bluuebunny/crossref_metadata_2025 huggingface dataset:
Chromosome 8 alterations and PTEN loss in Gleason grade 3 tumor to predict the presence of unsampled grade 4 tumor: Implications for active surveillance.
Authors: Trock Bruce J. , Jenkins Robert B. , Said Jonathan W. , Fine Samson , Knudsen Beatrice , Fedor Helen L. , Gurel Bora , Lotan Tamara L , De Marzo Angelo M
Published: February 2017

93

Background: A key eligibility criterion in many active surveillance (AS) programs is that the biopsy exhibit only Gleason pattern 3 (G3) for a Gleason score of 6 or less. However, 25 to 35% of biopsy Gleason 6 is upgraded to Gleason 7 or higher in the prostatectomy (RP) specimen. Thus, there is a great need for biomarkers that, when measured on G3 tissue in a Gleason 6 biopsy, can predict the presence of unsampled higher grade tumor in the whole prostate. We evaluated PTEN loss by immunohistochemistry (IHC), and PTEN deletion, chromosome 8q (MYC) gain and 8p (LPL) loss by fluorescence in situ hybridization (FISH) for their ability to predict unsampled G4 tumor. Methods: A tissue microarray (TMA) was constructed of RP tissue from three groups of patients (n=50 per group) whose prostates exhibited only Gleason 3+3, only 3+4, or only 4+3 tumor, matched on age, year of RP, and race. In each patient, multiple cores sampled only from areas of G3 were evaluated for PTEN deletion by FISH, PTEN loss by IHC, and chromosome 8p/8q alterations by FISH. Biomarker results were compared between Gleason 6 versus 7 tumors using conditional logistic regression. Results: Patients underwent RP in 2001 to 2009, had median age 60, and median prostate-specific antigen 5.2; 63% of tumors were organ confined. In univariate analyses 8q gain (odds ratio OR=8.9, p<.0001), 8p loss (OR=6.9, p<.0001), PTEN loss by IHC (OR=5.7, p=.025), but not PTEN deletion by FISH (OR=1.5, p=.477) were significantly more common in G3 cores from Gleason 7 tumors than G3 cores from Gleason 6 tumors. In multivariable analyses, 8q gain (OR=6.2, p=.002) and 8p loss (OR=5.2, p=.0002) remained highly significant. At least one high risk biomarker (8q gain, 8p loss, PTEN loss, or PTEN deletion) was found in 35.7% of Gleason 3+3 versus 77.1% of Gleason 3+4 versus 91.3% of Gleason 4+3 tumors, p<.0001. Adjustment for confounding factors did not change the results. Conclusions: Chromosomal 8q gains (MYC), 8p loss (LPL), and PTEN loss measured in Gleason G3 TMA cores strongly differentiate whether the core comes from Gleason 6 or Gleason 7 tumor. If validated in biopsy Gleason 6 cores to predict prostatectomy Gleason 7 tumor these biomarkers could facilitate safe selection of men for active surveillance.
Highly functional natural killer (NK) cells as predictive biomarkers associated with long response to castration in newly diagnosed metastatic prostate cancer.
Authors: Pasero Christine , Gravis Gwenaelle , Guerin Mathilde , Rocchi Palma , Thomassin Jeanne , Walz Jochen , Salem Naji , Dermeche Slimane , Brunelle Serge , Olive Daniel
Published: February 2017

95

Background: Immunotherapy is now investigated as a promising alternative treatment for patients (pts) with metastatic prostate cancer (PC). Natural killer (NK) cells are powerful effector cells with antitumoral activity and their role have been explored in solid tumors but not yet in prostate cancer. NK cell cytotoxicity is regulated by a balance between activating and inhibitory receptors. Here, we performed a restrospective study to evaluate the link between NK cells and the time of castration response in newly diagnosed PC patients with metastases. Methods: Newly diagnosed metastatic PC pts were divided according the time of castration response, with an 18-months cutoff value: 18 pts with long castration response (LCR, median = 64.6 months), and 14 pts with short castration response ([SCR] median = 11.2 months), with a median overall survival of 97.7 months and 33.8 months respectively. Circulating NK cells from these patients were studied by flow cytometry to evaluate the expression of activating receptors and the NK cell functionality. Results: We observed thatNK cells from LCR pts express higher levels of the maturation marker CD57 (43.3% vs. 23.3% positive cells, p= 0.002), the receptor CD16 involved in cytotoxicity (29,124 vs. 16,806 MFI, p= 0.02), and the activating receptors NKp46 and NKp30 (17.5 vs. 11.4 RMFI, p= 0.0146 , and 10.9 vs. 6.3 RMFI, p = 0.0128 respectively) than NK cells from SCR pts. This suggests that LCR pts have powerful NK cells. Indeed, NK cells from LCR pts are highly efficient in CD107 functional assay than NK cells from SCR pts (28.9% vs. 19.4%, p =0.002). In vitro blocking experiments show that NKp46 is precisely one of the NK cell receptors involved in the NK-mediated recognition of prostate tumor cells, thus higher expression of NKp46 would help to control PC progression. Conclusions: Together our results show for the first time that efficient NK cells are associated to a long response to castration and prolonged survival in newly diagnosed metastatic PC. NK cell receptors might be useful as predictive biomarkers in metastatic PC, to help in stratification of patients and to design NK cell–based immunotherapeutic strategies for PC.
Leveraging RB status to define therapy for castrate-resistant prostate cancer.
Authors: de Leeuw Renee , Comstock Clay de , Pollutri Daniela de , Schiewer Matthew Joseph , Ciment Stephen J , Mankame Tanmayi de , Ostrander William , Den Robert Benjamin , Kelly William Kevin , Gomella Leonard G. , Dicker Adam , Hussain Maha , Knudsen Karen E.
Published: February 2017

