bluuebunny/crossref_metadata_2025 huggingface dataset:
Anti-PD-1 (BMS-936558, MDX-1106) in patients with advanced solid tumors: Clinical activity, safety, and a potential biomarker for response.
Authors: Topalian Suzanne Louise , Brahmer Julie R. , Hodi F. Stephen , McDermott David F. , Smith David C. , Gettinger Scott N. , Taube Janis M. , Drake Charles G. , Pardoll Drew M. , Antonia Scott , Spigel David R. , Atkins Michael B. , Lawrence Donald P. , McDonald Dan , Jure-Kunkel Maria , Korman Alan , Kollia Georgia , Gupta Ashok Kumar , Wigginton Jon , Sznol Mario
Published: February 2017

CRA2509

Background: Blockade of programmed death-1 (PD-1), a co-inhibitory receptor expressed by activated T cells, can overcome immune resistance and mediate tumor regression. This study describes the activity and safety of BMS-936558, a fully human mAb blocking PD-1, and highlights the importance of the PD-1/PD-L1 pathway as a target for cancer therapy. Methods: Patients (pts) received BMS-936558 IV Q2WK at doses of 0.1 to 10.0 mg/kg during dose-escalation and/or cohort expansion. Tumors were assessed by RECIST 1.0 after each therapy cycle (4 doses). Pts received up to 12 cycles or until PD or CR. Results: As of July 1, 2011, 240 pts with melanoma (MEL, n=95), renal cell (RCC, n=33), colorectal (CRC, n=19), non-small cell lung cancer (NSCLC, n=75), castrate-resistant prostate cancer (CRPC, n=17), and unknown (n=1) were treated. Median duration of therapy was 15 wk (max 120 wk). MTD was not reached. Grade 3-4 related AEs occurred in 13% of pts. AEs of special interest included pneumonitis, hypophysitis, hepatitis, colitis, and thyroiditis. There were 2 related deaths due to pulmonary toxicity. In evaluable pts receiving ≥2 cycles, OR (objective responses; CR or PR) were observed in MEL, RCC, and NSCLC. Aggregate response rates [(OR +unconfirmed PR)/evaluable pts] were: MEL (0.1-10 mg/kg, 20+4/90; 27%), RCC (1-10 mg/kg, 8+2/32; 31%), and NSCLC (1-10 mg/kg, 10+3/73; 18%). OR were durable: among 38 pts with OR, 28 were enrolled ≥1 yr before data lock, and 18 of these had responses lasting ≥1 yr. Ten pts on study <1 yr had ongoing OR with a duration of 1.8 - 5.6 mo. Several pts had prolonged SD. Some had a persistent reduction in overall tumor burden in the presence of new lesions and were not categorized as responders. To assess PD-1 ligand (PD-L1) as a potential predictive biomarker, IHC was performed on pre-treatment tumor biopsies from 29 pts. Of 16 pts with PD-L1(+) tumors, 50% achieved OR vs. none with PD-L1(-). Conclusions: BMS-936558 produces durable activity in advanced NSCLC, MEL, and RCC. Preliminary data implicate PD-L1 expression on tumor cells as a potential predictive biomarker of response. These findings underscore the importance of the PD-1/PD-L1 pathway and support further clinical development of BMS-936558.
Bevacizumab (Bev) with or without erlotinib as maintenance therapy, following induction first-line chemotherapy plus Bev, in patients (pts) with metastatic colorectal cancer (mCRC): Efficacy and safety results of the International GERCOR DREAM phase III trial.
Authors: Tournigand Christophe , Samson Benoit , Scheithauer Werner , Lledo Gérard , Viret Frédéric , Andre Thierry , Ramée Jean François , Tubiana-Mathieu Nicole , Dauba Jérôme , Dupuis Olivier , Rinaldi Yves , Mabro May , Aucoin Nathalie , Khalil Ahmed , Latreille Jean , Louvet Christophe , Brusquant David , Bonnetain Franck , Chibaudel Benoist , De Gramont Aimery ,   GERCOR
Published: February 2017

LBA3500^

Background: Therapy targeting VEGF or EGFR demonstrated clinical activity in combination with chemotherapy (CT) in mCRC but monoclonal antibodies cannot be associated. The DREAM trial compares a maintenance therapy (MT) with bev +/- EGFR tyrosine kinase inhibitor erlotinib (E) after a first-line Bev-based induction therapy (IT) in pts with mCRC. Methods: Pts with previously untreated and unresectable mCRC were eligible. After a Bev-based IT with FOLFOX or XELOX or FOLFIRI, pts without disease progression were randomized to MT between Bev alone (Bev 7.5 mg/kg q3w; arm A) or Bev+E (B 7.5 mg/kg q3w, E 150 mg/day continuously; arm B). Pts were treated until progression or unacceptable toxicity. The primary endpoint was PFS on MT. Results: The study enrolled 700 pts from 01/2007 to 11/2011 in 3 countries (France, Canada, Austria). 446 (63.7%) pts were randomized for MT (arm A, N=224; arm B, N=222). Among the 446 randomized pts, IT regimen was FOLFOX-Bev in 265 pts (59.4%), XELOX-Bev in 135 pts (30.3%), and FOLFIRI-Bev in 46 pts (10.3%). Baseline characteristics of randomized pts were (arm A/B): ECOG PS 0, 60% in both arms; normal LDH level 47%/49%; normal alkaline phosphatase level 48%/50%; synchronous metastasis 83%/82%. The median no of MT cycles was 6 in both arms. With a median follow-up of 31.0 months, 327 PFS events were observed. Median MT-PFS were 4.6 m in arm A vs 5.8 m in arm B (HR 0.73 [95%CI: 0.59-0.91], P=.005). Median PFS from inclusion were 9.2 m vs 10.2 m. During MT, in arm A vs arm B, grade 3-4 diarrhea (<1% vs 9%) and grade 3 skin toxicity (0% vs 19%) were the main differences in toxicity. Severe adverse events from randomization related to B or E were 6 in arm A and 7 in arm B. Overall survival is not mature. Conclusions: The addition of erlotinib to bevacizumab after induction therapy significantly improves the duration of maintenance PFS, following induction with first-line chemotherapy plus bevacizumab, in patients with unresectable metastatic colorectal cancer.
Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach (ITACA-S) trial: Comparison of a sequential treatment with irinotecan (CPT-11) plus 5-fluorouracil (5-FU)/folinic acid (LV) followed by docetaxel and cisplatin versus a 5-FU/LV regimen as postoperative treatment for radically resected gastric cancer.
Authors: Bajetta Emilio , Floriani Irene , Di Bartolomeo Maria , Labianca Roberto , Landi Lorenza , Santoro Armando , Casaretti Rossanna , Pasquini Enzo , Di Fabio Francesca , Rondini Ermanno , Pinotti Graziella , Bidoli Paolo , Rosati Gerado , Mambrini Andrea , Ciarlo Andrea , Cordio Stefano Sergio , Ricci Sergio , Frassineti Luca , Di Costanzo Francesco , Bochicchio Anna Maria ,   on behalf of ITACA-S Study Group
Published: February 2017

