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Background: Pertuzumab (P) in combination with trastuzumab (H) based chemotherapy is FDA-approved as a standard neoadjuvant treatment for patients with clinical stage II-III HER2-positive (HER2+) breast cancer (BC). The goal of this study was to evaluate the pathologic complete response (pCR) rate for neoadjuvant HP-containing regimens compared to H-containing regimens and report the 3-year relapse-free survival (RFS) for patients who had a pCR compared to those with residual disease (RD). Methods: All patients with stage II-III non-inflammatory HER2+ BC who received neoadjuvant H-containing or HP-containing therapy and underwent definitive breast and axillary surgery were identified from 2005 to 2016 through an institutional database. Medical records were examined for patient demographics, breast cancer stage, pathology results, surgical outcomes, and treatment details. pCR was defined as ypT0/is, ypN0. RFS was defined as the interval from surgery to date of last followup or death from any cause. Descriptive statistics, Cox proportional hazards, and Kaplan-Meier estimates were used for statistical analysis. Results: Patient characteristics and results by pCR or RD status are shown in the table below. The median age was 51 (22-84) years for the HP group and 50 (21-87) years for the H group. The median follow-up time was 1.9 (0-4.2) years for the HP group and 5.3 (0.1-12) years for the H group. For the HP group, the 3-year RFS was 98% (95% CI: 95, 100) for the pCR group and 90% (95% CI: 83, 97) for the RD group; HR 0.17 (0.04, 0.82), p=0.012. For the H group, the 3-year RFS was 91% (95% CI: 88,94) for the pCR group and 75% (95% CI: 71-79) for the RD group; HR 0.31 (0.22, 0.44), p Conclusion: Patients who achieve pCR have an improved 3-year RFS compared to patients who have RD. Treatment with HP-containing neoadjuvant regimens is associated with a high 3-year RFS. VariableHP (n=215)H (n=807) pCR n=121RD n=94pCR n=399RD n= 408Age at Diagnosis Citation Format: Murthy RK, Raghavendra AS, Hess KR, Barcenas CH, Lim B, Moulder SL, Giordano SH, Mittendorf EA, Thompson A, Ueno NT, Valero V, Litton JK, Tripathy D, Chavez-Macgregor M. 3-year relapse-free survival of stage II-III HER2-neu positive breast cancer treated with pertuzumab and trastuzumab-containing neoadjuvant therapy compared to trastuzumab-containing therapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-04.

Background: Serial biopsies (bx) of triple-negative breast cancer (TNBC) in the curative neoadjuvant setting provides critical information on dynamic changes in the tumor in response to neoadjuvant systemic therapy (NAST) and can help inform the development of novel therapeutic strategies. However, neoplastic seeding following image guided breast bx has previously been reported in TNBC, raising concerns that serial bx may worsen clinical outcomes. Thus, we sought to determine if serial bx were associated with poorer clinical outcomes (using rates of pathologic complete response [pCR]) in TNBC pts receiving NAST. Methods: We identified 370 TNBC pts who received NAST at MD Anderson Cancer Center from 2011-2017. 200 pts did not have any research bx done (controls) on the index breast carcinoma and 170 pts had at least one research bx done (cases) on the index breast carcinoma as part of the prospective molecular triaging ARTEMIS trial. Baseline characteristics were compared between cases and controls using the Student t-test, Wilcoxon Rank Sum test or Fisher's exact test as appropriate. Univariable and multivariable logistic regression was used to determine if rates of pCR following NAST were significantly different between cases and controls. Results: Demographic characteristics demonstrate no significant differences (Table). However, cases were more likely to have received an anthracycline (99% vs 