96

Background: Loss of retinoblastoma (RB) tumor suppressor is overrepresented in castrate-resistant prostate cancer (CRPC) compared to primary PCa. We previously showed using analyses of human tissue and in vitro and in vivo modeling that RB constrains androgen receptor (AR) function, and that loss of RB is sufficient promote resistance to castration and AR antagonists. Thus, novel strategies are needed to treat RB-deficient tumor. By contrast, in tumors retaining RB, suppressing enhancing RB activity would be of therapeutic advantage, and may be accomplished through next-generation Cdk4/6 inhibitors. Methods: Stable isogenic pairs of prostate cancer cell lines either retaining RB or RB depleted (by shRNA) were assessed in vitro and in xenografts for response to Cdk4/6 kinase inhibitors or the cabazitaxel. In addition, using an ex vivo explant assay, fresh tumor tissue samples from radical prostatectomy were exposed to the Cdk4/6 inhibitor or cabazitaxel for up to 7 days, and evaluated by IHC for Ki67, Caspase-3, and AR. Results: Cdk4/6 inhibition blocks tumor cell proliferation dependent on RB status. This was further confirmed ex vivo, as evidenced by a marked reduction in Ki67 staining in Cdk4/6 inhibitor treated explant tissue from two prostate cancer patients. Conversely, in vitro studies revealed a modest sensitization of RB-depleted tumors to cabazitaxel that was dramatically enhanced in vivo and after castration. Cabazitaxel, like docetaxel, targets the cell architecture and induces cell death, but also induces a distinct gene expression profile that may partially explain efficacy in docetaxel-resistant tumors. Neither taxane showed affects on AR nuclear localization using in vivoor explant studies. Conclusions: These results strongly support our hypothesis that RB status can be used as a metric to define therapeutic response to cabazitaxel, as such that loss of RB function induces sensitization taxanes, whereas RB proficient tumors give an enhanced response to Cdk4/6 kinase inhibitors.
Impact of prior response to abiraterone acetate (AA) on subsequent activity of docetaxel (D) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts).
Authors: Azad Arun , Lester Renee , Heng Daniel Yick Chin , Eigl Bernhard J. , Chi Kim N.
Published: February 2017

97

Background: Questions about optimal sequencing of systemic agents in mCRPC and whether cross-resistance occurs between agents remain largely unanswered. Recently, it was reported that D is inactive in mCRPC pts who did not have a ≥ 50% PSA decline on prior AA (Ann Oncol 2012; 23(11):2943-7). To investigate this further, we evaluated the activity of D in mCRPC pts who had previously received AA. Methods: Cancer registries at two Canadian centers were used to identify mCRPC pts treated with D after AA. Outcomes from D treatment were compared between AA responders (≥ 50% PSA decrease with prior AA) and AA non-responders (< 50% PSA decrease with prior AA). Progression-free survival (PFS) (Prostate Cancer Working Group 2 criteria) and overall survival (OS) were estimated using the Kaplan-Meier method. Results: Of 40 eligible pts, 14 (35%) were classified as AA responders and 26 (65%) as AA non-responders (including 16 pts who had no PSA decline on AA). The median number of cycles of D administered to AA responders and non-responders was 6 (range: 1-10) and 4 (range: 1-13) respectively. Thirty (75%) pts had also received D prior to AA. Notably, among 39 pts evaluable for PSA response, no difference was seen in the proportion of AA responders and non-responders who had PSA falls ≥ 50% (p=0.72; Fisher’s exact test) or ≥ 30% (p=0.75; Fisher’s exact test) on D (Table). Analysis of survival outcomes from date of initiation of D also revealed similar median PFS (p=0.54; log-rank) and median OS (p=0.93; log-rank) in both groups (Table). Conclusions: PSA response rates to D did not differ between AA responders and non-responders. These data suggest that the anti-tumor activity of D in mCRPC may be independent of prior response to AA and that chemotherapy is still a therapeutic option in patients who do not respond to AA. Prospective studies evaluating optimal sequencing of AA and D in mCRPC are warranted. [Table: see text]
Evaluation of length, maximum Gleason score, and extension of disease at positive surgical margins during radical prostatectomy.
Authors: Djaladat Hooman , Alemozaffar Mehrdad , Day Christina , Aron Manju , Cai Jie , Campanelli Tracy , Lieskovsky Gary , Daneshmand Siamak
Published: February 2017

98

Background: Positive surgical margin (PSM) found following radical prostatectomy (RP) is known to affect subsequent recurrence and survival. The extent of PSM has been shown to impact clinical outcomes. We examined the effect of length of PSM, extent of disease at PSM and maximum Gleason score at PSM on oncologic outcomes. Methods: A retrospective review of 3971 patients undergoing RP for prostate cancer at our institution between1978-2009 revealed 1053 patients with PSM, out of whom 814 received no hormone therapy. The initial 175 patients were selected to maximize available follow-up, and their slides were re-reviewed for following parameters: length of PSM (mm), maximum Gleason score at PSM, and maximal extension of PSM (intraprostatic incision vs. extracapsular extension). Data was available in 107 patients who are the subject of this study. Multivariable Cox regression models were used to evaluate the impact of above features as well as age, preoperative PSA, pathologic Gleason score, stage and adjuvant radiotherapy on biochemical and clinical recurrence-free survival (RFS), and overall survival (OS). Results: Median follow-up was 17.6 years. Maximum extension of PSM was limited to intraprostatic incision in 63 (58.9%) and extracapsular in 44(41.1%) patients. Median length of PSM was 4 mm (range 1-55 mm); 41 (38.3%) with <3mm and 66 (61.7%) with >4mm. Maximum Gleason score at PSM was <6 in 70 (66.0%) and >7 in 36 (34%) patients. 10-yr PSA RFS, clinical RFS, and OS were 60.2%, 80.7%, and 60.2%, respectively. Multivariable Cox regression modeling showed the length of PSM >4mm and extracapsular extension as independent predictors of PSA RFS and clinical RFS. Age and extracapsular extension were independent predictors of OS. Conclusions: PSM >4mm and extracapsular extension have a higher risk of PSA and clinical recurrence after RP. These findings can help decision-making regarding adjuvant therapy in patients with PSM and should be reported by pathologists in addition to the presence of PSM. [Table: see text]
Enzalutamide in men with chemotherapy-naive metastatic prostate cancer (mCRPC): Results of phase III PREVAIL study.
Authors: Beer Tomasz M. , Armstrong Andrew J. , Sternberg Cora N. , Higano Celestia S. , Iversen Peter , Loriot Yohann , Rathkopf Dana E. , Bhattacharya Suman , Carles Joan , De Bono Johann S. , Evans Christopher P. , Joshua Anthony M. , Kim Choung-Soo , Kimura Go , Mainwaring Paul N. , Mansbach Harry H. , Miller Kurt , Noonberg Sarah B. , Venner Peter M. , Tombal Bertrand
Published: February 2017