LBA4001

Background: Following radical resection of gastric or gastroesophageal junction (GEJ) adenocarcinoma, a meta-analysis and randomized studies demonstrated better survival in pts treated with fluoropyrimidine regimens compared to surgery alone. ITACA-S trial is a no-profit, multicenter, randomized, open-label, superiority phase III study aimed at evaluating whether a more intensive postoperative chemotherapy improves efficacy, when replace fluoropyrimidine. Methods: Pts radically resected for gastric or GEJ adenocarcinoma, with ≥D1-lymphadenectomy, node involvement (pN+) or pN0 with pT2b-3-4; within 3-8 weeks after surgery were eligible. Treatment consisted in CPT-11 180 mg/m2 on d1, LV 100 mg/m2 d1-2, 5-FU 400-600 mg/m2 d1-2, q14; for 4 cycles (FOLFIRI regimen) followed by docetaxel 75 mg/m2 d1, cisplatin 75 mg/m2 d1, q 21; for 3 cycles (arm A) vs. LV 100 mg/m2 d1-2, 5-FU 400-600 mg/m2 d1-2, q 14 for 9 cycles (arm B). The primary hypothesis on disease-free survival (DFS) requires 636 events (first recurrence or death) to detect an hazard ratio (HR) of 0.80, with 2-sided 5% significance level for the log-rank test and a power of 80%. Results: From February 2005 to August 2009, 1,106 pts were randomized and 1,100 were analyzed (562 arm A, 538 arm B; 6 major violations) by 123 Italian centers. By March 2012, with a median follow-up of 49 months (quartile range: 36-62) we observed 558 events for DFS (HR 0.98; 95%CI 0.83-1.16;p=0.83) accounting for 88% of the target number and 440 deaths (HR: 1.00; 95%CI 0.83-1.20;p=0.98). Toxicity was consistent with literature. Given the data observed, both under the original hypothesis and the current trend, the probability to reach a statistically significant results at the target events is <0.0001. Conclusions: Adjuvant chemotherapy in gastric cancer with more intensive regimen did not result in a significant prolongation of DFS and OS when compared to bolus/infusion FU/LV regimen.
AURELIA: A randomized phase III trial evaluating bevacizumab (BEV) plus chemotherapy (CT) for platinum (PT)-resistant recurrent ovarian cancer (OC).
Authors: Pujade-Lauraine Eric , Hilpert Felix , Weber Béatrice , Reuss Alexander , Poveda Andres , Kristensen Gunnar , Sorio Roberto , Vergote Ignace B. , Witteveen Petronella , Bamias Aristotelis , Pereira Deolinda , Wimberger Pauline , Oaknin Ana , Mirza Mansoor Raza , Follana Philippe , Bollag David T. , Ray-Coquard Isabelle ,   AURELIA Investigators
Published: February 2017

LBA5002^

Background: In three phase III trials in OC (2 front line, 1 PT-sensitive recurrent), BEV + CT → BEV significantly improved progression-free survival (PFS) vs CT alone. AURELIA is the first randomized trial of BEV in PT-resistant OC. Methods: Eligible patients (pts) had OC (measurable by RECIST 1.0 or assessable) that had progressed ≤6 mo after ≥4 cycles of PT-based therapy. Pts with refractory OC, history of bowel obstruction, or >2 prior anticancer regimens were ineligible. After CT selection by the investigator (pegylated liposomal doxorubicin [PLD], topotecan [TOP], or weekly paclitaxel [PAC]), pts were randomized to CT either alone or with BEV (10 mg/kg q2w or 15 mg/kg q3w depending on CT) until progression (PD), unacceptable toxicity, or withdrawal of consent. Pts in the CT-alone arm could cross over to BEV monotherapy at PD. The primary endpoint was PFS by RECIST. Secondary endpoints included objective response rate (ORR), overall survival, safety, and quality of life. The design provided 80% power to detect a PFS hazard ratio (HR) of 0.7 with 2-sided log-rank test and α=0.05 after 247 events, assuming median PFS of 4.0 mo with CT and 5.7 mo with CT + BEV. Results: Between Oct 2009 and Apr 2011, 361 pts were randomized to receive selected CT (PLD: 126; PAC: 115; TOP: 120) alone or with BEV. Median follow-up after 301 PFS events was 13.5 mo. Conclusions: In PT-resistant OC, BEV + CT provides statistically significant and clinically meaningful improvement in PFS and ORR vs CT alone. Strict inclusion criteria minimized the incidence of BEV AEs. This is the first phase III trial in PT-resistant OC to show benefit with a targeted therapy and improved outcome with a combination vs monotherapy. [Table: see text]
Phase III, randomized, open-label, multicenter trial (BREAK-3) comparing the BRAF kinase inhibitor dabrafenib (GSK2118436) with dacarbazine (DTIC) in patients with BRAFV600E-mutated melanoma.
Authors: Hauschild Axel , Grob Jean Jacques , Demidov Lev V. , Jouary Thomas , Gutzmer Ralf , Millward Michael , Rutkowski Piotr , Blank Christian U. , Mirakhur Beloo , Guckert Mary E. , Swann R. Suzanne , Haney Patricia , Martin Anne-Marie , Ouellet Danielle , Grotzinger Kelly , Goodman Vicki L. , Chapman Paul B.
Published: February 2017