96%, p=0.02) and a targeted agent (22% vs 0%, p Conclusion: This is the first study examining the impact of serial bx on clinical outcomes in TNBC pts in the curative neoadjuvant setting. Our data suggest that research bx in this setting do not compromise rates of pCR. Baseline and Treatment CharacteristicsCharacteristicControls (n=200)Cases (n=170)p valueMean age - years (standard deviation [SD])52 (12)53 (12)0.54Ethnicity White – n (%)113 (57)115 (68)0.09Black – n (%)48 (24)29 (17) Other – n (%)39 (20)26 (15) Mean tumor size – cm (SD)3.2 (1.4)3.3 (1.7)0.62T stage – n (%) T134 (17)35 (21)0.96T2145 (73)111 (65) T314 (7)17 (10) T47 (4)7 (4) N stage – n (%) N0101 (51)89 (52)0.83N170 (35)55 (32) N27 (4)6 (4) N322 (11)20 (12) Stage – n (%) I19 (10)21 (12)0.74II140 (70)113 (66) III41 (21)36 (21) Grade – n (%) 19 (5)00.14227 (14)22 (13) 3164 (82)148 (87) Neoadjuvant therapy – n (%) Anthracycline191 (96)169 (99)0.02Taxane199 (100)166 (98)0.18Platinum23 (12)23 (14)0.63Targeted agent037 (22) Citation Format: Yam C, Raghavendra A, Hess KR, Adrada BE, Candelaria RP, Damodaran S, Gilcrease MZ, Helgason T, Hortobagyi GN, Huo L, Layman RM, Lim B, Litton JK, Mittendorf EA, Murthy RK, Piwnica-Worms H, Rauch GM, Santiago L, Symmans F, Thompson AM, Tripathy D, Ueno NT, Valero V, Barcenas CH, Moulder SL, Yang W. Impact of serial biopsies in triple-negative breast cancer patients receiving neoadjuvant systemic therapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-15-06.

Background Preclinical studies suggest that combining vandetanib (VAN), a multi-tyrosine kinase inhibitor of rearranged during transfection (RET) proto-oncogene, vascular endothelial growth factor receptor (VEGFR), and epidermal growth factor receptor (EGFR), with everolimus (EV), a mammalian target of rapamycin (mTOR) inhibitor, may improve antitumor activity. We determined the safety, maximum tolerated dose (MTD), recommended phase II dose (RP2D), and dose-limiting toxicities (DLTs) of VAN + EV in patients with advanced solid cancers and the effect of combination therapy on cancer cell proliferation and intracellular pathways. Patients and methods Patients with refractory solid tumors were enrolled in a phase I dose-escalation trial testing VAN (100-300 mg orally daily) + EV (2.5-10 mg orally daily). Objective responses were evaluated using RECIST v1.1. RET mutant cancer cell lines were used in cell-based studies. Results Among 80 patients enrolled, 72 (90%) patients were evaluable: 7 achieved partial response (PR) (10%) and 37 had stable disease (SD) (51%; duration range: 1-27 cycles). Clinical benefit (SD or PR ≥ 6 months) was observed in 26 evaluable patients [36%, 95% confidence intervals (CI) (25% to 49%)]. In 80 patients, median overall survival (OS) was 10.5 months [95% CI (8.5-16.1)] and median progression-free survival (PFS) 4.1 months [95% CI (3.4-7.3)]. Six patients (7.5%) experienced DLTs and 20 (25%) required dose modifications. VAN + EV was safe, with fatigue, rash, diarrhea, and mucositis being the most common toxicities. In cell-based studies, combination therapy was superior to monotherapy at inhibiting cancer cell proliferation and intracellular signaling. Conclusions The MTDs and RP2Ds of VAN + EV are 300 mg and 10 mg, respectively. VAN + EV combination is safe and active in refractory solid tumors. Further investigation is warranted in RET pathway aberrant tumors., Highlights • VAN + EV is safe, active and provides clinical benefit in some patients with refractory solid cancers. • Dual therapy is superior to monotherapy at inhibiting proliferation and intracellular signaling of RET mutant cancer cells. • This study highlights the importance of identifying novel combination therapies to overcome therapeutic resistance. • Next-generation sequencing of advanced solid tumors may inform treatment strategies and guide future drug development.