LBA1^

Background: Enzalutamide, an orally administered androgen receptor inhibitor, improved overall survival (OS) in men with mCRPC who had received prior docetaxel therapy (Scher et al, NEJM 367:13, 2012). This study examined whether enzalutamide could prolong OS and radiographic progression-free survival (rPFS) in asymptomatic or mildly symptomatic chemotherapy-naive men with mCRPC. Methods: In this randomized, double-blind, placebo-controlled, multinational phase 3 study (NCT01212991), chemotherapy-naive patients with mCRPC were stratified by site and randomized 1:1 to enzalutamide 160 mg/day or placebo. OS and rPFS were co-primary endpoints and analyzed for the intent-to-treat population. Planned sample size was 1,680 with 765 deaths to achieve 80% power to detect a target OS hazard ratio (HR) of 0.815 with a type I error rate of 0.049 and a single interim analysis at 516 (67%) deaths. The co-primary endpoint of rPFS had sufficient power to detect a target HR of 0.57 and a type I error rate of 0.001 with a minimum of 410 events. Results: A total of 1,717 men were randomized (1,715 treated) between September 2010 and September 2012. The interim analysis at 539 deaths showed a statistically significant benefit of enzalutamide over placebo with a 30% reduction in risk of death (OS: HR 0.70; 95% CI: 0.59-0.83; P< 0.0001) and an 81% reduction in risk of radiographic progression or death (rPFS: HR 0.19; 95% CI: 0.15-0.23; P< 0.0001). At the time of the analysis, 28% of enzalutamide patients and 35% of placebo patients had died. Estimated median OS was 32.4 months (mo) (95% CI, 31.5–upper limit not yet reached [NYR]) in the enzalutamide arm vs 30.2 mo (95% CI, 28–upper limit NYR) in the placebo arm. Median rPFS was NYR (95% CI: 13.8–upper limit NYR) in the enzalutamide arm vs 3.9 mo (95% CI: 3.7-5.4) in the placebo arm. Seizure events were reported in two patients. The Independent Data Monitoring Committee considered the benefit-risk ratio to favor enzalutamide and recommended stopping the study and crossing placebo patients to enzalutamide. Secondary endpoints and safety analysis will be presented. Conclusions: Treatment with enzalutamide significantly improves OS and rPFS in men with chemotherapy-naive mCRPC. Clinical trial information: NCT01212991.
Breast cancer survivorship in urban India.
Authors: Gadgil Pranjali V , Nag Shona Milon , Mane Anupama Dutt , DeSouza Rebecca , Sivaram Rama , Gupta Sudeep
Published: February 2017

108

Background: With increasing breast cancer burden, there is need for survivorship programs in developing countries. The Indian Breast Cancer Survivors Conference is a unique initiative, to address this need in urban India. A survey of participants at this meet was conducted to aid planning of future events. Methods: Participants filled a 3-page bilingual questionnaire. Data gathered included demographics, education, treatment and side effects, health behaviors, and social impact of diagnosis. Results: Demographic: 205 breast cancer survivors registered from 5 cities. 190 participated in the study. Mean age was 51.5 years (27-79). 61.6 % reported having one or more college degrees and 86.5% were married. Diagnosis and Treatment: Mean age at diagnosis was 47.5 yrs (22-72). Median time from diagnosis was 36 m (3m-19 yrs). Mastectomy was reported as the surgical treatment by 52.1% (6% reconstruction), 72.9 % reported lymph node removal and 10.8% could not specify surgical details. 90% received chemotherapy; 76.8% underwent radiation (97.3% in lumpectomy pts); 61% took endocrine therapy and 5.1 % interrupted it before 5 years. Side Effects:Arthralgia (64%) and anxiety (60.9%) were most frequent self- reported problems followed by surgical site pain (56.1%), depression (53.9%), cognitive deficits (52.2%), skin/ hair/ nail problems (48.2%), hot flashes (48.2%), arm swelling (48.2%) and vaginal dryness (38.2%). Social Impact:Survivors whowere married or in a relationship described their relationship as stronger after diagnosis in 57.8%, unchanged in 37.4% and weaker in 4.7%. Two were married after diagnosis and none reported separation or divorce. Health Behaviors: Regular surveillance visits were reported by 93.3 % (168/180) of participants (65 with their medical oncologist, 50 with surgeon, 23 with both) 5.5% had not seen their oncologist in 2 years. Alternative medical treatment was used by 29.1% (53/182); 26 used Ayurvedic, 13 homeopathic and 14 other. This was discussed with an oncologist by 62.3%. Regular exercise at least 3 times/week was reported by 73.7% and walking (88.8%) or yoga (22.2%) were preferred. Conclusions: The presented data highlights aspects of breast cancer survivorship in urban Indian women that can be used to plan survivorship programs in future.
Factors affecting nodal involvement in mucinous breast cancer.
Authors: Nguyen Tracy , Stash Bryce , Siwawa Portia , Misra Subhasis
Published: February 2017

