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PDF file - 64K, Gene expression levels of EMT-TFs in the tested cell lines (HMLE, HMLE-TWIST, MCF-7, BT-474, SKBR-3, MDA-MB-231)

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Currently, there is extensive information about circulating tumor cells (CTC) and their prognostic value; however, little is known about other characteristics of these cells. In this prospective study, we assessed the gene transcripts of epithelial-to-mesenchymal transition—inducing transcription factors (EMT-TF) and cancer stem cell (CSC) features in patients with HER2+ metastatic breast cancer (MBC). Epithelial cells were enriched from peripheral blood mononuclear cells (PBMC) using antibody-coated anti-CD326 antibody (CD326+) magnetic beads, and the residual CD326− PBMCs were further depleted of leukocytes using anti-CD45 antibody-coated magnetic beads (CD326−CD45−). RNA was extracted from all cell fractions, reverse transcribed to cDNA, and subjected to quantitative reverse transcription PCR to detect EMT-TFs (TWIST1, SNAIL1, ZEB1, and TG2) as a measure of CTCs undergoing EMT (EMT-CTCs). In addition, PBMCs were analyzed using multiparameter flow cytometry for ALDH activity and CSCs that express CD24, CD44, and CD133. Twenty-eight patients were included in this study. At least one EMT-TF mRNA was elevated in the CTCs of 88.2% of patients and in the CD326−CD45− cell fraction of 60.7% of patients. The CD326−CD45− fraction of patients with elevated SNAIL1 and ZEB1 transcripts also had a higher percentage of ALDH+/CD133+ cells in their blood than did patients with normal SNAIL1 and ZEB1 expression (P = 0.038). Our data indicate that patients with HER2+ MBCs have EMT-CTCs. Moreover, an enrichment of CSCs was found in CD326−CD45− cells. Additional studies are needed to determine whether EMT-CTCs and CSCs have prognostic value in patients with HER2+ MBCs treated with trastuzumab-based therapy. Mol Cancer Ther; 11(11); 2526–34. ©2012 AACR.

Purpose: We used a clinical next-generation sequencing (NGS) hotspot mutation panel to investigate clonal evolution in paired primary and metastatic tumors.Experimental Design: A total of 265 primary and metastatic tumor pairs were sequenced using a 46-gene cancer mutation panel capable of detecting one or more single-nucleotide variants as well as small insertions/deletions. Mutations were tabulated together with tumor type and percentage, mutational variant frequency, time interval between onset of primary tumor and metastasis, and neoadjuvant therapy status.Results: Of note, 227 of 265 (85.7%) tumor metastasis pairs showed identical mutation calls. Of the tumor pairs with identical mutation calls, 160 (60.4%) possessed defining somatic mutation signatures and 67 (25.3%) did not exhibit any somatic mutations. There were 38 (14.3%) cases that showed at least one novel mutation call between the primary and metastasis. Metastases were almost two times more likely to show novel mutations (n = 20, 7.5%) than primary tumors (n = 12, 4.5%). TP53 was the most common additionally mutated gene in metastatic lesions, followed by PIK3CA and SMAD4. PIK3CA mutations were more often associated with metastasis in colon carcinoma samples.Conclusions: Clinical NGS hotspot panels can be useful in analyzing clonal evolution within tumors as well as in determining subclonal mutations that can expand in future metastases. PIK3CA, SMAD4, and TP53 are most often involved in clonal divergence, providing potential targets that may help guide the clinical management of tumor progression or metastases. Clin Cancer Res; 21(11); 2644–51. ©2015 AACR.

Supplemental Tables 1 and 2. Table 1. Germline single nucleotide polymorphism (SNP) concordance between matched primary/metastasis pairs. Table 2. Mutations seen in tumor/metastasis pairs with identical signatures (non-divergent) for the two most common cancers studied: breast and colon carcinoma.

The Targeted Agent and Profiling Utilization Registry (TAPUR) Study identifies signals of antitumor activity of commercially available targeted agents in patients with advanced cancers that harbor genomic alterations known as drug targets. In this article, data from two cohorts of patients with pancreatic and biliary cancers withEligible patients age 12 years and older with advanced measurable or evaluable solid tumors are provided treatment according to protocol-specified genomic matching rules. The primary study end point is objective response or stable disease of at least 16 weeks duration. For each cohort, a Simon two-stage design was used with a futility evaluation after 10 patients. Secondary end points include safety, progression-free survival (PFS), and overall survival (OS).Between July 2016 and November 2017, 12 and 10 patients with pancreatic and biliary cancer, respectively, withPalbociclib monotherapy does not have clinical activity in patients with advanced pancreatic or biliary cancers with

The Targeted Agent and Profiling Utilization Registry (TAPUR) Study, a phase II basket study, evaluates anti-tumor activity of commercially available targeted agents in patients with advanced cancers harboring genomic alterations known as drug targets. With no known genomic targets predictive of sensitivity to cetuximab, cetuximab was evaluated in patients with breast cancer (BC), non-small cell lung cancer (NSCLC), and ovarian cancer (OC), without KRAS, NRAS, or BRAF mutations. Eligible patients with advanced BC, NSCLC, and OC received a cetuximab loading dose, then weekly infusions (250 mg/m2 over 60 min). A Simon two-stage design, requiring ten patients in stage I, was employed per each disease-specific cohort. The primary endpoint was disease control (objective response or stable disease for at least 16 weeks). If two or more patients in stage I achieved disease control, the cohort would enroll 18 more patients in stage II. Power and alpha of the design are 85% and 10%, respectively. Secondary endpoints included progression-free survival, overall survival, and safety. Patients with BC (n = 10), NSCLC (n = 10), and OC (n = 29) were enrolled between June 2016 and September 2018. No objective responses or stable disease for at least 16 weeks were observed in the BC and NSCLC cohorts. No objective responses and four patients with stable disease for at least 16 weeks were observed in the OC cohort. Six of 49 patients reported grade 3 or higher adverse events or serious adverse events at least possibly related to cetuximab. Cetuximab does not have clinical activity in patients with advanced BC, NSCLC, and OC without KRAS, NRAS, or BRAF mutations. NCT02693535 (26 February, 2016).

Background. Current standard of care for HR+HER2+ breast cancer >1cm per NCCN guidelines is chemotherapy with either trastuzumab(T) or trastuzumab and pertuzumab(TP) with anti-HER2 therapy continued for 1 year and anti-hormonal therapy for 5-10 years. Patients with HR+HER2+ breast cancer benefit less from chemotherapy than those with HR-HER2+ breast cancer. Recent studies show that pCR rates with aromatase inhibitor and dual-HER2 blockade for 3-6 months duration range between 21%- 33% with the highest pCR seen with 6 months. No clinical trial to date has looked at targeted therapy without chemotherapy for HR+HER2+ breast cancer up to 1 year. Methods. NEOADAPT is an IRB-approved phase II prospective single cohort study for patients with stage I-II HR+HER2+ breast cancer. Eligible pts received neoadjuvant aromatase inhibitor (and GnRH analogue or oophorectomy for premenopausal patients) and TP with q3w exams and q3mo breast MRI. Treatment may continue up to 1 year if ongoing response or radiographic CR (rCR) was observed. Surgery was allowed as soon as 3 months after the first MRI showing rCR provided the follow up MRI did not show further improvement. Primary endpoint was pCR rate defined as absence of invasive disease in the breast and lymph nodes. A Fleming two stage design was implemented with stopping rules with the null hypothesis being that the pCR rate is 40%. Secondary objective included median duration of treatment and exploratory analysis of correlation with Mammaprint Blueprint(MB) testing. 9 patients were enrolled before the study was prematurely closed. 3 patients who refused chemotherapy when the study was closed and were treated with the NEOADAPT protocol and fit the same inclusion/exclusion criteria are also included in this report. Results. Median age 55 (41-67); BMI 26.0 (22.2-37.6); T 2.75cm (1.3-4.8). 7 were premenopausal. 7 had disease that was HER2+ by FISH ratio >2.0 only (2+ IHC). All 12 patients had MB test done: 8 high risk luminal, 3 high risk HER2, and 1 low risk HER2. 5/12 patients achieved rCR, with median duration of treatment to achieve rCR in those 5 pts being 6 months (3-9). 11/12 patients have completed definitive surgery, with the outlier being a patient who refuses surgery. 4/11 patients achieved pCR all of whom received 12 months of targeted treatment before surgery. All 4 pCR patients had rCR before surgery. Of the other 3/7 pts who had rCR and not pCR, 2 had rCR at 3 months and both had surgery at 6 mo with 1.7cm and 1.5mm of residual disease seen and 1 had rCR at 6mo completed 1 yr of prescribed treatment but refused surgery. 2/12 patients were taken off study before surgery and switched to a standard of care chemotherapy regimen due to progression but remain in NED post-surgery to date. No patients to date have had local recurrence or metastatic disease. Discussion. These results from a prematurely closed study suggest as confirmed in other recent studies, that a chemotherapy-sparing endocrine and targeted neoadjuvant approach for HR+HER2+ breast cancer seems to be a feasible and reasonable option particularly for those desiring a clinically informed de-escalation to their treatment plan. Clinical trial: NCT02689921 Citation Format: Eugene R Ahn, Ricardo H Alvarez, Damien Hansra, Anjanette Sorensen, Jizhou Ai, Maurie Markman. Neoadjuvant aromatase inhibitor and pertuzumab and trastuzumab (NEOADAPT) up to one year for HR+HER2+ breast cancer: Results from a prematurely closed de-escalation study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-30.

PURPOSEThe Targeted Agent and Profiling Utilization Registry (TAPUR) Study identifies signals of antitumor activity of commercially available targeted agents in patients with advanced cancers that harbor genomic alterations known as drug targets. In this article, data from two cohorts of patients with pancreatic and biliary cancers with CDKN2A loss or mutation treated with palbociclib are reported.METHODSEligible patients age 12 years and older with advanced measurable or evaluable solid tumors are provided treatment according to protocol-specified genomic matching rules. The primary study end point is objective response or stable disease of at least 16 weeks duration. For each cohort, a Simon two-stage design was used with a futility evaluation after 10 patients. Secondary end points include safety, progression-free survival (PFS), and overall survival (OS).RESULTSBetween July 2016 and November 2017, 12 and 10 patients with pancreatic and biliary cancer, respectively, with CDKN2A loss or mutation were treated with palbociclib. Twenty evaluable patients (10 per cohort) were included in the analysis. No patients had objective response or stable disease at 16 weeks, and both cohorts were closed. Two patients, neither with response, were determined to be ineligible. All patients were evaluated for safety, PFS, and OS. A median PFS of 7.2 weeks (90% CI, 4.0 to 8.0 weeks) and median OS of 12.4 weeks (90% CI, 4.7 to 23.1 weeks) were observed in the pancreatic cohort. A median PFS of 7.3 weeks (90% CI, 3.9 to 7.9 weeks) and median OS of 11.1 weeks (90% CI, 5.1 to 14.0 weeks) were observed in the biliary cohort. No unexpected toxicities were observed.CONCLUSIONPalbociclib monotherapy does not have clinical activity in patients with advanced pancreatic or biliary cancers with CDKN2A loss or mutation. Toxicity is similar to reported experience with palbociclib in other tumor types.