LBA8500^

Background: Dabrafenib, a selective BRAF inhibitor, has shown activity with a manageable safety profile in phase I/II studies in patients (pts) with BRAFV600E-mutated metastatic melanoma (MM). This phase III trial (NCT01227889) compared progression-free survival (PFS) in pts with advanced MM treated either with dabrafenib or dacarbazine (DTIC). Methods: Pts with previously untreated, unresectable stage III or IV BRAFV600E-mutated melanoma were randomized (3:1) and stratified by stage to dabrafenib (150 mg po bid) or DTIC (1000 mg/m2, IV, q3w). Primary endpoint was investigator-assessed PFS. Primary analysis for PFS was planned after 102 events. Pts on the DTIC arm were allowed to cross over once progression was confirmed by independent review (IR). Secondary endpoints included PFS by IR, overall survival (OS), response rate (RR), duration of response, safety and pharmacokinetics. Results: 250 pts were enrolled at 93 centers globally from February to September 2011. 187 were randomized to dabrafenib and 63 to DTIC. 141pts were on study treatment at the data cut-off at December 19, 2011 (dabrafenib n = 127; DTIC n = 14), including 21/28 DTIC pts crossed over to dabrafenib. Median age was 52 years, 31% of pts were ECOG >1, 66% M1c, 33% LDH > ULN. Demographics were well balanced between the two arms. At the time of the primary analysis, there were 118 events (77 dabrafenib and 41 DTIC). The hazard ratio for PFS was 0.30 (95% CI: 0.18–0.53; p < 0.0001). Median PFS was 5.1 months for dabrafenib and 2.7 for DTIC. OS data were immature, with 30 deaths reported. Confirmed RR was 53% for dabrafenib and 19% for DTIC. Benefits in PFS and RR were observed in all subgroups evaluated. Common adverse events (AEs) on the dabrafenib arm were hyperkeratosis (37%), headache (32%), pyrexia (28%), arthralgia (27%), skin papillomas (24%). Serious AEs (> 1%) on the dabrafenib arm included pyrexia (4%), squamous cell carcinomas (6%), and new primary melanomas (2%). Conclusions: Dabrafenib demonstrated a significant improvement in PFS and ORR over DTIC with an acceptable safety profile.
Early efficacy analysis of the AE37 vaccine in patients with HER2 low-expressing and triple-negative breast cancer.
Authors: Mittendorf Elizabeth Ann , Perez Sonia A. , Hale Diane F. , Vreeland Timothy J. , Sears Alan K. , Clifton Guy T. , Ardavanis Alexandros , Shumway Nathan M. , Murray James L. , Ponniah Sathibalan , Papamichail Michael , Peoples George Earl
Published: February 2017

109

Background: Peptide vaccines comprised of HLA class II epitopes, which elicit CD4+ T cell responses, play a critical role in potentiating immune responses. We are conducting a randomized phase II trial of AE37, a hybrid peptide created by the addition of the Ii-Key moiety (LRMK) to the HER2 helper epitope, AE36 (HER2 aa776-790). Here, we present efficacy data focusing on outcomes in patients with low HER2 (IHC 1+ or 2+) expression and triple negative breast cancer (TNBC). Methods: The trial is enrolling node positive or high risk node negative breast cancer patients with any degree of HER2 expression (IHC 1+, 2+ or 3+ or FISH > 1.2) rendered disease-free following standard of care therapy. Patients are randomized to receive either AE37+GM-CSF or GM-CSF alone in 6 monthly intradermal inoculations followed by booster inoculations administered every 6 months. Results: The trial has enrolled 254 patients; 105 in the vaccine group (VG) and 149 in the control group (CG). After a median follow-up of 22.3 months, the disease-free survival (DFS) rate in the VG is 90.3% vs 81.1% in the CG (p=.46), a 49% risk reduction. Evaluating patients with low HER2 expression (IHC 1+ or 2+), there are 53 VG patients and 77 CG patients. The groups are well-matched with respect to the percentage of patients with high grade tumors, tumors > 2cm, the rate of node positivity and ER/PR status (all p>.5). The DFS rate in the VG of low HER2 expressers is 89.8% vs 68.2% in the CG (p=.12), a 68% risk reduction. When limiting analyses to patients with TNBC (ER/PR negative, HER2 1+ or 2+), there are 13 VG patients and 23 CG patients. The groups are again well-matched with the exception of control patients having a larger percentage of tumors > 2 cm (70% vs 31%; p=.02). The DFS rate in the VG of TNBC patients is 83.3% vs 47.6% in the CG (p=.23), a 68% risk reduction. Conclusions: Early analyses suggest clinical benefit to vaccination with AE37, particularly in patients with low HER2-expressing tumors. Importantly, the benefit appears to persist in TNBC patients. Patients will continue to be followed per protocol for 5 years; however, these data suggest that a subsequent phase III trial should evaluate the vaccine in patients with low HER2-expressing disease to include TNBC.
Phase II results of tasisulam-sodium in previously treated patients with metastatic breast cancer.
Authors: Schwartzberg Lee Steven , Soliman Hatem Hussein , Conlin Alison Katherine , Ruud Christopher O. , Tezcan Haluk , Bromund Jane , Hogeterp Kevin , Kaiser Christopher , Chen Jian , Chow Kay , Ilaria Robert L. , Miller Kathy
Published: February 2017