124

Background: Mucinous carcinoma of the breast is a rare type of invasive ductal breast cancer that accounts for 2-5% of all primary breast cancers. Axillary lymph node involvement for mucinous breast carcinoma is rare and correlated with a poor prognosis. However, the relation of lymph node involvement to certain factors is unknown, hence the purpose of our study. Methods: Retrospective chart review of patients diagnosed with mucinous breast carcinoma from 2004 to 2014 from the local tumor registry. Variables include age, tumor size, lymph node metastasis, diagnosis type (pure/mixed), and hormone status of patients. Chi square and T-test was performed. Results: 45 female patients were included in the study with the age range of 35 to 97 years old. 39 patients were diagnosed with mixed mucinous carcinoma and 6 had pure mucinous carcinoma. 9 patients had positive axillary lymph node involvement. 78% of patients with positive lymph node had mixed mucinous carcinoma and 22% had pure mucinous carcinoma. There is no statistical significance (p > 0.05) between lymph node involvement and diagnosis type. Tumor size ranged from 4 to 120 mm, with a mean of 28 mm. 78% of patients with positive lymph node had a tumor size smaller than 60 mm. The other two had a tumor size of 65 mm. and 120 mm. There is no statistical significance (p > 0.05) in the proportion of people who are lymph node positive to tumor size less than 60 mm. Out of the 45 patients, 42 patients expressed ER receptors, 36 expressed PR receptors, and 12 expressed HER2 receptors. 89% of positive lymph node patients express ER hormone receptors, 78% expressed PR receptors, and 56% expressed HER2 receptors. No correlation between ER/PR status and lymph node involvement (p > 0.05) was found but there was a positive correlation between HER2 receptor status and lymph node involvement (p < 0.05). Conclusions: No significant difference between diagnosis type/tumor size in relation to lymph node involvement. Although there is a trend between small tumor size to positive lymph node, it is not significant enough. There is a significant relationship between HER2 positive receptors and lymph node involvement. This is suggestive that the biological nature of the tumor has a larger influence on lymph node involvement than the physical nature.
Alterations in the cell cycle checkpoint pathway in breast cancer.
Authors: Basu Gargi Dan , White Tracey , LoBello Janine R , Kurdoglu Ahmet , Krishnan Subha , Gonzalez Laura , Royce Thomas , Kiefer Jeff , Cherni Irene , Aldrich Jessica , Izatt Tyler , Russell Megan , Nasser Sara , Carpten John D. , Craig David W. , Demeure Michael J.
Published: February 2017

126

Background: Breast cancer is a molecularly diverse disease with molecular subtypes defined by ER, PR and HER2 status. Dysregulation of the cell cycle pathway through activation of cyclin D1 and/or inactivation of CDKN2A is a mechanism of tumor progression in breast cancer and drugs targeting CDK4/6 is undergoing investigation in this disease with promising preliminary results. We investigated several key genetic alterations in cell cycle regulatory proteins in advanced breast cancer patient samples to identify potential targets for cell cycle related treatment options. Methods: A comprehensive genomic profiling was performed on 37 breast cancer samples with the majority being metastatic. Testing included targeted exome sequencing of 562 genes in tumor and paired normal DNA. Results: Patients’ ages ranged from 27-66 years. Analysis of cell cycle regulatory genes revealed focal amplification of cyclin D1/D2 or CDKN2A loss in 9/37 (24%) of cases, of which, 45% were hormone receptor (HR) positive, HER2 negative, 33% were HR positive, HER2 positive and 22% were triple negative (TNBC) subtype. Loss of RB1 was analyzed since it negatively regulates response to CDK4/6 inhibitors. Loss of RB1 was noted in 4/37 (10.8%) of cases, all of which were TNBCs. Only a single TNBC with RB1 loss had concurrent CDK4 amplification and loss of CDKN2A. No evidence of CCNE1 amplification was found in any samples. Incidence of CDK4 and CDK6 amplification was found in samples with cyclin D1 amplification or CDKN2A loss. Our cohort included a single male TNBC patient who harbored cyclin D1 amplification as well as CDKN2A loss. Overall, amplification of cyclin D1, cyclin D2, CDK4 and CDK6 was found in 16%, 5.4%, 2.7% and 2.7% respectively. Loss of CDKN2A was noted in 5.4% of tumors profiled. Conclusions: Exome sequencing identified subsets of patients with mutated cell cycle associated genes that may benefit from CDK 4/6 inhibitors. Our data suggests loss of RB1 is more frequent in TNBC subtype which may confer resistance to CDK4/6 inhibitors. Our analysis suggests that in addition to HR positive, HER2 negative patients, a subset of HR positive, HER2 positive patients could be sensitive to CDK4/6 inhibitors due to activation of the cell cycle pathway as evidenced by mutations in key genes.
Trastuzumab-induced cardiotoxicity in Uruguayan HER2-positive breast cancer patients.
Authors: Schiavone Andrea , Diaz Mariana , Camejo Natalia , Reborido Natalia , Vazquez Horacio , Parma Gabriel , Vazquez Alvaro , Castillo Cecilia , Krygier Gabriel David , Delgado Lucia Beatriz
Published: February 2017