Background Human epidermal growth factor 2 (HER2) is an effective therapeutic target in breast cancer; however, resistance to anti-HER2 agents such as trastuzumab and lapatinib develops. In a preclinical model, an HDAC inhibitor epigenetically reversed the resistance of cancer cells to trastuzumab and showed synergistic efficacy with lapatinib in inhibiting growth of trastuzumab-resistant HER2-positive (HER2+) breast cancer. Methods A phase 1b, dose escalation study was performed to assess maximum tolerated dose, safety/toxicity, clinical efficacy and explored pharmacodynamic biomarkers of response to entinostat combined with lapatinib with or without trastuzumab. Results The combination was safe. The MTD was lapatinib, 1000 mg daily; entinostat, 12 mg every other week; trastuzumab, 8 mg/kg followed by 6 mg/kg every 3 weeks. Adverse events included diarrhoea (89%), neutropenia (31%), and thrombocytopenia (23%). Neutropenia, thrombocytopenia and hypokalaemia were noted. Pharmacodynamic assessment did not yield conclusive results. Among 35 patients with evaluable response, PR was observed in 3 patients and CR in 3 patients, 1 maintained SD for over 6 months. Discussion This study identified the MTD of the entinostat, lapatinib, and trastuzumab combination that provided acceptable tolerability and anti-tumour activity in heavily pre-treated patients with HER2+ metastatic breast cancer, supporting a confirmatory trial.

PURPOSE: The carbohydrate Sialyl Lewis(X) (sLe(X)) mediates cell adhesion, is critical in the normal function of immune cells, and is frequently over-expressed on cancer cells. We assessed the association, differential levels, and prognostic value of sLe(X) and inflammatory cytokines/chemokines in breast cancer sera. METHODS: We retrospectively measured sLe(X) and a panel of cytokines/chemokines in the sera of 26 non-invasive ductal carcinoma in situ (DCIS), 154 invasive non-metastatic breast cancer (non-MBC), 63 metastatic breast cancer (MBC) patients, and 43 healthy controls. Differences in sLe(X) and inflammatory cytokines among and between patient groups and healthy controls were assessed with nonparametric tests and we performed survival analysis for the prognostic potential of sLe(X) using a cut-off of 8 U/ml as previously defined. RESULTS: Median serum sLe(X) was significantly higher than controls for invasive breast cancer patients (MBC and non-MBC) but not DCIS. In univariate analysis, we confirmed patients with serum sLe(X) >8 U/ml have a significantly shorter progression free survival (PFS) (P=0.0074) and overall survival (OS (P=0.0003). Similarly, patients with high serum MCP-1 and IP-10 had shorter OS (P=0.001 and P

The Targeted Agent and Profiling Utilization Registry (TAPUR) Study, a phase II basket study, evaluates anti-tumor activity of commercially available targeted agents in patients with advanced cancers harboring genomic alterations known as drug targets.With no known genomic targets predictive of sensitivity to cetuximab, cetuximab was evaluated in patients with breast cancer (BC), non-small cell lung cancer (NSCLC), and ovarian cancer (OC), without KRAS, NRAS, or BRAF mutations.Eligible patients with advanced BC, NSCLC, and OC received a cetuximab loading dose, then weekly infusions (250 mg/mPatients with BC (n = 10), NSCLC (n = 10), and OC (n = 29) were enrolled between June 2016 and September 2018. No objective responses or stable disease for at least 16 weeks were observed in the BC and NSCLC cohorts. No objective responses and four patients with stable disease for at least 16 weeks were observed in the OC cohort. Six of 49 patients reported grade 3 or higher adverse events or serious adverse events at least possibly related to cetuximab.Cetuximab does not have clinical activity in patients with advanced BC, NSCLC, and OC without KRAS, NRAS, or BRAF mutations.NCT02693535 (26 February, 2016).

Male breast cancer occurs rarely, comprising

Advanced-stage breast cancer patients comprise a smaller proportion of breast cancer patients than do early stage patients and are more likely to experience a poor outcome. Understanding the underlying molecular mechanisms and identifying new biomarkers for treatment in this subgroup of patients is paramount. With the aim of identifying microRNAs that are regulated in advanced-stage breast cancer, we found lower expression of miR-26b, a member of the miR-26 family, in inflammatory breast cancer and noninflammatory locally advanced breast cancer tissue than in normal breast tissue, by quantitative real-time polymerase chain reaction and in situ hybridization. Quantitative real-time polymerase chain reaction (but not in situ hybridization) also revealed lower miR-26b expression in inflammatory breast cancer than in noninflammatory locally advanced breast cancer. Furthermore, lower expression of miR-26b was correlated with shorter distant metastasis-free survival and overall survival in univariate analysis, and with shorter overall survival in multivariate analysis. The expression of miRNA-26b was inversely associated with EZH2 protein expression in several breast cancer cell lines, and overexpression and knockdown of miR-26b caused corresponding changes in EZH2 expression. Our study shows that miR-26b may regulate EZH2 expression in breast cancer and may be useful as a therapeutic target for inflammatory breast cancer and noninflammatory locally advanced breast cancer.

Background Inflammatory breast cancer (IBC) is associated with a poor prognosis and high risk of central nervous system (CNS) metastases. Methods We retrospectively reviewed stage III-IBC patients compared with noninflammatory invasive ductal carcinoma (NI-IDC) patients treated between January 1, 1984, and December 31, 2011, who began primary treatment within 1 year of diagnosis and had been followed up for at least 1 year before the development of CNS metastasis or death. Cumulative CNS metastasis incidence and post-CNS metastasis overall survival (OS) estimates were computed. Multivariable Cox proportional hazard models explored factors for post-CNS metastasis survival. Results A total of 2323 patients were identified (589-IBC/1734-NI-IDC). Eighty-one IBC patients developed CNS metastasis, versus 154 NI-IDC patients. The 2-, 5-, and 10-year cumulative CNS metastasis incidence rates in IBC and NI-IDC were 9.8%, 15.8%, 17.4% and 6.5%, 10.1%, and 12.7%, respectively. This was significantly different between IBC and NI-IDC patients (P = .0037). Multicovariate competing risk regression models in IBC and NI-IDC patients showed no statistically significant associations with the risk of developing CNS metastasis, except neoadjuvant taxane use in NI-IDC patients (hazard ratio, 0.45; 95% confidence interval, 0.24-0.83; P = .011). The median follow-up was 7.2 years, and the median post-CNS metastasis OS was not significantly different between IBC (7.6 months) and NI-IDC (5.6 months) patients. One hundred ninety patients with CNS metastasis died. HER2-positive patients had better OS, with a median 14.1 versus 4.3 months (P 50 years (P = .012) but not IBC status was a significant predictor of post-CNS metastasis survival. Conclusion IBC patients demonstrated higher CNS metastasis incidence rates but OS following CNS metastases is similar in both groups. HER2 status and age may play prognostic roles. Cancer 2018;124:2299-305. © 2018 American Cancer Society.

Background: Cancer patients (pts) are burdened by symptoms related to the disease itself or to the toxicities of treatment. A recent meta-analysis has shown that anxiety is the most common mental health issue among cancer survivors [Mitchell AJ, 2013]. The ASCO clinical oncology guideline adaptation recommends all health care providers routinely screen for the presence of emotional distress and symptoms of anxiety from the point of diagnosis onward [Andersen BL, 2014]. Consensus-based recommendations have been published to help cancer centers meet the American College of Surgeons Commission on Cancer's accreditation requirement to screen for distress [Pirl, 2014] At our comprehensive community cancer center we perform distress screening using the M.D. Anderson Symptom Inventory (MDASI), composed of 27 questions. Pts who report moderate and severe levels of distress (≥5) on the MDASI are identified and referred for therapeutic interventions offered by the facility's integrative oncology services. Materials and Methods: The MDASI is an assessment tool that captures pts' perceived symptom burden for real-time clinical intervention, taken at the point of no intervention (baseline) and every 21 days or greater. The 27-question MDASI is comprised of the M.D. Anderson Symptom Inventory (MDASI), a validated 19-item assessment instrument, with a Symptom Inventory Tool (SIT) added by our center of 8 questions and a free-text box. Symptoms are rated “at the worst” on an 11-point numeric scale ranging from 0 (“none present”) to 10 (“as bad as you can imagine”), as experienced by the patient in the past 24 hours. Results: Over a ten-month period (9/1/2014 to 6/30/2015), 247 breast cancer (BC) pts completed the MDASI at intake and again ≥ 21 days after. Analysis of their initial surveys identified 69 pts (27.9%) who rated their distress as ≥ 5 (1st MDASI mean = 6.83), scores which would have initiated a support system response with referrals to integrative medicine services for intervention. Second MDASI results from these 69 BC pts revealed an average 2.29 distress score reduction (2nd MDASI mean = 4.48), with 51 pts (73.9%) reporting a decrease in distress, 7 pts (10.1%) having no change, and 11 pts (15.9%) reporting increased distress. More specifically, the group with decreased distress levels documented a mean distress score of 3 on their 2nd MDASI, averaging a significant 4-point diminution of distress for three-fourths of the BC pts heavily burdened by this symptom. The integrative services most utilized by these pts were Nutrition Therapy (100%), Spiritual Care (96.1%), Mind-Body Counseling (82.4%), Rehabilitation Therapy (41.2%), Acupuncture (35.3%), and Massage Therapy (35.3%). Conclusions: Distress is a relevant symptom reported by cancer pts. This study demonstrates that early intervention in BC pts using integrative oncology approaches reduced distress in 74% of cases. Citation Format: Daneker SR, Bendinger GM, Thomas JW, Smith E, Kendrick D, Hartman S, Gordon C, Barber K, Langlois C, Pabbathi H, McKnight JE, Johnson AT, Lammersfeld C, Denny D, Markman M, Alvarez RH. Efficacy of screening and treatment of breast cancer patients reporting high level of distress [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-19-05.