114

Background: Tasisulam, a novel acylsulfonamide antineoplastic agent, promotes apoptosis, exhibits antiangiogenic activities, and demontrates antiproliferative activity against human breast cancer cell lines. In humans, tasisulam is highly albumin bound, with a median half-life of approximately 11 days. Previous phase II studies of tasisulam indicated that an albumin-corrected exposure (AUCalb) range of 1200 to 6400 h*mcg/mL provided the optimal balance of efficacy and safety. This study investigates the drug’s activity in previously treated patients (pts) with metastatic breast cancer (mBC). Methods: Pts with at least 2 prior therapies for mBC andserum albumin level ≥3.0 g/dL received tasisulam by 2-hour infusion every 28 days, dosed by a lean body weight-based dosing algorithm targeting an AUCalb range of 1200 to 6400 h*mcg/mL. Primary objective was to show at least a 10% response rate (RR) using RECIST 1.0. Secondary objectives included progression-free survival (PFS), overall survival (OS), pharmacokinetics (PK), and safety. Results: Thirty-three pts received at least 1 dose of tasisulam. All were women, with a mean age of 55.4 (±9.7) years. Pts received a median of 2 cycles (ranges 1-8). The majority of pts achieved the target AUCalb range of 1200 to 6400 h*mcg/mL or higher in cycles 1 and 2 (63% and 69%, respectively). The most common tasisulam-related hematologic toxicities were grade 3 anemia (3.0%) and grade 4 neutropenia (6.1%). Common nonhematological adverse events possibly related to tasisulam were fatigue (39.4%), diarrhea (24.2%), and nausea (18.2%). No deaths were considered related to the study drug. The RR (1 CR, 1 PR) was 6.1% (90% CI: 1.1, 17.9), stable disease rate was 24% (n=8; 90% CI: 12.7, 39.5), with a median PFS of 1.81 months (90% CI: 1.64, 2.17) and a median OS of 6.77 months (90% CI: 4.37, 11.63). Conclusions: Tasisulam was reasonably well tolerated, but did not meet its primary objective of overall RR of 10% in this heavily pretreated mBC patient population. PK analysis of the albumin-tailored dosing regimen indicated that the majority of the patients achieved the target AUCalb or higher, suggesting that the modest activity observed was not due to suboptimal dosing.
Adjuvant chemotherapy for early-stage breast cancer: Choice of regimen and associated hematologic toxicities in a metropolitan Australian hospital.
Authors: Lovat Katherine Mary , Christie Hayden , Che Ricky , Hill Andrew , Sanmugarajah Jasotha
Published: February 2017

123

Background: The commonly used adjuvant chemotherapy regimens for early breast cancer include 5-fluorouracil, epirubicin, cyclophosphamide and docetaxel (FEC-D), docetaxel and cyclophosphamide (TC), doxorubicin and cyclophosphamide with or without paclitaxel and/or herceptin (AC combination) and docetaxel, carboplatin and trastuzumab (TCH). Hematologic toxicity from these regimens can be life threatening as well as cause significant morbidity for the patient and major costs to the health system. Granulocyte colony stimulating factor (GCSF) is frequently used to try and reduce these complications. In Australia, GCSF is funded for use as primary prophylaxis with docetaxel in combination with an anthracycline and cyclophosphamide. Secondary prophylaxis is available only after demonstration of prolonged severe neutropenia or an episode of febrile neutropenia (FN). Methods: Patients treated with adjuvant chemotherapy for early breast cancer at Gold Coast Hospital, Qld, Australia from February 2010 to February 2012 were identified. Patient charts were reviewed for incidence of neutropenia (neutrophil count <1.0 x 109/L), FN (temp ≥38°C), dose reductions or delays and use of GCSF. Results: 102 patients were treated over this time. Incidence of neutropenia, FN and use of GCSF are summarised below. 30 patients receiving FEC-D had a dose delay or reduction with the majority due to non-haematologic toxicities. 96% patients completed 6 cycles of treatment. Of the patients with FN in the TC group, half had received primary GCSF. No patients who were given primary GCSF experienced a dose delay. Similar trends were observed in the other treatment groups. Conclusions: Our results show that patients receiving FEC-D along with GCSF had lower rates of neutropenia and hospitalisations. Rates of neutropenia and dose delay are higher in the other groups. FEC-D is the most commonly used regimen in our institution likely due to the availability of GCSF. [Table: see text]
Accelerated partial breast irradiation using a strut-based brachytherapy device: A multi-institutional initial report on acute and late toxicity with greater than 24-month follow-up.
Authors: Strasser Jon F. , Jacob Dayee , Koprowski Christoper D. , Attai Deanna J. , Butler Ernest , Finkelstein Steven E. , Han Ben , Hong Robert , Komarnicky Lydia T. , Kuske Robert R. , Lyden Maureen , Mahalingam Sudha B. , Mantz Constantine , Morcovescu Serban , Nigh Stephen S. , Perry Kerri , Pollock Jondavid , Reiff Jay E. , Scanderbeg Daniel , Yashar Catheryn M.
Published: February 2017