143

Background: To evaluate the incidence, severity and outcome of Trastuzumab-induced cardiotoxicity in HER2 positive Uruguayan breast cancer (BC) patients. Methods: Retrospective observational analysis of HER2 positive BC patients who were treated with Trastuzumab (TTZ) from January 2007 to December 2013 at two Uruguayan centers. Cardiac monitoring included physical examination and assessment of left ventricular ejection fraction (LVEF) by echocardiography that was evaluated before TTZ administration and every 12 weeks thereafter during the duration of therapy. Cardiovascular risk factors analyzed were: obesity (BMI ≥ 30 kg/m2), hypertension, diabetes, sedentary lifestyle and high cholesterol. Results: Sixty nine female patients were found in the databases of our institutions. Median age was 48 years (range: 27-73). Stage at diagnosis was as detailed: 19 % EI, 46 % EII, 29 % EIII and 4 % EIV. Eighty nine percent of patients received adjuvant TTZ , 4 % neoadjuvant TTZ and 7 % received it as a palliative therapy. Thirty patients (43, 5%) had at least one cardiovascular risk factors: 26% hypertension, 16% obesity, 9% sedentary lifestyle, and 4% high cholesterol. Median number of TTZ cycles was 15. Cycles were administered every 3 weeks at standard dose. Nineteen patients (27%) developed cardiotoxicity, of whom 12 had a transient suspension because of a reversible fall in LVEF, 2 had a irreversible reduction in LVEF, and 5 had a symptomatic heart failure. Eighty-nine percent of our patients (62 patients) completed treatment and the rest had a definitive suspension due to a irreversible reduction in LVEF or symptomatic heart failure. Most patients that developed cardiotoxicity (15 out of 19) had cardiovascular risk factors and also most of them (16 out of 19) had received anthracyclines before TTZ. Conclusions: Cardiotoxicity incidence was similar to the incidence reported in the literature and when it was present, in most cases was transient, asymptomatic, and reversible.
Dual inhibition of DNA double strand break (DSB) repair and PI3K pathway with BEZ235 (BEZ) to sensitize refractory metastatic (met) triple negative breast cancer (TNBC) to nab paclitaxel/cisplatin (pac/cis) in a patient with an exceptional response (ExRx).
Authors: O'Shaughnessy Joyce , Espina Virginia A. , Cherni Irene , Carpten John D. , Liotta Lance A. , Craig David W. , Kiefer Jeff , Hoke Nicholas N , Levin Maren K. , Wang Kai , Ramos Corinne
Published: February 2017

156

Background: Whether EGFR is a critical target in met TNBC is unknown. Here we report the clinical history & tumor molecular alterations in a patient with refractory metTNBC who had an ExRx to pac/cis. Methods: Following IRB-approved informed consent, targeted NGS (Foundation Medicine) and WGS (TGEN) was performed on the pt’s FFPE primary TNBC and 2 recurrent lymph nodes to characterize all classes of genomic alterations in cancer-related genes. RPPA was performed at a CLIA-certified laboratory (Theranostics Health) and George Mason Univ where immunostaining was directed against HER1/2/3 pathway and other proteins. Results: At age 58 in 2006, pt had T1c 1+ node TNBC treated with FAC/T. Between 2008 and 2011 she had 4 chemotherapy-refractory recurrences in axilla, supraclavicular (SC), internal mammary (IM) LNs treated unsuccessfully with surgery, radiation and multiple cytotoxic agents including carboplatin. In 2011, following SC LN biopsy, she was treated with BEZ, a PI3K/mTOR, ATM, ATR, DNA-PKcs inhibitor, had a 3 mo response, followed by rapidly enlarging progressive disease (PD) in IM LNs pushing sternum anteriorly. She was treated with pac/cis and had an ongoing complete response (CR) of 2.5+ yrs. NGS of 2011 SC LN (pre-BEZ) & 2012 IM LN (post-BEZ): TP53 & BRCA2 (somatic 15% mutant allele freq) mutations, FOXM1 amplification; SMARCA4 (BRG1) deletion RPPA (GMU) 2011 SC LN (Pre-BEZ): 3+ EGFR; 2+ p-EGFR, p-AKT, p-MEK1/2, p-mTOR RPPA (Theranostics) 2012 IM LN (post-BEZ): 3+ p-MEK1/2 (EGFR & p-EGFR 0) (AR-). Conclusions: Strong EGFR signaling associated with chemo-resistant metTNBC in 2011 SC LN was not present in post-BEZ rapid PD in IM LN which then had durable CR with pac/cis. BEZ inhibits DSB repair, sensitizing cancers to DNA damaging agents (Gil del Alcazar, Clin Ca Res 20:1235, 2014). Progression of p-AKT-activated TNBC following response to inhibitors of PI3K & DNA repair shows DSB repair-deficiency and MAPK activation (Juvekar, Cancer Dis 2:1048, 2012). A prospective trial of BEZ followed at PD by pac/cis in metTNBC is warranted.
Molecular profiling of triple-negative endometrial cancers (TNEC) and triple-negative breast cancers (TNBC) to reveal unique expression profiles.
Authors: Jones Nathaniel L. , Xiu Joanne , Reddy Sandeep K. , Wright Jason Dennis , Burke William M. , Tergas Ana Isabel , Hou June YiJuan
Published: February 2017

159

Background: “Triple negative” has been used to characterize a subtype of breast cancer that lacks estrogen, progesterone, and HER2 receptor expression. They are aggressive cancers with limited treatment options. It’s unknown if similar phenotype found in other cancer types, like endometrial cancer, harbor similar molecular alterations and prognosis. We aim to compare molecular features between TNEC and TNBC. Methods: A total of 3133 endometrial cancer samples were evaluated by Caris Life Sciences (Phoenix, AZ) from Mar, 2011 to Jul, 2014 by multiplatform profiling, which included a combination of sequencing (Sanger or NGS), protein expression (IHC), and/or gene amplification (CISH or FISH). 545 TNEC and 2049 TNBC were identified based on reported pathology and compared using Fisher exact tests. Results: Compared to an incidence of 15-20% TNBC in breast cancer, 17% (545/3133) TNEC was seen in our cohort, of which 13% were endometrioid, 22% serous, 26% carcinosarcoma, 7% clear cell, and 22% other. Compared with TNBC, TNEC showed 1.9 exonic mutations per case while TNBC showed 1.2 mutations per case. As shown in the table, AR expression is lower in TNEC than TNBC. TP53 mutation was common in both but more frequent in TNBC. While BRCA1/2 mutation rates were similar, low MGMT and ERCC1 were more common in TNEC, suggesting increased aberrant DNA repair. DNA synthesis protein expression was higher in TNEC including TS, RRM1, and TOPO2A, although TNBC had higher TOPO1. PD-1 expression was more common in TNEC suggesting immune pathway involvement. PI3K/AKT/mTor, MAPK and Wnt pathways were more involved in TNEC with greater PTEN, PIK3CA, FBXW7, KRAS and CTNNB1 mutations. Conclusions: Our study reveals significantly higher overall mutation rates in TNEC than TNBC, and specifically higher activations of multiple molecular pathways including PI3K/Akt/mTor, MAPK and Wnt. Further studies are warranted to validate these findings in clinical trials.
A new model for predicting breast cancer risk in women with atypical hyperplasia.
Authors: Degnim Amy C. , Pankratz V. Shane , Winham Stacey J , Dupont William D , Vierkant Robert A. , Frank Ryan D. , Frost Marlene H. , Vachon Celine , Ghosh Karthik , Hieken Tina J. , Carter Jodi M , Haddad Tufia C. , Denison Lori , Visscher Daniel W. , Hartmann Lynn C. , Radisky Derek C
Published: February 2017