BACKGROUND: A review of the literature identifies high levels of anxiety and depression as adverse effects of oncology diagnosis and treatment, even for patients with curable cancers such as early stage breast cancer (ESBC). Studies have reported that music therapy yields remarkable, multi-dimensional benefits on an individual's mood and state of mind. The purpose of this trial is to evaluate the impact of personalized music therapy (PMT) in reducing anxiety and other adverse mental health symptoms experienced by patients receiving chemotherapy treatment for ESBC. ELIGIBILITY: Females ≥ 18 years diagnosed with ESBC (Stage I-III) initiating intravenous chemotherapy as their only oncology treatment modality who report anxiety ≥ 4 on a numerical rating scale of 0-10. TRIAL DESIGN: This is a 4-week, two-arm, randomized (1:1) trial evaluating the anti-anxiety benefits of PMT for women with ESBC initiating intravenous (IV) chemotherapy. The patients randomized to the experimental group will participate in 30-minute PMT sessions conducted by a Licensed Musical Therapist (LMT). Initial PMT will occur within 1 hour of the patient's first chemotherapy infusion (C1D1), then once weekly for the remaining 3 weeks of the trial. Patients randomized to the control group will be referred to the medical oncologist for standard of care (SOC) anxiety treatment. Outcomes will be measured via the Generalized Anxiety Disorder Assessment (GAD-7), the Center for Epidemiologic Studies Depression Scale (CES-D), the Pittsburgh Sleep Quality Index (PSQI), and the Symptom Inventory Tool-M.D. Anderson Symptom Inventory (SIT-MDASI) to be completed by both cohorts at baseline and regular intervals for the duration of the study. AIMS: The primary endpoint is to determine the impact of PMT during chemotherapy treatment on patient reported anxiety (GAD-7). Secondary endpoints will determine the impact of PMT during chemotherapy treatment on patient reported depression (CES-D), sleep disturbances (PSQI), and quality of life (SIT-MDASI). STATISTICAL METHODS/TARGET ACCRUAL: Patients will be randomized to receive either PMT or SOC using the Pocock-Simon dynamic allocation method to balance tumor stage between the arms. With 30 patients in each arm and approximate target accrual of 60, the study achieves 80.0% power to detect a 0.65 standard deviation unit effect size of the change in scale measure between baseline and 4 weeks at the 0.05 significance level using a one-sided two-sample t-test. GAD-7 change will be compared between the two arms using a two-sample t-test (Pooled Standard error or Satterthwaite approximation as appropriate). The secondary outcomes include CES-D, PSQI, and SIT-MDASI for which a longitudinal analysis of subscale scores will be conducted using a generalized linear mixed-effects model with fixed effects for treatment group and time. All statistical analyses will be conducted using SAS 9.3 [SAS Institute Inc., Cary, NC, USA]. Statistical significance will be defined as p < 0.05. Citation Format: Toole Jr. M, Bendinger GM, Ensor Jr. JE, Alvarez Tapias C, Smith E, McGuire E, Rados K, McNight JE, Pabbathi H, Panicker R, Johnson AT, Lammersfeld C, Alvarez RH. A randomized study of personalized music therapy for patients with early stage breast cancer receiving chemotherapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT3-08-01.

BACKGROUND: Observational studies have repeatedly linked obesity to increased cancer incidence, recurrence, and mortality, leading to cancer treatment guidelines that call for maintenance of a healthy body weight, regular physical activity (PA) regardless of body mass index (BMI), and modest weight loss for overweight and obese cancer survivors (CS). Despite these recommendations, newly published reports suggest that more than 70% of CS are overweight or obese, and only 1/3 engage in the recommended levels of PA. Although trials have demonstrated that energy balance (EB) interventions are feasible in CS, it has been concluded that ongoing behavioral support is needed to implement and sustain changes in weight and PA. Through the subsequent Energy Balance Research (EnBaR) the incorporation of a weight management and PA program focused on ongoing behavioral support for breast cancer survivors (BCS) as an effective method for implementation of lifestyle modifications will be investigated. TRIAL DESIGN: This is a single-arm prospective observational study investigating if implementation of an EB Program for BCS is an effective intervention for producing lifestyle behaviors. Eligible subjects must be female BCS ≥18 years with BMI ≥25 who are initiating hormonotherapy (HT) as their only oncology treatment modality. Subjects will consult with a Registered Dietitian (RD) to establish goals based on specified interventions for reducing overall BMI at the time of initiating their prescribed HT. Subjects will subsequently receive telephone calls from the RD at bi-monthly intervals to discuss the established points of intervention, answering questions proposed by the RD from a set intervention measurement scale. Patients will also report for body composition analysis performed by the RD via InBody at Baseline, Day 90, and Day 180. InBody is a validated tool that utilizes direct segmental multi-frequency bioelectrical impedance analysis (DSM-BIA) to provide a highly accurate report of an individual's body composition. AIMS: Determine change in Percent Body Fat (PBF) and BMI during adjuvant hormone treatment for breast cancer patients. STATS/TARGET ACCRUAL: To assess % change in BMI and PBF between baseline and 180 days, one-sample t-tests will be used. Assuming an average (avg) baseline BMI of 33.7 with a standard deviation of 8.5; a sample of 120 patients will yield 89.4% power using a two-sided t-test to detect a 13% reduction in BMI to an avg of 29.32 and 82.8% power to detect a 12% reduction to an avg BMI of 29.656. Similarly, a t-test will have 83.7% power to detect a 12% decrease in % change in PBF assuming an avg baseline PBF of 41.36 with a standard deviation 10.5. The power calculations were accomplished by generating simulations of size 10,000 replications conducted at the 0.025 significance level using the TTEST procedure of SAS 9.4 [SAS Institute Inc., Cary, NC, USA]. The calculations assume a linear correlation of 0.5 between the baseline and Day 180 measurements and are Bonferroni corrected to maintain a familywise error of 0.05 for the primary analysis. All statistical analyses will be conducted using SAS 9.4. Statistical significance will be defined as p < 0.05. Citation Format: Scheuer R, Bendinger GM, Ensor Jr. JE, Nixon D, Randolph K, McGuirec E, Rados K, McNight JE, Pabbathi H, Panicker R, Johnson AT, Langlois C, Lammersfeld C, Alvarez RH. Positive behavior change and weight loss in breast cancer survivors on hormonal adjuvant therapy: An energy balance research in cancer (EnBaR) prospective study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT3-07-03.

Background: Neratinib (Puma Biotechnology Inc) is an irreversible pan-HER inhibitor in late-phase development for the treatment of early-stage and metastatic HER2+ BC. Diarrhea, the main toxicity of neratinib, requires active management with loperamide prophylaxis given early in the course of treatment. CONTROL (PUMA-NER-6201) is an international, open-label, phase II study investigating the efficacy of loperamide prophylaxis in the prevention of neratinib-associated diarrhea. CONTROL has recently been expanded to include prophylaxis with loperamide + budesonide, which targets inflammation identified in a preclinical model of neratinib induced diarrhea. Methods: Pts with HER2+ early-stage BC who had completed trastuzumab-based adjuvant therapy were eligible. All pts were to receive oral neratinib 240 mg/day for 1 year + structured loperamide prophylaxis on d1–56 (2 cycles). Adverse events were graded according to NCI-CTCAE, v4.0. Primary endpoint: incidence of grade ≥3 diarrhea. A protocol defined interim analysis (data cut-off July 2016) was performed when ∼120 pts had completed ≥2 cycles of neratinib + loperamide prophylaxis. A preliminary analysis of the loperamide + budesonide cohort was also performed at this time. Clinicaltrials.gov: NCT02400476. Results: For the interim analysis, 133 pts received neratinib + loperamide prophylaxis. A further 16 (of 40 planned) pts received neratinib + loperamide prophylaxis (2 cycles) + budesonide (1 cycle). Key results are shown in the table. Incidence of grade ≥3 diarrhea was 27.1% with loperamide prophylaxis and 12.5% with loperamide + budesonide prophylaxis vs 39.9% without protocol-mandated loperamide prophylaxis (ExteNET). Grade 2 diarrhea also decreased (20.3%, 18.8% vs 32.5%, respectively). Grade 3 diarrhea events were uncommon after cycle 1 in all CONTROL cohorts. StudyCONTROLExteNET4Antidiarrheal prophylaxisLoperamideLoperamideLoperamideLoperamide + budesonideLoperamide prnProtocolOriginal1Modified2Cumulative (Original + Modified)Amd 32,3–N (ITT at data cut-off)28105133161408Diarrhea, %Any grade82.169.572.268.895.4Grade 225.019.020.318.832.5Grade ≥3521.428.627.112.539.8Grade 400000.1Median diarrhea episodes/ptGrade ≥22.01.01.01.03.0Grade ≥31.01.01.01.52.0Median time on study (neratinib), mo69.73.764.561.0611.61. Oral loperamide 4 mg with first neratinib dose, then 2 mg q4h d1–3, then 2 mg q6–8h d4–56.2. Oral loperamide 4 mg with first neratinib dose, then 4 mg tid d1–14, then 4 mg bid d15–56.3. Oral budesonide 9 mg qd d1–28.4. Analogous patient population [Chan et al. Lancet Oncol 2016].5. Primary endpoint (CONTROL).6. Cohorts are ongoing. Conclusions: A structured loperamide prophylactic regimen for 2 cycles is associated with a lower incidence and severity of neratinib associated diarrhea, with notably less grade 2/3 diarrhea compared to ExteNET events. There appears to be some adaptation to the effects of neratinib, as higher-grade diarrhea occurs early and does not typically recur. Preliminary data suggest that adding budesonide may further improve outcomes; enrollment into the budesonide cohort continues. Citation Format: Barcenas C, Olek E, Hunt D, Tripathy D, Ibrahim E, Wilkinson M, Hurvitz S, Iannotti N, Kellum A, Manalo Y, Wong S, Hansen V, Alvarez R, Chan A, Gore I, Kendall D, Wade J, Ruiz R, Fang P, Bryce R, Moran S. Incidence and severity of diarrhea with neratinib + intensive loperamide prophylaxis in patients (pts) with HER2+ early-stage breast cancer (EBC): Interim analysis from the multicenter, open-label, phase II control trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-11-03.

Inflammatory breast cancer (IBC) is a virulent form of breast cancer, and novel treatment strategies are urgently needed. Immunohistochemical analysis of tumors from women with a clinical diagnosis of IBC (n = 147) and those with non-IBC breast cancer (n = 2510) revealed that, whereas in non-IBC cases cytoplasmic cyclin E was highly correlated with poor prognosis (P < 0.001), in IBC cases both nuclear and cytoplasmic cyclin E were indicative of poor prognosis. These results underscored the utility of the cyclin E/CDK2 complex as a novel target for treatment. Because IBC cell lines were highly sensitive to the CDK2 inhibitors dinaciclib and meriolin 5, we developed a high-throughput survival assay (HTSA) to design novel sequential combination strategies based on the presence of cyclin E and CDK2. Using a 14-cell-line panel, we found that dinaciclib potentiated the activity of DNA-damaging chemotherapies treated in a sequence of dinaciclib followed by chemotherapy, whereas this was not true for paclitaxel. We also identified a signature of DNA repair–related genes that are downregulated by dinaciclib, suggesting that global DNA repair is inhibited and that prolonged DNA damage leads to apoptosis. Taken together, our findings argue that CDK2-targeted combinations may be viable strategies in IBC worthy of future clinical investigation.