Background: Gene expression profiling (GEP) has identified several molecularly distinct subtypes of triple negative breast cancer (TNBC). Currently, GEP-based molecular diagnostics are not routinely used in clinical decision making due to the lack of proven benefit, costs involved and long turnaround time. However, two molecularly distinct subtypes of TNBC, the luminal androgen receptor (AR) and mesenchymal subtypes, have surrogate CLIA-certified immunohistochemical (IHC) markers, AR and vimentin (VM), respectively, which have the potential for application in the clinic. Here we report the rates of AR and VM positivity and their association with clinicopathological characteristics in a cohort of TNBC pts receiving NACT. Methods: As part of an ongoing molecular triaging protocol, 144 pts with stage I-III TNBC underwent a pretreatment biopsy for molecular characterization (MC) prior to initiating neoadjuvant chemotherapy (NACT). IHC for AR and VM were performed using commercially available antibodies. AR+ and VM+ were defined as ≥10% and ≥50% staining, respectively. Pts were randomized 2:1 to know (intervention arm, n=93) and not know (control arm, n=51) the MC results. The charts of pts randomized to the intervention arm were reviewed. Categorical variables were analyzed using Fisher's exact test. Ordinal and continuous variables were analyzed using the Wilcoxon rank-sum test and Student's t test as appropriate. Results: 31% (29/93) and 16% (15/93) of pts were AR+ and VM+, respectively. Only 4% (4/93) of pts were both AR+ and VM+. Clinicopathological characteristics are summarized in Table 1. AR+ pts were more likely to have clinically node positive disease as compared to AR- pts (66% vs 34%, p=0.007). There were no significant differences in clinical tumor size or grade between AR+ and AR- pts. VM+ and VM- pts had similar clinicopathological characteristics. Conclusion: Pts with AR+ TNBC were more likely to have node positive disease. The impact of AR+ on long term outcomes should be investigated in prospective studies. Table 1: Association between patient characteristics and AR/VM status AR VM AR+ (n=29)AR- (n=64)p-valueVM+ (n=15)VM- (n=78)p-valueAge - Median (years, interquartile range)58 (48-65)52 (46-61)0.05855 (48-64)56 (47-62)0.88Clinical Tumor Size Mean (cm, standard deviation)3.5 (1.8)3.0 (1.8)0.2872.7 (1.7)3.3 (1.9)0.31T1 – n(%)5 (17)21 (33)0.2307 (47)19 (24)0.098T2 – n(%)21 (72)36 (56) 7 (47)50 (64) T3 – n(%)3 (10)7 (11) 1 (7)9 (12) Clinical Nodal Status Negative – n(%)10 (34)42 (66)0.0078 (53)44 (56)1.00Positive – n(%)19 (66)22 (34) 7 (47)34 (44) Grade 2 – n(%)6 (21)5 (8)0.0763 (20)8 (10)0.293 – n(%)23 (79)59 (92) 12 (80)70 (90) Citation Format: Yam C, Huo L, Hess KR, Litton JK, Yang W, Piwnica-Worms H, Mittendorf EA, Ueno NT, Lim B, Murthy RK, Damodaran S, Helgason T, Thompson AM, Santiago L, Candelaria RP, Rauch GM, Adrada BE, Symmans WF, Gilcrease MZ, Moulder SL. Androgen receptor positivity is associated with nodal disease in triple negative breast cancer [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 P1-07-22.