2

Background: Women with atypical hyperplasia (AH) on breast biopsy have an aggregate increased risk of breast cancer (BC), but accurate personalized risk prediction is desirable to facilitate individual clinical management decisions. Currently used models provide poor BC risk prediction for women with AH. Our goal was to develop and validate an improved risk prediction model for women with AH. Methods: From a cohort of 13,538 women with benign breast disease from 1967-2001, pathology review confirmed 699 with AH. Clinical risk factors and histologic features of the tissue biopsy were recorded, and BC events were ascertained from study questionnaires, tumor registry, and review of medical records. Using a lasso approach, 23 variables were assessed for model inclusion. Lasso-identified features were then fit in a Cox regression model to estimate BC risk. Model discrimination was assessed with C-statistics in the model-building set and in a separate external validation set. Calibration was assessed by comparing observed to predicted breast cancer counts. Results: The model-building set comprised 699 women with 142 BC events (median follow-up 8.1 years), and the external validation set comprised 461 women with 114 BC events (median follow-up 11.4 years). The final model included three covariates: age at biopsy, age squared, and number of foci of AH. Model performance was good, with a C-statistic of 0.622 (SE = 0.027) in the model-building set and 0.594 (SE = 0.029) in the external validation set. The model is well-calibrated, with observed to expected numbers of BCs nearly equal across all post-biopsy follow-up years. Conclusions: We propose a new model for predicting BC risk in women with AH based on age at biopsy and number of foci of atypia. This model provides absolute risk estimates for women with AH, has good discriminatory ability, is well-calibrated, and validates in an external cohort.
Comparison of predictive models for local recurrence of DCIS after breast conserving surgery.
Authors: Young Rebekah L. , Desai Shiv , Kalnicki Shalom , Fox Jana Lauren
Published: February 2017

21

Background: Efforts have been made to identify women for whom radiotherapy (RT) after breast-conserving surgery (BCS) for ductal carcinoma in-situ (DCIS) can be omitted. These include development of the Memorial Sloan-Kettering (MSK) nomogram, the Van Nuys Prognostic Index (VNPI), and the DCIS Score. We assessed correlation of the predictive qualities of these 3 approaches to determine risk of local recurrence (LR) and need for RT. Methods: We calculated VNPI score and used the MSK nomogram to determine LR risks for 48 women on whom DCIS Scores were available since January 2012. Given that the DCIS Score does not account for HT, MSK risks were calculated with and without its use. 10-year LR risks from DCIS Score reports were compared with MSK nomogram estimates using the Pearson correlation coefficient. These comparisons were done for MSK LR risks with and without HT. VNPI scores yield low, intermediate and high risk categories. To compare the 3 predictive models, each patient was assigned an RT recommendation per instrument. Two 10-year LR risk “thresholds” to recommend RT were used - 10 and 15% - to account for M.D. preference. Results: For LR risk, the MSK nomogram (excluding HT) and the DCIS Score showed weak positive correlation (R = 0.346, p < 0.02), weaker when including HT (R = 0.179, p: 0.224). VNPI Score could not be calculated on 5 patients and they were excluded in comparisons involving VNPI. DCIS Score, using 15% LR risk as the RT recommendation threshold, and VNPI RT recommendations correlated in 72.1% of cases. Lowering the threshold to10% reduced the correlation to 32.6%. Comparison of the 3 approaches’ RT recommendations with a 15% threshold showed agreement in 65.1% (28/43) of cases, and a 10% threshold reduced the agreement to 18.6% (8/43). Conclusions: Our analysis shows some correlation between the MSK nomogram and the DCIS Score, more when HT is excluded. Lowering the threshold 10-year LR risk to recommend RT from 15 to 10% reduced agreement among the 3 instruments.
Analysis of clinical characteristics in breast cancer patients with the Japanese founder mutation of BRCA1 L63X.
Authors: Yoshida Reiko , Inuzuka Mayuko , Watanabe Tomoko , Yotsumoto Junko , Kuwayama Takashi , Sawada Terumasa , Akashi-Tanaka Sadako , Nakamura Seigo
Published: February 2017

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Background: Hereditary breast and ovarian cancer (HBOC) is a high-penetrance inherited disease, and founder mutation has been reported in the West. However, there are yet no reports of founder mutation of HBOC on breast cancer in the Japanese population. In this study, we report the breast cancer clinical characteristics of L63X, which is one of the founder mutations in BRCA1 in the Japanese population. Methods: Data on 223 affected breast cancer patients (28 BRCA1 carriers, 19 BRCA2 carriers, and 176 non-carriers) were collected at Showa University in Tokyo from September 2010 to June 2015. In 22 independent mutations of BRCA1, the L63X mutation was detected in 9 patients. Data regarding the age of breast cancer onset, pathological features, clinical features, and family history were collected. Results: The age of onset was no significant differences between the L63X mutation and other BRCA1 mutations (39.7 vs. 38.5years). The proportion of triple negative breast cancer patients was 87.5% in the L63X mutation carriers and 89.5% in other BRCA1 mutation carriers. No patients of the L63X affected bilateral breast cancers. On the other hand, 36.7% of other BRCA1mutations affected bilateral breast cancers. There was no significant difference in pathological features (intrinsic subtype, nuclear grade and ki-67 index). The L63X carriers tended to have a family history of breast cancers. All L63X mutations were detected in the Eastern part of Japan. Conclusions: The breast cancer clinical characteristics of L63X might be considered no different from other types of BRCA1 mutations. Recently, it has been reported that breast and ovarian cancer risks varied according to the type and location of BRCA1/2 mutations. L63X mutation is located in the breast cancer cluster region in BRCA1. Further investigation is necessary for appropriate validation and accumulation of data.
Surgical decisions of newly diagnosed breast cancer patients following genetic referral.
Authors: McAlister Jennifer , Dekhne Nayana , Yadav Siddhartha , Zakalik Dana , Lowry Heather , DeLaere Angela
Published: February 2017