149

Background: Accelerated partial breast irradiation (APBI) is commonly used in early-stage breast cancer. The SAVI Collaborative Research Group is a multi-institutional group created to study outcomes in patients who received APBI utilizing strut-based brachytherapy. This analysis reports the acute and late toxicities for patients with greater than 2-year follow-up (F/U) from this study. Methods: 904 APBI patients (ductal carcinoma in situ [n=267] or invasive breast cancer [n=637]), received HDR brachytherapy (34 Gy in 10 fractions) using the SAVI device (Cianna Medical). Patients with dosimetry and documented follow-up were evaluated within 6 weeks of treatment for early adverse events (AEs), and at 1 year, 2 years, and beyond for late AEs. Dosimetric parameters were evaluated with respect to toxicity and will be presented. Results: In 212 patients (median age 62.9 years, range 40-88) all with follow-up greater than 24 months, the median tumor size was 12mm. As of last follow-up (>24 months) cumulative rates of erythema and hyperpigmentation of grade 2 or higher were 1.4% and 0.5%. The incidence of grade 2 or higher telangiectasia, seroma and fat necrosis were 2.8%, 2.8%, and 0.5% respectively. Conclusions: Adverse events for APBI with SAVI are low in incidence, low in grade and compare favorably to other HDR APBI methods.
Long-term outcome after neoadjuvant radiochemotherapy in locally advanced noninflammatory breast cancer and predictive factors for a pathologic complete remission: Results of a multivariate analysis.
Authors: Matuschek Christiane , Boelke Edwin , Bojar Hans , Roth Stephan L. , Peiper Matthias , Speer Vanessa , Janni Johann Wolfgang , Audretsch Werner , Nestle-Kraemling Carolin , Sauer Rolf , Budach Wilfried
Published: February 2017

154

Background: An earlier published series of neoadjuvant radio-chemotherapy (NRT-CHX) in locally advanced noninflammatory breast cancer (LABC) has now been updated with a follow-up of more than 15 years. Long-term outcome data and predictive factors for pathologic complete response (PCR) were analyzed. Methods: 315 LABC patients (cT1-cT4 /cN0-N1) were treated during 1991-1998 with NRT-CHX. Preoperative radiotherapy (RT) consisted of external beam radiation therapy (EBRT) of 50 Gy (5 × 2 Gy/week) to the breast and the supra-/infraclavicular lymph nodes combined with an electron boost in 214 cases afterwards or—in case of breast conservation—a 10-Gy interstitial boost with 192Ir afterloading before EBRT. Chemotherapy was administered prior to RT in 192 patients, and concomitantly in 113; 10 patients received no chemotherapy. The update of all follow up ended in November 2011. Age, tumor grade, nodal status, hormone receptor status, simultaneous vs. sequential CHX and the time interval between end of RT and surgery were examined in multivariate terms with as endpoint pCR and overall survival. Results: The total PCR rate after neoadjuvant RT-CHX reached 29.2 % with LABC breast conservation becoming possible in 50.8%. In initially node-positive cases (cN+), a complete nodal response (pN0) after NRT-CHX was observed in 56% (89/159). The multivariate analysis revealed that a longer time interval to surgery increased the probability for a pCR (HR 1,17 [95% CI 1,05-1,31], p<0,01). However, in large tumors (T3-T4) a significantly reduced pCR rate (HR 0.89 [95% CI 0.80 to 0.99], p = 0.03) could be obtained. Importantly, a pCR was the strongest prognostic factor for long-term survival (HR 0.28 [95% CI 0.19-0.56], p<0.001). Conclusions: A PCR identifies patients with a significant better prognosis for long-term survival. However, a long time interval to surgery (> 2 months) increases the probability of a pCR after NRT-CHX.
Pleomorphic lobular carcinoma in situ: A distinct entity of controversial significance.
Authors: De Brot Marina , Muhsen Shirin , Andrade Victor P. , Koslow Mautner Starr , Murray Melissa , Giri Dilip D. , Sakr Rita A. , Brogi Edi , King Tari A.
Published: February 2017

177

Background: Pleomorphic lobular carcinoma in situ (PLCIS) is an increasingly diagnosed variant of lobular carcinoma in situ. Histologically, it resembles ductal carcinoma in situ (DCIS), leading to controversy over proper management. Yet, the natural history of PLCIS is unknown. Here we describe our experience with PLCIS. Methods: Review of pathology reports (1995–2012) identified 233 cases of LCIS variants. Patients with synchronous ipsilateral DCIS or invasive cancer (IC) were excluded leaving 25 cases for review. Consensus review by 3 pathologists further excluded 7; leaving 18 cases, 12 of which were classified as PLCIS and 6 as LCIS with pleomorphic features (LCIS-PF). (Table) PLCIS was defined by cellular dyshesion, nuclear pleomorphism with a 2-3 fold size variation, conspicuous nucleoli, mitoses and abundant cytoplasm; lesions not meeting all parameters were classified as LCIS-PF. Loss of e-cadherin was confirmed; clinical data were obtained from medical records. Results: Mean patient age at diagnosis of PLCIS/LCIS-PF was 57 yrs (42-67 yrs). All cases presented with imaging abnormalities. A previous history of breast cancer was present in 7/18 (39%) pts (3/7, ipsilateral; 4/7, contralateral). Following PLCIS/LCIS-PF diagnosis, 6/18 (33%) pts underwent mastectomy and 12/18 had excision alone, with (n=3) or without chemoprevention (n=9). Margin status was negative in 4/12 pts; close in 3/12 pts and positive in 5/12 pts undergoing excision. At a median follow-up of 27 mos (2-148 mos), 2/12 pts treated with excision developed ipsilateral breast cancer (1 DCIS; 1 IC). Both had close margins at initial excision; median time to cancer, 54 mos. Conclusions: Pure PLCIS is an uncommon lesion. Synchronous malignancy or prior history of breast cancer are often present in patients with PLCIS, contributing to the difficulty in determining the actual risk conferred by this lesion and appropriate management. Efforts to systematically characterize LCIS variants and prospective documentation of outcomes are needed to clarify the significance of these lesions. [Table: see text]
Intraoperative radiotherapy in previously augmented patients with early-stage breast cancer.
Authors: Holmes Dennis R. , Lewinsky Bernard S. , Rashtian Afshin , Robertello William J. , Rivera Ronald J. , Feiler Karen
Published: February 2017