Background: Triple Negative Breast Cancer (TNBC) accounts for 15-20% of breast cancers, and has a poor prognosis compared with hormone receptor-positive or HER2-amplified disease. There is currently no targeted therapy to salvage chemotherapy resistant TNBC confirming a need for predictive biomarkers of sensitivity to therapy. This study aimed to evaluate the impact of TP53 mutations, common in TNBC, on sensitivity to therapy and patient outcomes. Methods: TNBC samples (pretreatment biopsies and surgical specimens, n=106) had annotated response to standardized anthracycline/taxane based neoadjuvant chemotherapy (NACT) and 3-year survival data, by which time most recurrences occur in TNBC. RNAseq was performed using Illumina HiSeq with mRNA library preparation protocol to identify TP53 mutations, which were then scored using the Evolutionary Action Score (EAS), a novel computational model shown to be successful at identifying deleterious mutations. This work was supported by an ASCO Conquer Cancer Foundation Young Investigator Award grant. Results: 106 TNBC patients were enrolled on this study, 14 had stage I, 65 stage II, and 24 had stage III disease. 64 patient samples have been analyzed to date, of which 39 (61%) harbored a TP53 mutation, and 24 (38%) were TP53 wildtype. Pathologic complete response (pCR) and survival Of 47 patients who received NACT, 14 (30%) achieved a pCR, and 33 (70%) had residual disease (RD). Patients who achieved a pCR had a significantly better 3-year recurrence free survival (RFS) (100% vs 59%, p=0.011) and overall survival (OS) (100% vs 62%, p-0.01) compared to patients who had residual disease. TP53 status and pCR The rate of pCR was significantly higher in the TP53 mutant group (11/29, 38%) compared to TP53 wildtype (2/17, 12%) TNBC (OR = 4.6, (0.9, 24), p = 0.046). Patients with wild-type and mutant TP53 TNBC who achieved a pCR had excellent 3-year RFS and OS at 100%. Among patients with RD, TP53 wild-type TNBC exhibited a non-significant trend towards higher 3-year RFS (72% vs 49%,HR = 2.5 (0.8, 8.0) p = 0.12) and OS (79% vs 48%,HR = 2.6 (0.8, 8.4) p = 0.11) compared to TP53 mutant TNBC. TP53 status and survival The 3-year OS for TP53 mutant TNBC was 72%, compared to 86% for TP53 wildtype TNBC (HR = 1.5 (0.5, 4.3), p = 0.48). There was no difference in 3-year RFS between the two groups. TP53 EAS and survival Among 39 non-silent TP53 mutant cases, EAS ranged from 42.3 to 100 with a median score of 87.6. The 3-year OS for patients with EAS ≥86.7 was 73%, compared to 74% for patients with EAS Conclusion: TP53 mutations were associated with a higher chance of achieving a pCR; NACT Patients who achieved a pCR to NACT had excellent outcomes, regardless of TP53 mutation status. In patients with RD following NACT, TP53 mutant TNBC had a trend towards worse outcomes compared to TP53 wild-type TNBC. Larger cohorts are required to further evaluate the impact of TP53 mutations and TP53 EAS on survival outcomes in TNBC. Citation Format: Mitri Z, Lin C-H, Hess KR, Thompson A, Lichtarge O, Hubbard R, Fu C, Symmans WF, Moulder-Thompson SL. The impact of TP53 mutation and pathological response to neoadjuvant chemotherapy on triple negative breast cancer outcomes [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 P2-10-05.

Background Mutations in the ligand-binding domain of ESR1 have been demonstrated to mediate resistance to aromatase inhibitors (AI) and are associated with poor survival. Analyses of circulating tumor DNA (ctDNA) offer a minimally invasive and real-time approach to characterize genomic landscape, clonal evolution, and treatment response. Early detection and intervention with alternate therapy to overcome resistance at minimal disease burden progression could have a larger impact than treating higher burden disease at clinical progression. However, whether treatment decisions made based on the emergence of secondary resistance mutations or mutant allele fraction (MAF) changes in ctDNA can improve clinical outcomes is unknown. Currently, the most effective therapy for patients harboring ESR1 mutations is unclear; although, pre-clinical and retrospective clinical trial analyses have suggested that some of these mutations may exhibit greater sensitivity to fulvestrant, a selective estrogen receptor down-regulator, compared to AI. This study