Background. Recent clinical trial results indicate that it is more appropriate than ever to conduct de-escalation clinical trials looking at less chemotherapy for patients with relatively early stage HER2+ breast cancer, particularly those with so called triple positive breast cancer (ER+PR+HER2+, or TPBC). TBCRC 006 showed that if hormone therapy is added to dual-HER2 blockade (lapatinib and trastuzumab) pathological complete response rate (pCR) can increase to 21% with another 22% having low residual disease (40% pCR rate. The potential impact of this trial is to provide more treatment options for women with early stage TPBC in a current environment when more than 40% of such patients are currently getting chemotherapy. Trial Design. This single arm prospective cohort study is IRB approved and currently enrolling (NCT02689921). Intervention will be neoadjuvant aromatase inhibitor +/- LHRH agonist or oophorectomy if premenopausal with trastuzumab and pertuzumab in standard q 3-week dosing schedules. Duration of treatment will be determined by clinical exam, q 3mo dynamic breast MRI but no longer than 1 year maximum before surgery. Study ends upon definitive surgery. Duration of treatment will be 3 months after last radiographic CR seen on MRI barring progression or patient/physician choice. Eligibility Criteria. Patients with stage I-II biopsy confirmed invasive breast cancer that is ER/PR+ and HER2+ by latest ASCO guidelines. Multifocal breast cancer is allowed on the provision that all lesions are biopsied and confirmed to also be TPBC and felt by the pathologist to be the same tumor. Age >18 yrs, ECOG PS 0-2, LVEF >50% at baseline. Rest of inclusion and exclusion criteria are typical for most studies in this setting. Specific Aims. The primary endpoint is to document pCR rate. Secondary endpoints are to conduct an exploratory analysis of whether Mammaprint can identify patients who are more likely to obtain pCR or not and to describe sensitivity and specificity of breast MRI in predicting pCR. Statistical Design. To identify a hypothesized pCR rate of >40% with 80% power, 32 patients will be enrolled. The Fleming two stage design will be implemented with stopping rules with the first stage of interim analysis done when the first 15 evaluable patients have surgical results. Further details will be provided in poster. Present accrual and target accrual. At time of abstract submission 5 of 32 patients have been enrolled and the study is currently available at 2 Cancer Treatment Centers of America sites, Midwestern and Southeastern Regional Medical Center. Plan is to open the study at all 5 CTCA sites before end of 2017. Contact information for those specifically interested in this trial. Principal investigator Eugene Ahn MD eugene.ahn@ctca-hope.com. Citation Format: Ahn ER, Alvarez R, Maurie M. A phase II study of neoadjuvant aromatase inhibitor with pertuzumab and trastuzumab for patients with ER+HER2+ stage I-II breast cancer (NEOADAPT) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT1-03-04.

Background: We retrospectively evaluated the correlation between a baseline measurement of circulating tumor cells (CTCs) and inflammation-based scores in patients with metastatic breast cancer (MBC). Methods: The optimal value of inflammation-based scores as the neutrophil–lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR), monocyte–lymphocyte ratio (MLR) and systemic immune-inflammation index (SII) to predict survival was determined and compared with CTC Results: In the overall population of 516 women with MBC, CTCs correlated with peripheral blood monocytes ( p = 0.008) and neutrophils ( p = 0.038). In triple-negative tumors, CTCs correlated with monocyte count ( p = 0.009); in HER2+ tumors, CTCs correlated with neutrophil count ( p = 0.009), with a trend versus monocyte count ( p = 0.061), whereas no correlation was found in HER2– estrogen receptor-positive (ER+) tumors. In multivariate analysis only monocytes were associated with ⩾5 CTCs (OR = 2.72, 95% CI 1.09–6.80, p = 0.033). In multivariable analysis for predictors of overall survival, CTC (⩾5 versus 1 versus 1), tumor subtypes (triple-negative versus HER2– ER+ tumors) and MLR only remained significant. Conclusions: CTC and MLR are predictors of overall survival in MBC. CTC correlates with monocytes, in particular in triple-negative tumors.

// Reva K. Basho 1,* , Debora de Melo Gagliato 2,* , Naoto T. Ueno 2 , Chetna Wathoo 3 , Huiqin Chen 4 , Maryam Shariati 5 , Caimiao Wei 4,6 , Ricardo H. Alvarez 2,7 , Stacy L. Moulder 2 , Aysegul A. Sahin 8 , Sinchita Roy-Chowdhuri 8 , Mariana Chavez-MacGregor 2,9 , Jennifer K. Litton 2 , Vincent Valero 2 , Raja Luthra 8 , Jia Zeng 3 , Kenna R. Shaw 3 , John Mendelsohn 3,10 , Gordon B. Mills 3,11 , Debu Tripathy 2 and Funda Meric-Bernstam 3,5,12 1 Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 2 Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 3 Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 4 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 5 Investigational Cancer Therapeutics (Phase I Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX, USA 6 Pfizer, Inc, New York, NY, USA 7 The Cancer Treatment Centers of America, Chicago, IL, USA 8 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 9 Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 10 Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 11 Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 12 Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA * These authors have contributed equally to this work Correspondence to: Funda Meric-Bernstam, email: // Keywords : metastatic breast cancer, genomics, TP53, PIK3CA Received : April 06, 2016 Accepted : October 13, 2016 Published : October 28, 2016 Abstract BACKGROUND: Identifying the clinical impact of recurrent mutations can help define their role in cancer. Here, we identify frequent hotspot mutations in metastatic breast cancer (MBC) patients and associate them with clinical outcomes. PATIENTS AND METHODS: Hotspot mutation testing was conducted in 500 MBC patients using an 11 gene ( N = 126) and/or 46 or 50 gene ( N = 391) panel. Patients were stratified by hormone receptor (HR) and human epidermal growth factor 2 (HER2) status. Clinical outcomes were retrospectively collected. RESULTS: Hotspot mutations were most frequently detected in TP53 (30%), PIK3CA (27%) and AKT1 (4%). Triple-negative breast cancer (TNBC) patients had the highest incidence of TP53 (58%) and the lowest incidence of PIK3CA (9%) mutations. TP53 mutation was associated with shorter relapse-free survival (RFS) (median 22 vs 42months; P < 0.001) and overall survival (OS) from diagnosis of distant metastatic disease (median 26 vs 51months; P < 0.001). Conversely, PIK3CA mutation was associated with a trend towards better clinical outcomes including RFS (median 41 vs 30months; P = 0.074) and OS (52 vs 40months; P = 0.066). In HR-positive patients, TP53 mutation was again associated with shorter RFS (median 30 vs 46months; P = 0.017) and OS (median 30 vs 55months; P = 0.001). When multivariable analysis was performed for RFS and OS, TP53 but not PIK3CA mutation remained a significant predictor of outcomes in the overall cohort and in HR-positive patients. CONCLUSIONS: Clinical hotspot sequencing identifies potentially actionable mutations. In this cohort, TP53 mutation was associated with worse clinical outcomes, while PIK3CA mutation did not remain a significant predictor of outcomes after multivariable analysis.

Background: Neoadjuvant chemotherapy (NACT) is an integral component for locally advanced and large operable breast cancer. The sequence of taxanes followed by anthracyclines has been the standard of care for almost 20 years. Eribulin (E) is a synthetic analogue of halichondrin B with distinct mechanism of action as microtubule dynamics inhibitor. The FDA approved E in 11/2010 for the treatment of patients (pts) with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Research Hypothesis: Sequential administration of eribulin followed by FAC/FEC-regimen, would have greater pathologic complete response (pCR) rate than sequential administration of paclitaxel followed by FAC/FEC-regimen as primary systemic therapy for woman with operable breast cancer. Methods: This is a phase II, randomized, single institution, open label study. Pts were randomized 1:1 to receive E (1.4 mg/m2 d1 and d8 q 21 days x 4) or paclitaxel (P) (80 mg/m2 weekly x12). Both arms received FAC/FEC regimen x 4 doses followed by surgery. Eligible pts were women age 18 or older, Karnosfky PS 80 – 100, histologically confirmed invasive breast cancer, clinical T2-T3, N0-3, M0, HER2-negative. Baseline LVEF of > 50% and normal hematology, liver and kidney laboratory function tests. Primary endpoint was pathologic complete response (pCR/RCB-0) assessed by residual cancer burden (RCB). [Symmans F, 2007]. This protocol (2012-0167) IRB of The University of Texas, MD Anderson Cancer Center. Results: A preplanned interim analysis aimed to validate trial assumption was conducted after treatment of 54 randomized pts. Between 8/2012 to 7/2014, 54 pts were randomized and 49 were evaluable for pCR(27 P arm and 22 E arm). Tumor response by RCB is shown in the table. pCR rates were 30% and 4.5% in the P and E arm, respectively. Table 1.ResponsePaclitaxel - FAC/FEC Arm (N=27)Eribulin - FAC/FEC Arm (N=22)RCB 0 (pCR)8 (30%)1 (4.5%)RCB I6 (22.2%)1 (4.5%)RCB II9 (33%)10 (45%)RCB III4 (14.8%)10 (45%) 53 pts were evaluable for toxicity. The combination was safe with mostly grade 1 and 2 toxicities in both arms. In the P arm grade 3 peripheral neuropathy and neutropenia was seen in 3% and 7%, respectively. In the E arm one patient died due to multiorgan failure during cycle 1. There was no other grade 3-5 toxicity. Biomarker analysis using CTCs by AdnaTest Breast were evaluated in 39 pts at baseline. 5/39 pts were positive for CTCs. 3 pts had transcripts for EpCAM, 1 for Muc-1 and another had both. 30 pts had an additional sample post therapy. 2 pts were positive for CTC at baseline as well as at follow up (FU) visit at 180 days. None of the samples showed CTC-EMT at baseline or at FU visits. Conclusions: The interim analysis demonstrated that E arm lead to significantly lower pCR/RCB1 rate compared to P arm. Ongoing biomarker analyses include TIL, hot spot mutation analysis (HSMA) and molecular inversion probes (MIP) will be presented at the time of the meeting. Clinical trial information: NCT01593020. Citation Format: Alvarez RH, Koenig KB, Ensor JE, Ibrahim NK, Chavez-MacGregor M, Litton JK, Schwartz Gomez JK, Cyriac A, Krishnamurty S, Caudle AS, Shaitelman SF, Whitman GJ, Booser DJ, Reuben JM, Valero V. A randomized phase II neoadjuvant (NACT) study of sequential eribulin followed by FAC/FEC-regimen compared to sequential paclitaxel followed by FAC/FEC-regimen in patients (pts) with operable breast cancer not overexpressing HER-2. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-14-04.