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Background: In response to many recent publications and mandates to assure referrals to genetic counseling for oncology patients, the Royal Oak (RO) Breast Care Center (BCC) at Beaumont Health System (BHS) evaluated the surgical outcomes of genetic referral(GR) in breast cancer (BC) patients. The goal of this study was to determine the impact of GR on surgical decision making and evaluate outcomes in this population. Methods: A retrospective chart review was performed, to identify patients who had a BC diagnosis and met criteria for GR from July 2012- July 2014. Age, histology, laterality of cancer, prior history of cancer, neoadjuvant chemotherapy, plastic surgery consultation, MRI, reason for MRI, additional testing, type of surgery, laterality of surgery, reconstruction, lymph node surgery, and time from diagnosis to surgery were evaluated using Chi Square analysis. Results: A total of 506 patients with a new BC diagnosis seen at the RO BCC at BHS within the inclusion dates were analyzed. There were 191 patients referred to the GP for counseling and possible genetic testing. Eighty percent of the referred patients underwent genetic testing. Twelve patients tested positive for deleterious mutations in BRCA 1 or 2. A statistically significant difference was found in the BC patients referred to the GP with respect to age, MRI usage, neoadjuvant chemotherapy, type and laterality of surgery, ALND, plastic surgery consult & reconstruction, and time from diagnosis to surgery. MRI usage in patients referred to GP was 43.5% vs. 12.7% in those not referred. Mastectomy rate in patients referred to GP was 51.3% vs. 25.5% (p<0.001) in those not referred. Bilateral mastectomy was 30.9% vs. 5.8% (p<0.001). Conclusions: We have found that patients referred to the GP have increased the use of MRI testing, which in itself has been shown to increase mastectomy rates. We also identified a trend in these patients toward bilateral mastectomy. According to our outcomes, there are multiple possible reasons for this trend, including family history, physician bias, stage at diagnosis, age and factors intrinsic to the patient. Furthermore, a multivariate analysis is needed to assess the relationship between a GR and a patient’s surgical decision.
Can adding contrast-enhanced digital mammography (CEDM) as an adjunct to diagnostic mammography/US help decrease biopsy rates in women with suspicious (BIRADS 4) breast lesions?
Authors: Patel Bhavika K , Giurescu Marina , Eversman Sarah , William Eversman , Kosiorek Heidi , Victor Pizzitola , Lorans Roxanne , Pockaj Barbara A.
Published: February 2017

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Background: Traditional screening mammography (MG) enables early detection of breast cancer and therefore results in decreased mortality. Mammography, however, is an imperfect tool and limited by an overall sensitivity of 75-85%. Specificity is limited as well resulting in many false-positive examinations and unnecessary follow-up examinations. The recent development of contrast-enhanced digital mammography (CEDM) has made the usage of IV contrast enhancement with mammography a possibility. CEDM is an angiographic technique that uses digital subtraction, which removes the normal mammary gland on images in order to detect breast tumors and visualize their vascularity. The literature is promising with regard to CEDM as studies have found that CEDM achieves increased sensitivity without reductions in specificity in comparison to MG, US and/or MRI. Methods: In this multi-reader study we compared the diagnostic accuracy of CEDM as an adjunct to MG/US in patients with suspicious findings (BI-RADS 4). The study population included 31 patients who were imaged with CEDM prior to their scheduled US or stereotactic-guided biopsy. We compared the relative performance of MG/US alone versus MG/US/CEDM in determining the probability of malignancy. Histology served as the gold standard. Results: See table below. Conclusions: The addition of CEDM to the workup of suspected lesions on MG and/or US preliminarily decreases the number of false-positive MG thereby with potential to reduce cost and unnecessary patient harm. [Table: see text]
Outcomes and feasibility of nipple-sparing mastectomy for node-positive breast cancer patients.
Authors: Murphy Brittany L. , Hoskin Tanya L. , Boughey Judy Caroline , Degnim Amy C. , Jakub James W. , Krajewski Adam C , Jacobson Steven R. , Hieken Tina J.
Published: February 2017

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Background: Indications for nipple-sparing mastectomy (NSM) with immediate reconstruction have expanded. For cancer patients, NSM is thought best-suited for early stage patients, with nodal involvement initially viewed as a relative contraindication. We undertook this study to evaluate the use and early outcomes of NSM in node-positive (LN+) breast cancer. Methods: We identified 240 cancers in 226 patients (14 bilateral) scheduled for NSM and operated on at our institution 1/2009-6/2014. Data on intraoperative conversion from NSM, recurrence and follow-up was abstracted from the medical record. Chi-square and long-rank tests were used for statistical analysis. P-values < 0.05 were considered significant. Results: Of 240 cancers, 182 were LN- and 58 were LN+. More LN+ patients had T2/T3 tumors (27/58, 47%) than LN- patients (31/182, 17%), p < 0.0001, but ER and HER2 status was similar. Of 58 LN+ cases, 19 (33%) were cN1 confirmed by positive LN cytology and 39 (67%) were cN0 but LN+ at operation. 10 patients LN+ at diagnosis received neoadjuvant therapy (NT) followed by operation (at which 6 were pLN+ and 4 rendered ypN0); 39 cN0 (4 NT, 35 primary surgery) and 9 cN1 primary surgery patients were pLN+ at operation with a median of 1 LN+. NSM was successful in 13/14 LN+ NT patients (93%) and 39/44 LN+ primary surgery patients (89%), p = 0.64. Six LN+ patients (10%) were converted to skin-sparing mastectomy (SSM) at initial operation based on frozen section pathology (n = 5) or at a second operation (n = 1) vs 13/182 LN- patients (7%), p = 0.44. Among cancer patients treated with NSM, 7 locoregional recurrences (5 in LN+, 2 in LN- patients) occurred at 25 mos median follow-up. 3-year locoregional disease-free estimates were 87% (95% CI 75-100%) for LN+ vs 99% (95% CI 97-100%) for LN- patients, p = 0.007. One nipple-areolar recurrence occurred, in a LN- patient. 3-year breast cancer-specific survival was 97% (95% CI 92-100%) in LN+ vs 99% (95% CI 98-100%) in LN- patients, p = 0.40. Conclusions: Conversion from planned NSM to SSM did not differ significantly between LN+ and LN- patients. Short-term oncologic outcomes were satisfactory. These data suggest that NSM may be appropriate for carefully selected LN+ breast cancer patients.
Avoidance of axillary dissection in cN0 breast cancer patients with metastatic sentinel lymph node(s) using ACOSOG Z-0011 criteria: Is it appropriate for Indian patients?
Authors: Agarwal Gaurav , Gambhir Sanjay , Lal Punita , Krishnani Narendra , Rajan Sendhil
Published: February 2017