186

Background: Breast conservation therapy (BCT) is the preferred treatment for early stage breast cancer (ESBC), providing equivalent survival to mastectomy with improved quality of life (QOL). Nevertheless, previously augmented women (PAW) with ESBC are often denied access to BCT due to potential complications arising from capsular contracture from exposure to whole breast radiation therapy (WBRT). Instead of BCT, PAW are commonly advised to undergo total, skin-sparing, or nipple-sparing mastectomy with or without breast reconstruction to eliminate the need for WBRT. These more extensive procedures alter the form and function of the breast, increase the risk of perioperative morbidity, prolong postoperative recovery, and add incremental costs. Intraoperative radiotherapy (IORT) emerged as a strategy for delivering breast radiotherapy that preserves the option of BCT in PAW with ESBC. IORT confines the effects of radiotherapy to the quadrant of the breast and to the portion of the prosthesis in proximity to the cancer. Since IORT is administered at the time of BCT, it permits insertion of a radiation barrier to further shield the prosthesis from effects of radiotherapy. Methods: We present several examples of PAW who underwent BCT combined with IORT for the treatment of ESBC. Results: Four women with an average age of 51.8 years (range: 47-57) were treated with BCT and IORT for ESBC using the Intrabeam System (Carl Zeiss-Meditec, Inc., Oberkochen, GE). All women had either saline (SA), silicone (SI), or combination retropectoral implants (RP). All pathological margins were clear and IORT was administered without complications. Average follow-up was 26 months (range: 1-72 months). None experienced a recurrence and breast cosmesis was acceptable in all women. Conclusions: IORT preserves the option of BCT in PAW by reducing the impact of radiotherapy on the breast. This radiotherapy approach eliminates the physical burden, impact on QOL, and cost of more extensive breast procedures. Consequently, IORT should be considered a preferred treatment for PAW facing a diagnosis of ESBC. [Table: see text]
Experience and outcomes of nipple-sparing mastectomy following reduction mammoplasty.
Authors: Alperovich Michael , Blechman Keith M. , Samra Fares , Shapiro Richard , Axelrod Deborah M. , Choi Mihye , Karp Nolan S. , Guth Amber Azniv
Published: February 2017

193

Background: Breast cancer resection strives for less radical approaches that offer superior aesthetic results without compromising oncologic safety. Nipple-sparing mastectomy (NSM) has gained popularity, but usually has been offered to smaller breasted and minimally ptotic women without history of extensive breast surgery. We present a series of nine nipple-sparing mastectomies following reduction mammoplasty. Methods: Charts of patients who underwent NSM following reduction mammoplasty at the NYU Medical Center from 2006 through 2011 were reviewed. Outcomes measured include post-operative complications, breast cancer recurrence, presence of cancer in the nipple-areolar complex, and nipple-areolar complex viability. Results: In total, the records of 235 (145 prophylactic, 90 therapeutic) NSM patients at NYU Medical Center were reviewed. Six patients for a total of 9 breasts had NSM following reduction mammoplasty. This subset of patients had a mean age of 46.2, mean BMI of 25.1, no history of diabetes and 1 smoker. Seven of 9 breasts were therapeutic resections and 2 of 9 were prophylactic. Time elapsed between reduction mammoplasty and NSM ranged from 33 days to 11 years. The majority of resections were in Stage 0 patients (6/9) with 1/9 in Stage I and 2/9 in Stage IIA. In all cases, prior reduction mammoplasty incisions were utilized for NSM. Eight patients were reconstructed immediately with tissue expanders, and 1 patient had a latissimus dorsi flap with immediate implant. Complications included 1 hematoma requiring evacuation and 1 displaced implant requiring revision. There were no positive subareolar biopsies and 100% nipple viability. Mean follow-up time was 9.4 months. Conclusions: Our experience demonstrates that NSM can be offered following reduction mammoplasty with comparable reconstructive outcomes to NSM alone. Reduction mammoplasty followed by NSM has potential as a reconstructive tool in prophylactic cases unsuited for primary NSM.
Early diagnostic value of survivin and its alternative splice variants in breast cancers.
Authors: Khan Salma , Yuan Yuan , Valenzuela Malyn May , Turay David , Ferguson Heather , Wong Siu-Fun , Perez Mia , Mirshahidi Saied , Wall Nathan R
Published: February 2017

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Background: The inhibitor of apoptosis (IAP) protein Survivin and its splice variants are differentially expressed in breast cancer tissues and have recently been shown to be released from tumor cells via small membrane-bound vesicles called exosomes. Tumor-derived exosomes play multiple roles in tumor growth and metastasis and may produce these functions by impacting immune escape, tumor invasion and angiogenesis. We, therefore, hypothesize that analysis of exosomal Survivin and its splice variants may provide a novel biomarker for early diagnosis of breast cancer in addition to current recommended methods. Methods: Twenty paired breast cancer patient’s sera and tumor tissue, and ten normal control sera were used for analysis. ELISA was performed to quantitate serum levels of Survivin. Exosomes were isolated from the sera using Exoquick. RT-PCR, western blots with densitometry, and immunohistochemistry followed by confocal microscopy were then performed. Results: For each breast cancer patient serum, Survivin levels were significantly higher compared to control (p<0.05). While Survivin and the DEx3 splice variant expression and localization were similar, differential expression of Survivin and the 2B splice variant protein and mRNA existed in the exosomes and tissue samples. Survivin and -DEx3 proteins were the predominant forms detected in 100% (20/20) of the breast cancer tissues evaluated, whereas a more variable expression of Survivin-2B, with enhanced levels found in areas of necrosis. We also for the first time here show the exosomal localization of Survivin and its splice variants DEx3 and 2B in sera from breast cancer patients. Conclusions: The result of the proposed project supports our hypothesis that differential expression of exosomal-Survivin and its alternative splice variants may serve as a diagnostic marker in breast cancer patients. For future direction, we plan to study the prognostic value of exosomal-Survivin and its splice variants on a large panel of primary breast cancers within a setting of well-followed clinical outcomes.
Metastatic breast cancer and the elderly: A single institution, retrospective review.
Authors: Kidd Michael , Karlin Nina J. , Dueck Amylou C.
Published: February 2017