Background: Our in vitro and in vivo preclinical data showed that entinostat enhances the efficacy of lapatinib in HER2 positive (HER2+) breast cancer cells via FOXO3-mediated Bim1 expression, which resulted in enhanced apoptosis in HER2 targeted therapy (lapatinib and trastuzumab)-resistant breast cancer (IBC and non-IBC) cells [Lee et al.]. Based on these findings, we conducted a phase 1b trial of entinostat to determine the maximal tolerated dose (MTD) in combination with lapatinib alone and in combination with lapatinib and trastuzumab for metastatic HER2+ breast cancer patients (pts), who progressed on trastuzumab. Method: This was a single-center, open-label phase 1b study to evaluate the dose limiting toxicity (DLT) and determine MTD. 3+3 dose escalation schedule was used for Cohorts 1 and 2. Pts received lapatinib and entinostat (Cohort 1) or entinostat, lapatinib, and trastuzumab (Cohort 2). Initial dose of lapatinib 1250mg in Cohort 1 and 1000mg for Cohort 2 to match standard dose in combination with trastuzumab dose. In Cohort 1, entinostat was given PO on day 1 and 15 every 28 days cycle at dose levels 10 mg (level 0), 12 mg (level 1), or 15 mg (level 2). The dose levels for Cohort 2 were 12 mg (co-level 0) or 15 mg (co-level 1) on day 1 and 15 every 28 days cycle. While lapatinib and entinostat were given 28 days cycle due to entinostat dosing, the dosing of trastuzumab followed approved schedule every 21 days starting at 8mg/kg loading followed by 6mg/kg q 3 wks in Cohort 2 and 3. After the MTD of entinostat in cohort 2 was determined at 12mg, an expansion cohort of 10 pts (cohort 3) was conducted. Results: Median age was 52 (26-69 yrs). Median number of prior trastuzumab-based regimens was 2 (1-6), 8 pts had lapatinib containing treatment prior to the trial, including 5 pts who had clinical benefit. 16 had ER+ and 13 ER negative, and 9 had IBC. Clinical efficacy and toxicity of treatment is summarized in table 1. Out of 14 pts who had clinical benefit (CR, PR, SD), 6 had IBC. Three pts are still on therapy (1CR, 1PR, 1SD). Table 1. Clinical Efficacy, Toxicity of combination Receptor StatusResponseGrade 3 toxicityGrade 4 toxicityCohort 1HER2+/ER- (N=8) HER2+/ER+ (N=7)CR (N=1; 8M), SD (N=4;1,2,4M)Lapatinib dose reduction: 3 pts Rash (2) Abdominal pain + dyspnea (1)Entinostat dose reduction: 2pts Neutropenia (1 at 12mg, 1 at 15mg)Cohort 2/3HER2+/ER- (N=8) HER2+/ER+ (N=6)CR (N=2; 3,6M), PR (N=2;4,5M) SD (N=5;1,2,4,6M)Lapatinib dose reduction: 2 pts Diarrhea (N=1 at 12mg N=1 at 10mg) Entinostat dose reduction: 5 pts Neutropenia (N=2 at 12 mg) Leukopenia (N=1 at 12mg) Anemia (N=1 at 12mg)Entinostat dose reduction: 2pts Hypokalemia (N=1 at 12mg) Thrombocytopenia (N=1 at 15mg)CR: complete response, PR: partial response, SD: stable disease, N=number of pts, M=months Conclusion: MTD was reached at 12mg q 2wkly entinostat, lapatinib 1000 mg daily and trastuzumab 8 mg/kg followed by 6mg/kg q 3 wks. This combination was safe and had promising clinical efficacy in patients with trastuzumab-resistant metastatic HER2+ breast cancer including IBC, warranting further study. Citation Format: Lim B, Jackson S, Alvarez RH, Ibrahim NK, Willey JS, Murthy RK, Booser DJ, Giordano SH, Barcenas CH, Brewster A, Walters RS, Brown PH, Tripathy D, Valero V, Ueno NT. A single-center, open-label phase 1b study of entinostat, and lapatinib alone, and in combination with and trastuzumab in patients with HER2+ metastatic breast cancer after progression on trastuzumab. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-22.

BACKGROUND: Breast cancer and its treatments produce multiple symptoms that significantly impact patient quality of life (QOL). Distress and impaired function are the most commonly referred symptoms [Cleeland CS, 2007]. Routine cancer care assessment of patient-reported outcomes (PROs), including symptoms, function, and QOL, has been shown to improve symptom management, identification of psychosocial problems, and patient-provider communication. The Symptom Inventory Tool (SIT) is an assessment tool that captures the patients' perceived symptom burden for real-time clinical intervention, taken at the point of no intervention (baseline) and every 21 days or greater. The SIT is comprised of 27 questions utilizing the M.D. Anderson Symptom Inventory tool (MDASI) [Cleeland CS, Cancer 2013], and validated assessment instrument with 8 questions added and a free text box by Cancer Treatment Centers of America (CTCA). CTCA is a national network of five hospitals that specialize in cancer treatment and integrative oncology. PATIENTS & METHODS: Patients reported symptoms intensity using 19-item MD Anderson Symptom Inventory (MDASI) and 8 additional questions created by CTCA (constipation, swelling, mouth soreness, bleeding, sexual interest, family, hope & QOL). Symptoms were rated "at the worst" on an 11-point numeric scale ranging from 0 ('no present") to 10 ("as bad as you can imagine") in the previous 24 hours. SIT became an integral part of patient care at CTCA beginning in 2012. RESULTS: From July 2012 to February 2015, a total of 3,740 outpatients with breast cancer were evaluated at CTCA. A total of 13,852 assessments were analyzed. The assessments consisted of 3,513 completed at baseline, 2,237 completed at the 2nd follow up (FU), and 8,014 completed at 3rd FU or greater. Median age was 50 (range, 17-88), 60% of patients were ER+. Race: White (68%), Black (29%), and other (3%). Disease extension: locoregional (86%) and metastatic (13.6%). The average time since cancer was diagnosed were 35 months, and 50.7% of the patients received prior systemic therapy: chemotherapy (55%), hormone-therapy (41%), and immunotherapy (4%). Mean, standard deviation and inter quartile ranges at baseline assessment are depicted in. Table 1.Patient Reported SymptomBaseline assessment statisticsPercentage of patients with severe symptoms at baseline and reporting a clinically significant change (2 points) at 2nd SIT assessment Mean +/- STDInterquartile range (IQR)Significant decreaseNo changeDistress3.0 +/- 3.0[0.5]695 (31.3%)594 (26.8%)414 (18.7%)Sadness2.5 +/- 2.9[0.4]622 (28%)718 (32.3%)358 (16.1%)Disturbed Sleep3.3 +/- 3.2[0.6]550 (24.8%)517 (23.3%)642 (28.9%)Mood2.6 +/- 2.7[0.4]549 (24.7%)678 (30.5%)447 (20.1%)Pain2.7 +/- 3.0[0.5]523 (23.9%)675 (30.8%)519 (23.7%)*IQR is a measure of variability, based on dividing a data set into quartiles. Quartiles divide a rank-ordered data set into four equal parts CONCLUSIONS: The SIT was successful in identifying symptoms burden and interference with life issues in breast cancer patients. Distress, sadness, disturbed sleep, mood and pain were the most common reported symptoms. Early identification of patient burden symptoms allowed immediate intervention and improvement in approximately a quarter of patients. Citation Format: Alvarez RH, Hartman S, Bosch B, Kendrick D, Cohen L, Fridman J, Ottersen D, Walcott K, Ware S, Castro I, Thomas J, Niu J, Ahn E, Denny D, Markman M. Self-reported symptoms and interference issues in breast cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-10-27.

Background. The present study was performed to determine whether the human epidermal growth factor receptor-related 2 (HER2)/centromeric probe for chromosome 17 fluorescence in situ hybridization (FISH) ratio is a predictor of a pathologic complete response (pCR), recurrence-free survival (RFS), and/or overall survival (OS) in patients receiving neoadjuvant systemic treatment (NST) with trastuzumab (NST-T) for HER2+ locally advanced breast cancer (LABC). Patients and Methods. The present retrospective study included 555 patients with HER2+ LABC who had undergone NST and definitive surgery (1999–2012); 373 had concurrently received trastuzumab. HER2-positivity was considered present with an immunohistochemical score of 3+ and/or HER2 FISH ratio of ≥2.0. We used logistic regression analysis and Cox proportional hazard modeling to determine whether a high HER2 FISH ratio, either as a continuous variable or with a cutoff of ≥7.0, would predict for pCR (no invasive disease in the breast and no tumor in the ipsilateral axillary lymph nodes), RFS, and/or OS. Results. The pCR group's median HER2 FISH ratio was significantly higher than that of the non-pCR group (6.4 vs. 5.2; p = .003). The logistic regression model demonstrated that the independent predictors of pCR included a high HER2 FISH ratio as a continuous variable (p = .04). The multicovariate Cox proportional hazard model showed that a high HER2 FISH ratio (with a cutoff of ≥7.0 or as a continuous variable) was a significant prognostic indicator of longer RFS time (p = .047 and p = .04, respectively). Similarly, a high HER2 FISH ratio of ≥7.0 was associated with longer OS (p = .06). Conclusion. A high HER2 FISH ratio is a predictor of pCR in patients with HER2+ LABC who receive NST-T.

Background To date, studies on inflammatory breast cancer (IBC) lack comprehensive epidemiological data. We analyzed detailed prospectively collected clinical and epidemiological data from the IBC Registry at The University of Texas MD Anderson Cancer Center. Methods Patients with IBC (n = 248) were consecutively diagnosed and prospectively enrolled between November 2006 and April 2013. All patients were newly diagnosed and at least 18 years old. Secondary IBC was excluded. Overall 160 variables were collected and evaluated including sociodemographics, anthropometrics, tobacco and alcohol consumption, reproductive variables, and family history data. Results Mean age at diagnosis was 51.6 (±11.5 SD) years, and the majority of patients were White (77.8%). A mean BMI ≥ 25 kg/m2, irrespective of menopausal status, was observed in 80.2% of all patients, with 82.6% of African Americans being obese. Approximately 42.2% of patients were ever smokers, and 91% reported ever being pregnant. A history of breastfeeding was reported in 54% of patients, with significant differences between ethnic groups in favor of White women (P

Importance Combining conventional chemotherapy with targeted therapy has been proposed to improve the pathologic complete response (pCR) rate in patients with inflammatory breast cancer (IBC). Epidermal growth factor receptor (EGFR) expression is an independent predictor of low overall survival in patients with IBC. Objective To evaluate the safety and efficacy of the anti-EGFR antibody panitumumab plus neoadjuvant chemotherapy in patients with primary human epidermal growth factor receptor 2 (HER2)-negative IBC. Design, Setting, and Participants Women with primary HER2-negative IBC were enrolled from 2010 to 2015 and received panitumumab plus neoadjuvant chemotherapy. Median follow-up time was 19.3 months. Tumor tissues collected before and after the first dose of panitumumab were subjected to immunohistochemical staining and RNA sequencing analysis to identify biomarkers predictive of pCR. Intervention Patients received 1 dose of panitumumab (2.5 mg/kg) followed by 4 cycles of panitumumab (2.5 mg/kg), nab-paclitaxel (100 mg/m 2 ), and carboplatin weekly and then 4 cycles of fluorouracil (500 mg/m 2 ), epirubicin (100 mg/m 2 ), and cyclophosphamide (500 mg/m 2 ) every 3 weeks. Main Outcomes and Measures The primary end point was pCR rate; the secondary end point was safety. The exploratory objective was to identify biomarkers predictive of pCR. Results Forty-seven patients were accrued; 7 were ineligible. The 40 enrolled women had a median age of 57 (range, 23-68) years; 29 (72%) were postmenopausal. Three patients did not complete therapy because of toxic effects (n = 2) or distant metastasis (n = 1). Nineteen patients had triple-negative and 21 had hormone receptor–positive IBC. The pCR and pCR rates were overall, 11 of 40 (28%; 95% CI, 15%-44%); triple-negative IBC, 8 of 19 (42%; 95% CI, 20%-66%); and hormone receptor–positive/HER2-negative IBC, 3 of 21 (14%; 95% CI, 3%-36%). During treatment with panitumumab, nab-paclitaxel, and carboplatin, 10 patients were hospitalized for treatment-related toxic effects, including 5 with neutropenia-related events. There were no treatment-related deaths. The most frequent nonhematologic adverse event was skin rash. Several potential predictors of pCR were identified, including pEGFR expression and COX-2 expression. Conclusions and Relevance This combination of panitumumab and chemotherapy showed the highest pCR rate ever reported in triple-negative IBC. A randomized phase 2 study is ongoing to determine the role of panitumumab in patients with triple-negative IBC and to further validate predictive biomarkers. Trial Registration ClinicalTrials.gov Identifier:NCT01036087