hypothesizes that real-time monitoring of ctDNA for secondary ESR1 alterations can identify subclinical progression and early intervention with a targeted-agent that has greater efficacy against ESR1 mutations can improve disease-free survival. Trial Design This is a randomized, open-label, Phase-2 study for HR-positive MBC patients who are on AI and CDK 4/6 inhibitor as first line therapy. Patients on treatment for at least 12 months without evidence of clinical progression would be screened for ESR1 mutations using Guardant360 ctDNA assay. Patients with positive ESR1 mutations would be randomized to change of endocrine therapy to fulvestrant vs. continuing AI. Eligibility criteria -Histologically confirmed HR-positive (ER and/or PR >10%) and HER2-negative MBC -On AI with CDK4/6 inhibitor as first line therapy for 12 months without evidence of clinical progression -Activating ESR1 mutation identified on ctDNA -ECOG performance status ≤1 -Normal organ and marrow function Specific aims - To assess progression-free survival (PFS) with transition to fulvestrant compared with continuing AI therapy in patients with emergence of ESR1 mutations in plasma -To assess ctDNA ESR1 mutant allele fraction and kinetics with transition to fulvestrant compared with AI -To assess the prevalence of ESR1 mutations in patients with exposure to endocrine therapy -To assess overall survival with fulvestrant transition compared with continuing AI therapy in patients with emergence of ESR1 mutations Statistical methods To detect a change in median PFS from 5 months (for AI arm) to 9 months (with fulvestrant arm) would require about 124 patients (5% two-sided alpha, 80% power, log rank testing). Interim analysis will be performed when 42 PFS events are observed. Using O'Brien-Fleming stopping boundaries, we will stop for futility if the log rank test p-value > 0.72 and stop for success if it is < 0.004. Citation Format: Damodaran S, Meric-Bernstam F, Hess KR, Litton JK, Raymond V, Lanman R, Ueno NT, Hamilton S, Wistuba II, Valero V, Moulder SL, Tripathy D. INTERACT- INTegrated Evaluation of Resistance and Actionability using Circulating Tumor DNA in hormone receptor (HR) positive metastatic breast cancers (MBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-03-04.

This study was undertaken to determine the feasibility of enrolling breast cancer patients on a single-agent-targeted therapy trial before neoadjuvant chemotherapy. Specifically, we evaluated talazoparib in patients harboring a deleterious BRCA mutation (BRCA+). Patients with a germline BRCA mutation and ≥1 cm, HER2-negative primary tumors were eligible. Study participants underwent a pretreatment biopsy, 2 months of talazoparib, off-study core biopsy, anthracycline, and taxane-based chemotherapy ± carboplatin, followed by surgery. Volumetric changes in tumor size were determined by ultrasound at 1 and 2 months of therapy. Success was defined as 20 patients accrued within 2 years and

Pazopanib is US FDA approved for the treatment of advanced soft tissue sarcomas. All patients with this disease ultimately develop resistance to therapy. Mechanisms of resistance include activation of the mTOR, histone deacetylase (HDAC), MAPK, and ERBB4 pathways. We hypothesized that combining pazopanib with other targeted agents inhibiting these pathways would increase response rates. We retrospectively evaluated the safety and efficacy of pazopanib plus vorinostat, everolimus, lapatinib or trastuzumab, and MEK inhibitor in patients with advanced sarcoma. The Cancer Geneome Atlas (TCGA) data was analyzed for HDAC, PI3K, HER2, and MAPK/RAS/RAF gene alterations from sarcoma TCGA. Of the 44 advanced sarcoma patients in these trials, 27 (61%) were male; 18 (41%) had bone sarcoma, and 26 (59%) had soft tissue sarcoma. Best response was partial response (PR) in four patients [(overall response rate (ORR) = 9%, 95% confidence interval [CI] 3% to 22%)]. The median progression-free survival (PFS) for all patients was 9.6 weeks (95% CI 8.0 to 15.7 weeks). Analysis of TCGA data revealed HDAC, PI3K, HER2, and MAPK/RAS/RAF gene alterations in 112/243 (46%) of patients predominantly HDAC1–11 (41%) alterations. Pazopanib combinations did demonstrate safety in combination with other agents. TCGA data suggests further evaluation of epigenetic pathway inhibitors in sarcoma.