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Background: The aim of this retrospective study was to examine the overall survival (OS) of metastatic breast cancer patients over a decade and assess for any differences with respect to age, tumor characteristics, and ECOG status. Methods: Data on metastatic breast cancer cases from 1999-2010 were retrieved from the institutional cancer registry and linked to electronic medical records. Through chart review of 240 metastatic breast cancer cases, we determined hormone receptor (HR), HER2/neu (HER2), ECOG, age at diagnosis of metastatic cancer and mortality data. Kaplan-Meier survival curves for OS were used and compared between HR status, HER2 status, ECOG, and age at diagnosis using log-rank regression and Cox Regression analysis was performed to control for these variables. A 95% confidence interval (CI) was used. Results: The median OS of the sampled cases was 2.2 years (CI: 1.8-2.5 years). Analysis for overall survival by pre-determined age groups demonstrated no significant difference between the age groups (p value 0.46), but did yield a statistical difference based on ECOG status (p value 0.0001). Cox regression analysis showed consistent findings where survival was significantly affected by HR, HER2 status and ECOG but not age (HR: p value <0.0001; HER2: p value 0.0132; ECOG: p value <0.0001; age at diagnosis: p value 0.8462). Analysis for OS based on HR yielded a median survival of 1.4 years (CI: 0.9-1.6 years) for HR negative and 2.5 years (CI: 2.2-3.0 years) for HR positive (p value 0.0018). HER2 yielded a median survival of 1.8 years (CI: 1.4-2.3 years) for no amplification and 3.0 years (CI: 2.5 - 3.4 years) for amplification (p-value 0.0043). HR negative, HER2 non-amplified tumors had the poorest median OS at 0.7 years (CI: 0.5 - 1.1 years) whereas those tumors with HR positive, HER2 amplified had the best median OS at 3.0 years (CI: 2.5 - 4.7 years) with a p value < 0.0001. Conclusions: In this retrospective analysis, there was no significant survival difference with respect to age. Age continued to have no significant effect on survival when adjusting for ECOG, hormone status, and HER2/neu status. Those factors that did act as determinants of survival were ECOG status, hormone status and HER2/neu status of the tumor.
Making it work: Breast cancer survivorship care at Johns Hopkins.
Authors: Bantug Elissa Thorner , Peairs Kimberly S. , Shockney Lillie D. , Zafman Nelli , Riley Carol D. , Reese Jennifer Barsky , Snyder Claire Frances , Stearns Vered , Wolff Antonio C.
Published: February 2017

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Background: Breast cancer survivor numbers are increasing due to population aging and improved treatment outcomes but many of their long-term health care needs are unmet. Integrated follow-up care strategies that enhance care coordination, education, and access to survivorship resources are needed to provide patients with evidence-based care that addresses medical and psychosocial needs after cancer treatment. Methods: In 2008, we established the Johns Hopkins Breast Cancer Survivorship Program with representation from the Schools of Nursing, Public Health, and Medicine to address the needs of patients completing initial cancer treatment and transitioning to long-term follow-up. Patient educational resources were created within an interactive website ( http://bit.ly/hZfzFi ) including > 35 patient/provider educational video clips, blogs and social media. Activities including provider educational events, educational folders, and trainee curriculum additions have been ongoing. Starting May 2011, Hopkins patients were offered a one-time transition visit with a nurse practitioner focusing on individualized treatment summary/survivorship care plan activities (e.g., cancer screening/surveillance, medical intervention, psychosocial support, and care coordination with non-cancer providers). Results: Our website is averaging 3,000 hits monthly. We have participated in 22 provider/trainee formal educational presentations. In the pilot phase of these transition visits (n=40), age/race breakdown of participants were representative of our breast cancer population (median age 51, range 34-69; 17% African Americans). Our post-visit survey (n=37), 97% found the survivorship visit beneficial and all reported that this one-time consultation helped with transitioning away from treatment. Conclusions: A multidisciplinary patient-centered approach to breast cancer survivorship allowed us to develop comprehensive clinical and educational service models to benefit patients and their cancer/non-cancer providers. This program aims to enhance education, overcome the fragmentation of the health care system, and improve overall health and wellness of breast cancer survivors as they transition to long-term survivorship.
Risk of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) after adjuvant chemotherapy (CT) for early breast cancer (BC) in the community setting.
Authors: Denduluri Neelima , Espirito Janet L. , Turnwald Brian , Wang Yunfei , Asmar Lina , Hoverman J. Russell , Neubauer Marcus A. , Bosserman Linda D. , Busby Leslie T. , Brooks Barry Don , Cartwright Thomas H. , Sitarik Mark A. , Schnadig Ian D. , Winter William E. , Garey Jody S. , Bergstrom Kimberly A. , Beveridge Roy A. , Patt Debra A. ,   on behalf of The US Oncology Network Pathways Task Force
Published: February 2017