Background Olaparib (Lynparza®) is a poly(ADP-ribose) polymerase (PARP) inhibitor approved as maintenance treatment of PSR OC. MEDIOLA assessed olaparib in combination with the anti-programmed cell death ligand1 antibody, durvalumab, in germline BRCA1 and/or BRCA2 mutated (gBRCAm) PSR OC (NCT02734004). The 12-week (wk) disease control rate (DCR) = complete response [CR] + partial response + stable disease) was presented at SGO 2018 (late-breaker abst. 4). Methods Pts had PSR OC, gBRCA1 or gBRCA2 mutation, and had received at least one prior line of platinum. Pts received olaparib 300mg PO BID for a 4-wk runin, then olaparib 300mg PO BID and durvalumab 1.5g IV q 4 wks until progressive disease. Tumours were assessed by RECIST 1.1 at baseline, 4 wks, then every 8 wks. Primary endpoints were 12wk DCR and safety. Secondary endpoints were 28-wk DCR, objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and biomarker analyses. Results Thirty-two/thirty-four pts treated were eligible. With the data cut-off on 1 Nov 2018, 28% pts were still on treatment. Most common ≥Grade 3 AEs were anaemia (17.6%), elevated lipase (11.8%), neutropenia (8.8%), and lymphopenia (8.8%). Five pts discontinued olaparib and three discontinued durvalumab due to an adverse event. The 28-wk DCR was 65.6% (90% CI: 49.6%, 79.4%). ORR was 71.9% (95% CI: 53.25%, 86.25%) with a total of seven CRs. Median PFS was 11.1 months (95% CI: 8.2, 15.9) with a median DoR of 10.2 months (25/75th percentile: 5.6, NC). Second-line pts (N=13, 40.6%) had not yet reached the medians for PFS or DoR. Median OS for all pts was not yet reached, with 87.0% of pts alive at 24 months (median follow up=20.4 months). Updated results will be presented. Conclusions The combination of olaparib and durvalumab was well tolerated and showed promising median PFS and DoR. Median PFS and DoR for pts with fewer prior lines of chemotherapy was not yet reached, suggesting that these pts may derive a greater benefit from the combination. The CR rate was higher than anticipated. This cohort has been expanded to further explore the durability of this chemotherapy-sparing combination. Clinical trial identification NCT02734004. Editorial acknowledgement Emma Robinson, Mudskipper Business, Ltd, funded by AstraZeneca. Legal entity responsible for the study AstraZeneca. Funding AstraZeneca. Disclosure Y. Drew: Advisory / Consultancy, Research grant / Funding (institution): Clovis Oncology; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Merck; Advisory / Consultancy, Research grant / Funding (institution): Tesaro ; Advisory / Consultancy: Genmab; Research grant / Funding (institution): Oncology; Research grant / Funding (institution): Veratsem. B. Kaufman: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Medison. S. Banerjee: Honoraria (self), Research grant / Funding (self): AstraZeneca; Honoraria (self): Tesaro; Honoraria (self): Clovis Oncology; Honoraria (self): Merck; Honoraria (self): PharmaMar; Honoraria (self): Roche; Honoraria (self): Seattle Genetics; Honoraria (self): Nucana. A. Lortholary: Honoraria (self): AstraZeneca; Honoraria (self): Tesaro. P. Roxburgh: Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Research grant / Funding (institution), Travel / Accommodation / Expenses: Tesaro. R.H. Alvarez: Honoraria (self): Eisai; Honoraria (self): Puma; Leadership role: Cancer Treatment Center of America. S. Domchek: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Clovis Oncology; Honoraria (self): Bristol-Myers Squibb; Research grant / Funding (institution): PharmaMar. C. Gresty: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. H.K. Angell: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. V. Rocher Ros: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. K. Meyer: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. M. Lanasa: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. P. Herbolsheimer: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. All other authors have declared no conflicts of interest.

Purpose: We used a clinical next-generation sequencing (NGS) hotspot mutation panel to investigate clonal evolution in paired primary and metastatic tumors. Experimental Design: A total of 265 primary and metastatic tumor pairs were sequenced using a 46-gene cancer mutation panel capable of detecting one or more single-nucleotide variants as well as small insertions/deletions. Mutations were tabulated together with tumor type and percentage, mutational variant frequency, time interval between onset of primary tumor and metastasis, and neoadjuvant therapy status. Results: Of note, 227 of 265 (85.7%) tumor metastasis pairs showed identical mutation calls. Of the tumor pairs with identical mutation calls, 160 (60.4%) possessed defining somatic mutation signatures and 67 (25.3%) did not exhibit any somatic mutations. There were 38 (14.3%) cases that showed at least one novel mutation call between the primary and metastasis. Metastases were almost two times more likely to show novel mutations (n = 20, 7.5%) than primary tumors (n = 12, 4.5%). TP53 was the most common additionally mutated gene in metastatic lesions, followed by PIK3CA and SMAD4. PIK3CA mutations were more often associated with metastasis in colon carcinoma samples. Conclusions: Clinical NGS hotspot panels can be useful in analyzing clonal evolution within tumors as well as in determining subclonal mutations that can expand in future metastases. PIK3CA, SMAD4, and TP53 are most often involved in clonal divergence, providing potential targets that may help guide the clinical management of tumor progression or metastases. Clin Cancer Res; 21(11); 2644–51. ©2015 AACR.

Comprehensive analysis of factors impacting risks and outcomes of therapy-related myeloid neoplasms following breast cancer treatment

Purpose, Low molecular weight cyclin E (LMW-E) isoforms, overexpressed in a majority (~70 %) of triple-negative breast cancers (TNBC), were found in preclinical models to mediate tumorigenesis through binding and activation of CDK2. CDK1/CDK2 inhibitors, such as dinaciclib, combined with anthracyclines, were synergistic in decreasing viability of TNBC cell lines. Based on this data, a phase 1 study was conducted to determine the maximum tolerated dose of dinaciclib in combination with epirubicin in patients with metastatic TNBC. Methods, Cohorts of at least 2 patients were treated with escalating doses of dinaciclib given on day 1 followed by standard dose of epirubicin given on day 2 of a 21 day cycle. No intra-patient dose escalation was allowed. An adaptive accrual design based upon toxicity during cycle 1 determined entry into therapy cohorts. The target acceptable dose limiting toxicity (DLT) to advance to the next treatment level was 30 %. Results, Between 9/18/2012 and 7/18/2013, 9 patients were enrolled and treated at MD Anderson Cancer Center. DLTs included febrile neutropenia (grade 3, n = 2), syncope (grade 3, n = 2) and vomiting (grade 3, n = 1). Dose escalation did not proceed past the second cohort due to toxicity. After further accrual, the first dose level was also found to be too toxic. No treatment responses were noted, median time to progression was 5.5 weeks (range 3–12 weeks). Thus, accrual was stopped rather than explore the −1 dose level. Conclusion, The combination of dinaciclib and epirubicin is associated with substantial toxicities and does not appear to be an effective treatment option for TNBC.

Background: IBC is a rare but highly aggressive form of locally advanced breast cancer (5-year OS rate: 40.5% IBC vs 85% non-IBC patients) accounting for 10% of all breast cancer deaths. To date, no unique molecular diagnostic or prognostic biomarker has been identified for IBC. Increasing evidence supports the potential value of miRNA as prognostic and predictive serum biomarker in cancer. We found that IBC cells expressed high levels of miR-19a and patients with metastatic IBC HER2+ (MIBC HER2+) and high miR-19a serum levels had better prognosis than patients with MIBC HER2+ and low miR-19a serum levels. As one of the mechanisms of action of trastuzumab is the induction of antibody-dependent cell-mediated cytotoxicity (ADCC), we hypothesized that the increased miR-19a serum levels in MIBC HER2+ patients with favorable clinical outcome could result from an effective ADCC and be used as biomarker to monitor the response to trastuzumab. Methods: Total RNA was isolated using the Total RNA Purification Kit (Invitrogen, Norgen Biotek). MiR-19a levels in tumor tissue, serum, cell lines and supernatants were evaluated by qRT-PCR (Applied Biosystems). ADCC was evaluated by Annexin V-FITC Apoptosis Detection Kit I (BD Pharmingen). Results: Microarray was performed in IBC (n=23) and non-IBC (n=24) tumors and normal tissue (n=12). Microarray showed higher miR-19a expression in IBC compared with non-IBC (p=0.028) and normal tissue (p=0.0002). The two IBC cell lines SUM149 (triple receptor-negative) and KPL-4 (HER2-amplified) expressed higher levels of miR-19a compared with the non-IBC cell lines MDA-231 (triple receptor-negative), SKBR3 (HER2-amplified), and MCF-7 (HER2-non-amplified) (p Conclusion: High miR-19a serum levels are associated with favorable prognosis in patients with MIBC HER2+ and could result from an effective NK cell-mediated ADCC. MiR-19a may represent a novel serum biomarker to monitor the response to trastuzumab therapy and predict clinical outcome in patients with MIBC HER2+. Citation Format: Simone Anfossi, Antonio Giordano, Lei Huo, Ricardo H Alvarez, Vicente Valero, Gabriel N Hortobagyi, Wendy A Woodward, Naoto T Ueno, George A Calin, James M Reuben. High miR-19a serum levels correlate with favorable prognosis in patients with metastatic HER2+ inflammatory breast cancer and may result from an effective antibody-dependent cell-mediated cytotoxicity induced by trastuzumab [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-14-07.