Background: Lapatinib (L) is approved in combination with capecitabine for patients with trastuzumab-resistant HER2-positive metastatic breast cancer (MBC) and in combination with letrozole for HER2-positive and ER/PR-receptor-positive MBC for whom hormonal therapy is indicated. However, there are no data on the activity of L in patients who received prior pertuzumab (P) and ado-trastuzumab emtansine (TDM-1), now included as standard first and second line therapies. The goal of this study was to assess the efficacy of L in routine clinical practice in a contemporary patient population that received prior P and/or TDM-1. Methods: We identified all patients with trastuzumab-resistant HER2-positive MBC who received L-based therapy (n=570) between 2003 and 2016 through a departmental database at MD Anderson Cancer Center and reviewed the medical records of each patient to confirm treatment sequencing and outcome. Of these patients, we identified a target cohort who received L after prior P or TDM-1 (n=34). Analysis used Kaplan-Meier statistics. Results: Of the 34 patients identified as the target cohort with prior P and/or TDM-1 exposure, 29 patients were available for outcome analysis since 5 patients were started on L-based treatment within 4 months of this analysis. In the comparison cohort (n=536) who had received L-based therapy without prior P and/or TDM-1 exposure, 445 patients were available for outcome analysis. Table 1: ResultsCharacteristicsTarget Cohort (N=34)Comparison Cohort (N=536)Median Age, years (range)51 (31,78)52 (24,85)Median lines of metastatic therapy prior to L, n (range)2.5(1-6)1 (0-12)Discontinuation of L due to toxicity, n (%)1 (3)54 (10)CBR, % (95% CI)58 (39, 79)78(74, 84)Median TTP, months (95% CI)4.9 (3.0, 7.6)5.7 (0.0, 82.3) De novo7.4 (2.9, NR)5.9 (5.5, 9.0) Recurrent4.5 (2.9, 8.3)6.7 (6.0, 7.8)Median OS, months (95% CI)23.9 (20.5, NR)25.8 (23.1, 30.6) De Novo26.1 (23.9, NR)27.8 (22.8, 36.9) Recurrent20.5 (12.7, NR)25.5 (22.5, 30.7)Abbreviations: NR – not reached; CI – confidence interval In we display the patient characteristics and results. Clinical benefit rate (CBR), defined as complete or partial response or stable disease > 6 months, was 58% (95% CI, 39%, 79%) for the target cohort and 78% (74%, 84%) for the comparison cohort. In the target cohort, nearly 25% (n=8) had received > 3 lines of therapy and in the comparison cohort only 10% (n=71) had received > 3 lines of therapy. The median duration on L was 4.9 months (range 0.7-19.2) in the target cohort and 5.6 months (range 0.0-82.3) in the comparison cohort. In both cohorts, median TTP and OS were longer in patients with de novo disease compared to patients with disease recurrence. Conclusions: In the target cohort with prior P and TDM-1, nearly one third of patients received L for > 6 months and over half the patients obtained clinical benefit for > 6 months with no significant toxicity. This suggests clinically relevant benefit to L in a contemporary population of patients who have received prior P and TDM-1. However, clinical benefit and median duration on L were decreased in the target cohort versus the comparison cohort, which may reflect heavier pretreatment. Citation Format: Báez-Vallecillo L, Singareeka Raghavendra A, Hess K, Moulder SL, Tripathy D, Valero V, Murthy RK. Lapatinib after pertuzumab and ado-trastuzumab emtansine in metastatic HER2-positive breast cancer [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 P4-21-20.