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Background: AML and MDS complicate adjuvant CT in BC. Incidence Rates of MDS/AML with pegfilgrastim (PGCSF) use and newer adjuvant regimens in large patient (pt) populations are not widely characterized. Methods: We queried the iKnowMed electronic health record from a large network of community oncology practices for pts diagnosed with stage I-III BC from 2007-2010 with at least 5 visits and follow up (f/u) through 2/2012 for our retrospective study. We stratified pts by adjuvant CT utilization (yes/no), regimen type, PGCSF use, age, and characterized the incidence of MDS/AML captured as a secondary diagnosis. Fisher’s exact test and student t-test were used for categorical and continuous variables, respectively; Cox proportional hazard model was used to estimate hazard ratios (HR) for risk factors associated with AML/MDS development. Results: We identified 20,900 pts with median f/u of 2.8 years (yrs) (1.2-5.2 yrs). 11,295 pts (54%) received CT, 41% of whom received anthracyclines (A); 9,605 (46%) did not receive CT. Median age of diagnosis in the CT and non-CT arms was 54 and 64 yrs, respectively (p < 0.01). Among the CT-treated group, 12 pts or 0.11% (95% CI, 0.06-0.19) developed AML/MDS with median time to onset of 1.8 yrs and median f/u of 2.7 yrs. Of these 12 pts, 8 received A and 11 PGCSF. In the non-CT group, 18 pts or 0.19% (95% CI, 0.11-0.30) developed AML/MDS with median time to onset of 2.2 yrs and median f/u of 3 yrs (p=NS). Multivariate analysis of pts who received CT revealed pts ≥70 vs. <70 yrs and those that received A-containing vs. alternate regimens were more likely to develop AML/MDS. Conclusions: Adjuvant CT did not increase risk of AML/MDS compared with those that did not receive CT. However, our findings confirm that increased age and A-containing CT regimens are associated with increased risk. The low event rate in our study population may be due to short f/u, younger age in the CT treated arm, and high utilization of non-A CT. Association with PGCSF warrants further evaluation. [Table: see text]
A 5-year review of an educational program focused on meeting the needs of patients with advanced breast cancer.
Authors: Ahmed Ivy A. , Harvey Allison , Amsellem Marni
Published: February 2017

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Background: Women living with advanced breast cancer have distinct often unmet needs, even compared to other women with breast cancer. For the past five years, the Cancer Support Community has been committed to delivering Frankly Speaking About Cancer: Advanced Breast Cancer, a comprehensive psychosocial education program created for women with metastatic breast cancer and their families. The program’s clinically facilitated evidence-based education workshops have reached 2,690 attendees since its inception in 2006. The workshop provides valuable information about current treatments, clinical trials, side-effect management, and social and emotional challenges of an advanced breast cancer diagnosis. Workshop outcomes are analyzed annually, informing program content and ensuring the program is meeting the needs of those served. As the program enters its sixth year, data were consolidated across years to investigate how the program has been meeting the needs of these women and their loved ones. Methods: 1,827 workshop attendees since the program’s beginning have completed evaluations (68% response rate) which included assessing levels of pre- and post-workshop knowledge about advanced breast cancer, patient-provider communication, and general workshop feedback. Results: 64.9% of respondents were survivors, 78.5% were Caucasian, and the average age was 56. Most workshop respondents (89.6%) reported gaining a high or very high level of knowledge about advanced breast cancer, with significant increases compared with pre-workshop levels (p <.01). Most reported intent to increase communication with their clinical team following the workshop. A majority reported feeling better equipped to ask questions to their health care team (92.1%), and discuss the possibility of clinical trials with their healthcare team (77.7%). Furthermore, 90% of attendees felt confident that after the workshop they could speak knowledgably about side effects of cancer treatment with their doctor, a key issue in regards to quality of life. Conclusions: Taken together, the data indicate the continued relevance of this program for those affected by advanced breast cancer.
Circulating tumor cell (CTC) counts and CTC telomerase activity (TA) as prognotic markers of overall survival (OS) in SWOG S0421: Docetaxel with or without atrasentan for metastatic castration-resistant prostate cancer (mCRPC).
Authors: Goldkorn Amir , Vogelzang Nicholas J. , Fink Louis M. , Ely Benjamin , Quinn David I. , Tangen Catherine M. , Tai Yu-Chong , Twardowski Przemyslaw , Van Veldhuizen Peter J. , Agarwal Neeraj , Carducci Michael Anthony , Monk J. P. , Garzotto Mark , Mack Philip C. , Lara Primo , Higano Celestia S. , Hussain Maha , Cote Richard J. , Thompson Ian Murchie ,   Southwest Oncology Group
Published: February 2017

1

Background: CTCs are promising biomarkers in mCRPC, and telomerase activity (TA) is a recognized cancer marker. In this phase III trial we analyzed CTCs using 2 methods: CellSearch for fixed cell enumeration, and a novel Parylene-C slot filter for live CTC capture and TA measurement. Methods: Blood samples (7.5 ml) were drawn at baseline (d1) and pre-cycle 2 (d21) of Rx and shipped overnight for central processing. For CellSearch enumeration, Cox regression was used to evaluate the association between OS, baseline CTC counts, and CTC dynamics (d1 to d21). For TA, filter-trapped cells were lysed and assayed for TA using qPCR-based telomeric repeat amplification. Cox regression evaluated the association between OS and TA overall and within subgroups characterized by good vs. poor (<5 vs. >=5) prognosis baseline CTC counts. For all measurements, receiver operator characteristic (ROC) analysis and characteristics and regression trees (CART) were used to explore further prognostic cutpoints. Results: Samples were obtained from 263 men. Median d1 CTC count was 5, and there was a significant difference in OS for d1 CTC < vs. >=5, hazard ratio (HR) 2.92 (p<0.001) after adjustment for other factors. D1 CTC and OS had ROC AUC of 0.781. In men with low d1 CTC (< 5), an increase in CTC was associated with shorter OS, HR 4.04 (p=0.004); in men with high d1 CTC (>=5), a >=2-fold decrease in CTC was associated with longer OS, HR 0.45 (p=0.012); adjusting for risk factors. For TA, men with baseline CTC >=5 (41% of cohort) who had high CTC TA had HR 1.14 (p<0.005) for OS after adjustment for other factors including CTC counts. CART identified additional risk subgroups based on CTC counts and TA. Conclusions: In this phase III trial, d1 CTC and d1 to d21 CTC dynamics were prognostic of OS after risk factor adjustment, comprising the largest docetaxel-based prospective cohort to date which validates a 5 CTC prognostic threshold and identifies new potentially useful enumeration subgroups. In men with CTCs >=5, TA from cells live-captured on a new slot filter constitutes the first CTC-derived biomarker prognostic of OS in a prospective clinical trial.