Background: Our preclinical data show that entinostat enhances the efficacy of lapatinib in HER2 positive (HER2+) breast cancer cell lines via FOX-03-mediated Bim1 expression. In-vitro and in- vivo, the combination of entinostat and lapatinib enhanced apoptosis in lapatinib-resistant cells. We conducted a phase I study with the primary objective to determine the RP2D of entinostat plus lapatinib in patients with HER2+ metastatic breast cancer with progressive disease (PD) after trastuzumab treatment. Methods: This was a single-center, open-label study to evaluate the dose limiting toxicity (DLT) and determine the MTD of every-other-week entinostat plus daily lapatinib in 28-day cycles. Patients with locally recurrent or metastatic breast cancer in whom trastuzumab had failed were enrolled. DLT was defined as: any toxicity resulting in 14 or more days of treatment delay, febrile neutropenia (NTP), grade 4 NTP for over 7 days, any grade 3 or higher non-hematologic toxicity, grade 3 nausea, vomiting, diarrhea or electrolyte imbalance lasting over 48 hours despite adequate supportive care, or a platelet count less than 10,000. Grading was assigned according to common toxicity criteria (CTC 4). A standard 3+3 dose escalation design was used. Entinostat was given at 10 mg (level 0), 12 mg (level 1), or 15 mg (level 2) by mouth every 14 days. Lapatinib was given at 1250 mg by mouth daily. Toxicity was evaluated on day 15 and day 28 for C1 and C2, and at the end of each cycle thereafter. Results: Fifteen patients with HER2+ metastatic breast cancer were enrolled. Median age was 52 years (range 26-69), median of all prior systemic treatment was 4 (range 1- 12), and median prior trastuzumab-based regimens was 2 (range 1-6). Eight patients had prior lapatinib exposure. Seven patients had ER+/HER2+ tumors. Median number of cycles completed was 2 (range 1-13). DLT was observed in 0 of 3 patients at level 0, 1 of 6 at level 1, and 1 of 6 at level 2. 3 patients at level 1 had lapatinib dose reductions because of grade 3 rash (n=2) or grade 3 dyspnea (n=1) or grade 3 abdominal pain (n=1). 2 patients at level 2 had entinostat dose reductions because of grade 4 NTP in cycle 1 (n=1) or grade 3 NTP in cycle 5 and grade 4 neutropenia in cycle 6 (n=1). Five patients had SD (defined per 2009 RECIST guidelines): two at dose level 1 for 6 months and 13 months, three at level 2 for 3, 4, and 8 months. Median time to progression was 2 months (range 1-13). The most common treatment related adverse events were fatigue (n=15), myalgia (n=14), nausea (n=14), diarrhea (n=13), anemia (n=11), and rash (n=11). Conclusion: MTD was not reached. Cumulative toxicity of entinostat plus lapatinib was fairly well tolerated. The combination therapy suggests there was clinical activity in at-least 5 patients who had SD in this cohort of heavily pretreated trastuzumab-resistant MBC. Data from the EG104900 clinical trial showed that lapatinib plus trastuzumab significantly improved median overall survival compared with lapatinib alone. Therefore, this study was modified after 15 patients to add trastuzumab to the combination. We are currently conducting a phase 1b trial to determine the MTD of entinostat, trastuzumab and lapatinib. Citation Format: Jie Willey, Ricardo H Alvarez, Daniel J Booser, Sharon H Giordano, Ana M Gonzalez-Angulo, James L Murray, Vincente Valero, Jangsoon Lee, Naoto T Ueno, Summer A Jackson, Fahad A Faruqi. A phase I clinical trial of entinostat and lapatinib in patients with trastuzumab refractory HER2-positive metastatic breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-22.

SummaryCancer is a risk factor for venous thromboembolism (VTE). Elevated plasma D-dimer and fibrinogen levels are also risk factors for VTE. Furthermore, in patients with metastatic breast cancer (MBC), the presence of circulating tumour cells (CTCs) is a risk factor for VTE. The relationship between CTCs and D-dimer is unknown. The aim of this study was to determine whether CTCs correlate with plasma D-dimer level, fibrinogen level, and risk of VTE in MBC. This prospective study included 47 MBC patients treated from July 2009 through December 2010 at the MD Anderson Cancer Center. CTCs in peripheral blood were detected and enumerated using the CellSearch system. D-dimer and fibrinogen were measured in plasma at the time of CTC detection. Thirty-three patients (70 %) had ≥ 1 CTC, and 22 patients (47 %) had ≥ 5 CTCs. Patients with ≥ 1 CTC or ≥ 5 CTCs had significantly higher mean plasma D-dimer levels (g/mL) than patients with no CTCs and < 5 CTCs (2.48 and 3.31 vs 0.80 and 0.84, respectively; p=0.006 for cut-off ≥ 1 CTC and p=0.003 for cut-off ≥ 5 CTCs). In multivariate analysis, presence of CTCs and number of metastases were positively associated with plasma D-dimer level. CTCs were not associated with plasma fibrinogen level. At median follow-up of 13.5 months, three of 33 patients (9 %) with ≥ 1 CTC had VTE, vs no patients with undetectable CTCs. In conclusion, the presence of CTCs was associated with higher levels of plasma D-dimer in MBC patients. This study further confirms an association between CTCs and risk of VTE.

The purpose of this study was to determine the association between body mass index (BMI) measurements (baseline BMI and changes in BMI during neoadjuvant systemic treatment [NST]) and clinical efficacy (pathologic complete response [pCR] rate and survival outcomes) in locally advanced breast cancer (LABC). We hypothesized that high baseline BMI and increases in BMI during NST are associated with lower pCR rates and poorer clinical outcomes in LABC. We retrospectively reviewed the medical records of 1002 patients, 204 with primary inflammatory breast cancer (IBC) and 798 with stage III non-IBC, who underwent standard NST and definitive surgery between November 1, 2006, and December 31, 2012. The median follow-up time for the survivors was 19.6 months (0.4 - 67.8 months). The pCR rates of patients whose BMI increased or decreased were 23.2% and 18.1%, respectively, (p=0.048). The unadjusted overall survival (OS) was significantly better in the group with increased BMI (p=0.006). However, increased BMI was not an independent predictor of pCR and clinical outcomes (recurrence-free survival and OS) after adjusting for other clinical variables. In subset analyses, increased BMI as a continuous variable was an independent predictor of higher pCR rates in the normal BMI/underweight group (odds ratio [OR]=1.35, 95% confidence interval [CI]: 1.06-0.71, p=0.015). Increased BMI (BMI change ≥0 vs.

Substantial improvements in the early detection and treatment of breast cancer have led to improvements in survival, but breast cancer remains a significant cause of morbidity and mortality in women. In 2012, the mammalian target of rapamycin (mTOR) inhibitor everolimus was approved by the U.S. Food and Drug Administration for the treatment of advanced breast cancer in patients resistant to endocrine therapy. Although everolimus is generally well tolerated, mTOR inhibitor-associated pneumonitis is one of the most common adverse drug events leading to treatment discontinuation. To date, the underlying pathophysiology of this toxicity is unclear, and this uncertainty may hinder the optimization of management strategies. However, experiences from breast cancer and renal cell carcinoma clinical trials indicate that mTOR inhibitor-associated pneumonitis can be effectively managed by early detection, accurate diagnosis, and prompt intervention that generally involves everolimus dose reductions, interruptions, or discontinuation. Management can be achieved by a multidisciplinary approach that involves the collaborative efforts of nurses, oncologists, radiologists, infectious disease specialists, pulmonologists, clinical pharmacists, and pathologists. Comprehensive education must be provided to all health care professionals involved in managing patients receiving everolimus therapy. Although general recommendations on the management of mTOR inhibitor-associated pneumonitis have been published, there is a lack of consensus on the optimal management of this potentially serious complication. This article provides an overview of mTOR inhibitor-associated pneumonitis, with a focus on the detection, accurate diagnosis, and optimal management of this class-related complication of mTOR inhibitor therapy.Implications for PracticeThis article summarizes the pathogenesis, clinical presentation, incidence, detection, and optimal management of everolimus-related noninfectious pneumonitis in breast cancer. In particular, this article provides a detailed overview of the important aspects of the detection, accurate diagnosis, and appropriate management of mammalian target of rapamycin inhibitor-associated pneumonitis. In addition, this article emphasizes that effective management of this adverse drug event in patients with breast cancer will require a multidisciplinary approach and collaboration among various health care professionals.

Inflammatory breast cancer (IBC) is associated with a poor prognosis and high risk of central nervous system (CNS) metastases.We retrospectively reviewed stage III-IBC patients compared with noninflammatory invasive ductal carcinoma (NI-IDC) patients treated between January 1, 1984, and December 31, 2011, who began primary treatment within 1 year of diagnosis and had been followed up for at least 1 year before the development of CNS metastasis or death. Cumulative CNS metastasis incidence and post-CNS metastasis overall survival (OS) estimates were computed. Multivariable Cox proportional hazard models explored factors for post-CNS metastasis survival.A total of 2323 patients were identified (589-IBC/1734-NI-IDC). Eighty-one IBC patients developed CNS metastasis, versus 154 NI-IDC patients. The 2-, 5-, and 10-year cumulative CNS metastasis incidence rates in IBC and NI-IDC were 9.8%, 15.8%, 17.4% and 6.5%, 10.1%, and 12.7%, respectively. This was significantly different between IBC and NI-IDC patients (P = .0037). Multicovariate competing risk regression models in IBC and NI-IDC patients showed no statistically significant associations with the risk of developing CNS metastasis, except neoadjuvant taxane use in NI-IDC patients (hazard ratio, 0.45; 95% confidence interval, 0.24-0.83; P = .011). The median follow-up was 7.2 years, and the median post-CNS metastasis OS was not significantly different between IBC (7.6 months) and NI-IDC (5.6 months) patients. One hundred ninety patients with CNS metastasis died. HER2-positive patients had better OS, with a median 14.1 versus 4.3 months (P.0001). Age50 years (P = .012) but not IBC status was a significant predictor of post-CNS metastasis survival.IBC patients demonstrated higher CNS metastasis incidence rates but OS following CNS metastases is similar in both groups. HER2 status and age may play prognostic roles. Cancer 2018;124:2299-305. © 2018 American Cancer Society.

BACKGROUND To the authors' knowledge, the benefit of primary tumor resection among patients with metastatic inflammatory breast cancer (IBC) is unknown. METHODS The authors reviewed 172 cases of metastatic IBC. All patients received chemotherapy with or without radiotherapy and/or surgery. Patients were classified as responders or nonresponders to chemotherapy. The 5-year overall survival (OS) and distant progression-free survival (DPFS) and local control at the time of last follow-up were evaluated. RESULTS A total of 79 patients (46%) underwent surgery. OS and DPFS were better among patients treated with surgery versus no surgery (47% vs 10%, respectively [P

Cancer-related pain, reported by more than 70% of patients, is one of the most common and troublesome symptoms affecting patients with cancer. Despite the availability of effective treatments, cancer-related pain may be inadequately controlled in up to 50% of patients. With the growing focus on ‘value’ (healthcare outcomes achieved per dollar spent) in healthcare, the management of cancer-related pain has assumed novel significance in recent years. Data from initiatives that assess the quality of pain management in clinical practice have shown that effective management of cancer-related pain improves patient-perceived value of cancer treatment. As a result, assessment and effective management of cancer-related pain are now recognized as important measures of value in cancer care.