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Background: A relatively newer algorithm for surgical management of axilla, where axillary node dissection (ALND) is avoided in cN0 EBC patients with 1 to 2 metastatic sentinel nodes (SLN) is now widely practiced in North America. ASCO & NCCN guidelines, and St Gallen consensus statement too have endorsed this strategy. This algorithm, based on the ACOSOG-Z0011 trial results has evoked quite a debate in India too. Concerns relating the quality of Z0011 data and its wide applicability persist. On the other hand, avoidance of ALND and its morbidity seems attractive to the oncologists and patients. In a single institution validation SLN Biopsy (SLNB) data-set, we evaluated the applicability of the “Z0011 strategy” to know its impact on an Indian patient cohort. Methods: In a prospective data-set of 120 cN0 EBC patients (mean age 51.1 years, T1 = 14, T2 = 106, mean tumor size 3.8 cm, 51.7% ER/PR+) who underwent validation SLNB (ALND irrespective of SLNB histology), such patients who fulfilled the selection criteria of ACOSOG-Z0011, i.e. those who underwent BCS and tangential field whole breast irradiation, and 1-2 metastatic SLNs were identified. Results: 66 (55%) of the 120 patients underwent BCS and tangential field whole breast irradiation. Of the 25 out of 66 patients with metastatic SLNs, 5 patients had 3 or more metastatic SLNs, and 2 had extra-nodal spread, thus not fitting the Z0011 criteria. Thus only 18 patients (15% of entire study cohort, and 27.3% of those undergoing BCS) with 1 to 2 metastatic SLNs were eligible for avoidance of ALND based Z0011 criteria. Of these 18 eligible patients, 7 (38.9%) had non-sentinel metastatic nodes. These 7, and the 3 with false negative SLNs could be seen as being left with undertreated axillae. Conclusions: In Indian context, where the majority of patients have large tumors and many opt for mastectomy, avoidance of ALND in presence of metastatic SLNs can be offered to a small proportion of patients. In a single institution validation SLNB data-set, only 15% patients qualified for avoidance of ALND using the Z0011 trial criteria. Besides, avoidance of ALND would have left 8.3% patients potentially undertreated in the axilla.
Locoregional failure rates after mastectomy for breast cancer patients with T1-2 tumors and axillary nodal microscopic metastases.
Authors: Majithia Lonika , Bazan Jose , Quick Allison Marie , Terando Alicia Maria , Agnese Doreen Marie , Mrozek Ewa , Farrar William Blair , White Julia R.
Published: February 2017

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Background: The indications for postmastectomy radiotherapy (PMRT) are expanding to include patients 1-3 axillary nodal metastases (ALN). Improvements in diagnostic evaluation have led to increasing numbers of breast cancer (BC) patients who are found to have microscopic nodal metastases (N1mic). The challenge today is whether these BC patients have risk that warrants the routine delivery of PMRT. Methods: We reviewed patients with pathologic T1-2N1 BC treated with initial mastectomy (mast) and adjuvant systemic therapy (ST) from 2000-2013. The primary endpoint was locoregional failure (LRF), defined as a recurrence in either the ipsilateral chestwall or regional lymphatics (axillary, internal mammary, or supraclavicular). Secondary endpoints were disease-free survival (DFS, failure or death) and overall survival (OS). The log-rank test was used to compare survival between groups. Results: We identified 550 eligible patients from our prospectively maintained cancer registry with 5 year median follow-up. 95 patients (17%) had N1mic disease. Baseline characteristics include: median age 53 yrs, 61% pathologic T2, 39% grade 3, 72% hormone receptor positive, 16% HER2+, 12% triple-negative. Treatment included chemotherapy in 78% (n = 428), PMRT in 15% (n = 82), and anti-endocrine therapy in 70% (n = 385). A median of 18 ALN (range, 1-68) were removed. Among the patients with N1mic disease, 81 had 1+ node, 13 had 2+ nodes, and 1 had 3+ nodes. The 5 yr LRF was 0% for patients with N1mic disease vs. 4.6% in those macro metastases (p = 0.84). The 5 yr LRF rate for the entire cohort was 3.9%; patients with 1+, 2+, and 3+ nodes had 5 yr LRF of 2.6%, 4.7% and 6.4%, respectively (p = 0.79). Patients with N1mic disease had a trend towards improved DFS (91.6% vs. 82.3%, p = 0.07) and significantly improved OS (96.9% vs. 87.6%, p = 0.03) compared to patients with macrometastases. Conclusions: In a cohort of patients with T1-2,N1 BC treated with modern therapy, we found overall low rates of LRF. Patients with N1mic disease had no LRF events and improved OS compared to patients with macrometastases. These findings support that PMRT should not be routinely recommended for N1mic BC patients with T1-2 tumors.