Zagar Timothy , Tang Xiaoli lily , Jones Ellen , Matney Jason , Das Shiva , Green Rebecca L , Sheikh Arif , Khandani Amir H , McCartney William H , Wong Terence Z. , Marks Lawrence Bruce
Published: February 2017

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Background: Radiation therapy (RT) for left-sided breast cancer can cause regional cardiac perfusion abnormalities in nearly half of patients at 6 months post-RT. While the significance of these perfusion abnormalities remains unclear, RT is a well-accepted risk factor for heart disease. We herein report the results of a single-arm prospective clinical study to assess deep inspiratory breath hold (DIBH; using AlignRT) as a means to prevent the development of perfusion abnormalities in patients with left-sided breast cancer. Methods: Patients about to receive left-sided tangential RT had a pre-RT cardiocentric single photon emission computed tomography with CT based attenuation correction (IQ SPECT-CT) rest-cardiac gated perfusion scan (to assure a normal baseline). DIBH and conformal blocking was used to assure that the heart was excluded from the primary RT beam. Doses to the heart were computed. At 6-months post-RT, the SPECT-CT was repeated. The perfusion and motion images were assessed qualitatively by a nuclear medicine physician. Results: Twenty-four patients have been enrolled. Four were not evaluable (e.g. due to an abnormal pre-RT SPECT scan); one has been lost to follow-up. All patients received tangential radiation to the breast/chest wall (typical doses 200 cGy x 25 or 267 cGy x 16); five also received regional nodal RT as well; and 18/19 received a tumor bed boost. The mean heart dose ranged from 42-160cGy for all 19 patients (mean of the means = 78 cGy). Of the 19 potentially evaluable patients, post-RT SPECTs have been obtained in ten. All ten have a normal post-RT SPECT scan; and/or no change from pre-RT scan. Conclusions: In patients receiving tangential RT for left-sided breast cancer, cardiac avoidance with DIBH (e.g. with AlignRT) and conformal field shaping, appears to be able to prevent the development of RT-associated cardiac perfusion abnormalities. The mean dosages to the heart are quite low. Updated information on the remaining patients will be presented. Funded in part by VisionRT. Clinical trial information: NCT01849614.
Use of a 3-dimensional lumpectomy marker for targeting interstitial accelerated partial breast irradiation (APBI).
Authors: Smith Linda Ann , Nelums Erika N. , Snyder Margaret B. , Kuske Robert R.
Published: February 2017

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Background: APBI via high-dose-rate (HDR) interstitial catheter implants is an effective, highly customizable method of delivering radiotherapy in breast cancer patients. The technique is amenable to challenging anatomy such as pendulous and/or very small breasts, augmented breasts or superficial lumpectomy sites. The challenge for any APBI technique is identification of the lumpectomy cavity, which can be difficult to visualize after surgery due to post-surgical changes or tissue mobilization for oncoplastic closure. In the past we have used x-ray contrast injected into the cavity to facilitate the radiographic visualization of the cavity or individual clips. A new 3-D tissue marker (BioZorb, Focal Therapeutics, Inc.) has recently been used by surgeons to mark the area of the lumpectomy cavity at greatest risk for recurrence. In effect this acts as a communication tool to help guide the radiation oncologist for treatment planning and delivery. We examined this device for target volume localization in 15 patients receiving interstitial HDR APBI. Methods: The marker mimicking the tumor size was surgically sutured at the base of the lumpectomy cavity in 15 patients with T1T2N0N1 breast cancer with a variety of closure techniques. The clinical target volume (CTV) was taken as the 3-D outline made by the six embedded titanium markers and a 2 cm margin expanded around that structure (the planning target volume, PTV). Multiple interstitial catheters were spaced 1.5 cm apart within the PTV and 34 Gy was delivered in 10 fractions delivered over 5 treatment days. Results: The marker/CTV was easily visualized on CT images, without clips or injected contrast, making catheter insertion and planning more efficient, easier, and reproducible. The CTV volume was small (12.5 +/- 8.7cc; mean +/- SD, range 4.4–33.4cc) as was the PTV (137 +/- 60cc; mean +/- SD, range 75–327cc), relative to typical HDR APBI implants. Conclusions: The technique facilitated identification of the lumpectomy cavity in all patients treated regardless of surgical closure technique. The unambiguous margin demarcation facilitated target contouring and reproducibility for APBI.