Background: TAPUR is a phase II multi-basket study evaluating the anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations known to be drug targets. S is an oral multi-kinase inhibitor that inhibits Fms-like tyrosine kinase-3 (FLT-3) in biochemical and cellular assays. Results from mCRC pts each with FLT-3 amplification treated with S are reported. Methods: Simon’s optimal two stage design was used to test the null hypothesis of 15% response rate versus the alternative of 35%. Power and alpha were set at 85% and 10%, respectively. Response was assessed per RECIST v1.1. This design requires 10 pts in stage 1 and if Results: Ten pts were enrolled from November 2016 to April 2018. Pts received S at a dose of 50 mg orally once daily for four weeks followed by two weeks off. All pts had mCRC with FLT-3 amplification. All pts are included in the data analysis for demographics, safety, PFS and OS (Table 1). No ORs were observed and despite observation of 2 pts with SD at 16 wks, the cohort was closed after further examination revealed both pts with SD died due to disease progression shortly after the 16 wk evaluation. Grades 3-4 AEs at least possibly related to drug are required to be reported. A single grade 3 diarrhea was reported as possibly related to S. Conclusions: Monotherapy with S does not have sufficient clinical activity in mCRC pts with FLT-3 amplification for continued evaluation in this pt population. Other treatments should be considered for these pts, including treatments offered in clinical trials. Table 1:Baseline demographics, clinical characteristics and outcomes by cohortSunitinib targeting FLT-3Tumor TypemCRC (N=10)Median age, yrs (range)56 (41, 71)Male, %80ECOG Performance Status, %01230700Median PFS, wks (90% CI)10.1 (7.4, 15.9)Median OS, wks (90% CI)29.5 (15.7, 39.9)Drug-related AEs, grades 3-4 (% of pts)10 Citation Format: Ricardo H. Alvarez, Elizabeth Garrett-Mayer, Susan Halabi, Pam K. Mangat, Tareq Al Baghdadi, Eugene R. Ahn, Seungjean Chai, Andrew L. Rygiel, Kaitlyn R. Antonelli, Samiha Islam, Suanna S. Bruinooge, Richard L. Schilsky. Sunitinib (S) in patients (Pts) with metastatic colorectal cancer (mCRC) with FLT-3 alterations: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT146.

Background: The TAPUR Study is a phase II multi-basket study that evaluates the anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations known to be drug targets. Results in two cohorts of BC and NSCLC pts each without reported KRAS, NRAS, BRAF mutationstreated with C are reported. Methods: Simon’s optimal two stage design was used to test the null hypothesis of 15% response rate versus the alternative of 35%. Power and alpha were set at 85% and 10%, respectively. Response was assessed per RECIST v1.1. This design requires 10 pts in stage 1 and if Results: Ten pts were enrolled in the BC cohort from June 2016 to May 2018. Ten pts were enrolled in the NSCLC cohort from January 2017 to May 2018. Pts received C at an initial intravenous infusion of 400 mg/m2 over 120 minutes and subsequent weekly infusions of 250 mg/m2 over 60 minutes. All pts are included in the data analysis for demographics, safety, PFS and OS (Table 1). No ORs or SD at 16 wks were observed in either cohort and both were therefore closed. Grades 3-4 adverse events (AEs) at least possibly related to drug are required to be reported. A single grade 3 AE of hypomagnesemia was reported in the NSCLC cohort as possibly related to C. Conclusions: Results from these cohorts suggest monotherapy with C does not have clinical activity in BC or NSCLC pts without reported KRAS, NRAS, BRAF mutations. Other treatments should be considered for these pts, including treatments offered in clinical trials. Table 1:Baseline demographics, clinical characteristics and outcomes by cohortCetuximab targeting tumors without reported KRAS, NRAS, BRAF mutationsTumor TypeBC (N=10)NSCLC (N=10)Median age, yrs (range)59 (45, 65)60 (55, 82)Male, %060ECOG Performance Status, %01260301010900Median PFS, wks (90% CI)6.7 (4.0, 7.9)8.0 (7.6, 8.4)Median OS, wks (90% CI)11.0 (4.9, 30.1)19.6 (8.6, 25.6)Drug-related AEs, grades 3-4 (% of pts)010 Citation Format: Julie Fisher, Elizabeth Garrett-Mayer, Susan Halabi, Pam K. Mangat, Ricardo H. Alvarez, Timothy L. Cannon, Pamela Crilley, Theodore Pollock, Tareq Al Baghdadi, Jared A. Cotta, Andrew L. Rygiel, Kaitlyn R. Antonelli, Samiha Islam, Suanna S. Bruinooge, Richard L. Schilsky. Cetuximab (C) in patients (Pts) with breast cancer (BC) and non-small cell lung cancer (NSCLC) without reported KRAS, NRAS, BRAF mutations: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT135.

e17022 Background: Tumor genomic profiling is a critical component of precision oncology allowing the detection of genomic alterations (GA) that have the potential to be targeted therapeutically. We present an analysis of comprehensive genomic profiling (CGP) of a large series of cervical cancer (CC) patients assayed in a nationwide cancer network. Methods: 118 Pts with advanced CC underwent CGP with hybrid capture of up to 406 cancer-related genes on tumor tissue or for 62 genes on circulating tumor DNA ordered during clinical care for treatment decision-making between 01-2013 to 05-2018. Clinically relevant genomic alterations (CRGA) were defined as associated with targeted therapies or mechanism-driven clinical trials. The treatment histories for these patients were obtained with IRB-approved retrospective review. Results: Median age was 47 years (range, 27-71), 69% were Caucasian. GA were identified in 88% (104/118) of CC, of which 87 (74%) had a clinically relevant genomic alteration (CRGA). PI3K/AKT/mTOR pathway ( PIK3CA, AKT1/2/3, PIK3R1, PTEN, MTOR, STK11, FBXW7) CRGA were most commonpresent in 73.5% (64/87) of CC. CRGA in other targetable pathways were identified: 24.1% (21/87) in MEK ( KRAS, NRAS, HRAS, BRAF, RAF1, GNAS, NF1, NF2), 9.1% (8/87) in HRD (BRCA1/2, ATM, PALB2, BRIP1) and 24.1% (21/87) in ERBB ( ERBB2, ERBB3, ERBB4, EGFR). One patient was MSI-high and one patient was TMB-high. 29.8% (26/87) of CC patients were ordered a genomically-matched treatment, and 24 pts received treatment; 61.5% (16/26) were agents that were FDA approved in a different tumor type, and 34.6% (9/26) through referral to a matched mechanism driven clinical trial. With access to the clinical trial TAPUR, the frequency of matched treatment through clinical trials increased over time from 2013 to 2018. The PFS for non study related patients was 7 weeks and OS was 19 weeks. Conclusions: In a large series of Cervical Cancer patients assayed with CGP, 27.5% (24/87) of pts received matched treatment, which was predominantly targeted therapy. The comprehensive sensitive and unbiased nature of CGP, coupled with a multidisciplinary molecular tumor board and staff dedicated to genomic interpretation, assisted in achieving a high frequency of patients’ participation in clinical trials and gene-directed treatment.

1098 Background: MBC is a rare entity comprising less than 1% of breast cancers [Siegel RL 2017]. Due to the low incidence of MBC, information about the genomic landscape of MBC is lacking. Here we describe detailed pathologic and genomic characteristics of MBC patients. Methods: IRB approval was obtained for a retrospective analysis of archived pathology on patients treated at Cancer Treatment Centers of America. Comprehensive genomic profiling of tumors was derived from Foundation One next generation sequencing. Clinical information was derived from retrospective chart review. Inclusions: adult males with breast cancer with stage IV metastatic disease. Exclusions: Females, stage 0-IIIC disease, missing genomic and pathology information. Results of clinical, pathology and genomic data were summarized. Results: 10 patients met study criteria. Median age: 56 yrs., range 39-61 yrs. Race: 5/10 (50%) Caucasian, 5/10 (50%) African American. Number of prior treatment regimens: mean = 2.6 (range 0-6). Intrinsic subgroup: hormone receptor (HR)+/ HER2- 7/10 (70%), HR+/ HER2+ 2/10 (20%), HR-/ HER2+ 1/10 (10%), triple negative breast cancer (TNBC) 0/10 (0%). Tumor histology: invasive ductal carcinoma 10/10 (100%). Histology grade: poorly differentiated (diff.) 4/10 (40%), moderate diff. 4/10 (40%), well diff. 1/10 (10%), unknown 1/10 (10%). Biopsy site: primary tumor 4/10 (40%), metastatic site 4/10 (40%), liquid biopsy 1/10 (10%). Most frequent genomic alterations: PIK3CA 5/9 (56%), CCND1 4/9 (44%), ZNF703 3/9 (33%), FGF4 3/10 (33%), GATA3 3/9 (33%) FGF 19 3/9 (33%), FGF3 3/9 (33%) Alterations in FGF seen 14/38 (36.8%) of total genomic alterations. Most frequent alterations by primary tumor: ZNF703 3/4 (75%), FGF3 2/4 (50%), FGFR1 2/4 (50%), CCND1 2/4 (50%), FGF19 2/4 (50%), FGF4 2/4 (50%); by metastatic site: PIK3CA 4/5 (80%), GATA 3 2/5 (40%), CCND1 2/5 (40%), FGF3 1/5 (20%), FGF19 1/5 (20%), FGF4 1/5 (20%). Genomic alteration by histologic subgroup; HR+ HER2- PIK3CA 3/6 (50%), CCND1 3/6 (50%), FGF4 3/6 (50%), ZNF703 3/6 (50%), FGF19 3/6 (50%), FGF3 3/6 (50%); HR+/ HER2+: PIK3CA 2/2 (100%), CCND1 1/2 (50%), GATA3 1/2 (50%), MLL3 1/2 (50%); TNBC: BRCA2 1/1 (100%), BARD1 1/1 (100%). Microsatellite status was stable in 6/6 (100%) of patients. Conclusions: MBC patients display a heterogeneous variety of complex genomic alterations. Mutations in FGF genes were most commonly observed. Other common alterations seen in this series include PIK3CA, CCND1, ZNF703, and GATA3. Furthermore, the genomic profile of primary tumor site differed from the genomic profile of the metastatic site.

9041 Background: TAPUR is a phase II basket study evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of NSCLC pts with CDKN2A loss or mutation treated with P are reported. Methods: Eligible pts had advanced NSCLC, no standard treatment options, measurable disease, ECOG PS 0-2 and adequate organ function. Genomic testing was performed using commercially available tests. Pts matched to P had NSCLC with CDKN2A loss or mutation and no RB mutations. A Simon two-stage design was used to test a null rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have disease control (DC) (objective response (OR) or stable disease at 16 weeks (wks) (SD16+)), an additional 18 pts are enrolled. If ≥7 of 28 pts have DC, the drug is considered worthy of further study. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: Twenty-nine pts were enrolled from January 2017 to June 2018; 1 pt was unevaluable for response but is included in safety analyses. Pts received P at 125 mg orally once daily for 21 days, followed by 7 days off. Demographics and outcomes are summarized in Table (N = 28). One PR and 6 SD16+ were observed for a DC rate of 29% (90% CI, 15% to 37%). 10 pts had at least one grade 3 or 4 AE or SAE at least possibly related to P with the most common being cytopenias. Other grade 3-4 AEs or SAEs at least possibly related to P included fatigue, anorexia, febrile neutropenia, myocardial infarction, sepsis, vomiting, and hypophosphatemia. Conclusions: Monotherapy with P demonstrated evidence of anti-tumor activity in heavily pre-treated NSCLC pts with CDKN2A loss or mutation . Additional study is warranted to confirm the efficacy of P in pts with NSCLC with CDKN2A loss or mutation. Clinical trial information: NCT02693535. [Table: see text]