Background Patients with rare cancers account for 25% of cancer-related deaths but have limited treatment options. As immunotherapy has potential applicability across cancer types, we conducted an open-label phase II trial of pembrolizumab in patients with advanced rare cancers. Methods Eligible patients who had progressed on standard therapies in the last 6 months were enrolled in 9 tumor-specific cohorts and in a 10th cohort for other histologies. Pembrolizumab 200 mg every 3 weeks was administered for 2 years or until disease progression or intolerable toxicity. Tumor imaging was performed every 9 weeks; response was assessed by RECIST v1.1 and irRECIST. Adverse events (AEs) were graded per NCI-CTCAE v4.03. Results A total of 127 patients with advanced rare cancer were treated. Median age = 56 years and median number of prior therapies = 2. At data cutoff date, the non-progression rate (NPR) at 27 weeks was 28%, ORR 14% (immune-related [ir] complete response [irCR] = 1 and partial response [irPR] = 14, 11 continuing therapy at data cut-off), and clinical benefit rate (CBR; irCR + irPR + ir stable disease ≥4 months) 38%. In the squamous cell carcinoma (SCC) of the skin cohort, NPR at 27 weeks was 36%, ORR 31% (5 of 16 evaluable; irCR = 1 and irPR = 4, 4 continuing therapy), and CBR 38%. In the adrenocortical carcinoma (ACC) cohort, NPR at 27 weeks was 31%, ORR 15% (2 of 13 evaluable; irPR = 2), and CBR 54%. In the carcinoma of unknown primary (CUP) cohort, NPR at 27 weeks was 33%, ORR 23% (3 of 13 evaluable; irPR = 3, all continuing therapy), and CBR 54%. In the paraganglioma-pheochromocytoma cohort, NPR at 27 weeks was 43% and CBR 75% (6 of 8 evaluable). A higher proportion of patients with baseline PD-L1 H-score >42.5 were alive and progression free at 27 weeks (47%, vs 20% for H-score ≤ 42.5; p = 0.02). During the study, 66 (52%) patients had drug-related AEs, 12 (9%) with grade ≥3 AEs. irAEs were observed in 20% of patients. The most common AEs were fatigue (n = 25) and rash (n = 17) and irAEs were hypothyroidism (n = 14), pneumonitis (n = 4) and hyperthyroidism (n = 4). There were 6 deaths during the study, 5 due to progressive disease and 1 due to acute kidney injury secondary to sepsis. Conclusions Toxicity with pembrolizumab was manageable and antitumor activity was observed in patients with SCC of skin, ACC, CUP, and paraganglioma-pheochromocytoma. Clinical trial identification NCT02721732. Legal entity responsible for the study Aung Naing, MD. Funding Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. Disclosure All authors have declared no conflicts of interest.

Background: Triple negative breast cancer (TNBC) is molecularly heterogeneous disease. Genomic profiling to identify the distinct TNBC subtypes is costly with long turnaround time. Early ultrasound after two cycles of neoadjuvant chemotherapy (NAC) has the potential to identify patients who are likely to have pathological complete response. Suspected non-responder patients can undergo comprehensive genetic testing and triaged for specific targeted therapeutic trials. Aim: To determine the value of ultrasound evaluation after two cycles of NAC to predict complete pathologic response in TNBC breast cancer patients. Methods: 98 patients enrolled in “A randomized triple Negative Breast Cancer Enrolling Trial to Confirm Molecular Profiling Improves Survival” (Artemis) at the University of Texas MD Anderson Cancer Center had ultrasound evaluation before treatment and after two cycles of NAC (Adriamycin and Cyclophosphamide). Three-dimensional measurements of the tumor were obtained at baseline and after 2 cycles of the NAC. Change in the tumor volume after 2 cycles of NAC was calculated. Residual cancer Volume (RCB) was calculated based on the final histopathology at surgery. Linear regression analysis evaluated associations between residual cancer burden (RCB) and change in volume of the index tumor. Results: Median tumor size at diagnosis was 3 cm, range 0.6-11.9cm. Median size after two cycles was 2 cm, range 0.6-12.8 cm. RCB 0-I was seen in 55% of patients (54/98). Linear regression analysis demonstrated that of 22 patients with volume reduction >75%, 18 patients (82%) had RCB0-I (95%CI, 61%-93%). Conclusion: Our data suggest that ultrasound exam after 2 cycles of NAC can identify TNBC patients who are unlikely to respond to standard NAC. These non-responder TNBC patients can be triaged for additional genetic testing and subsequent targeted clinical trials. Study on the larger number of patients is currently on the way. Citation Format: Adrada BE, Candelaria R, Moulder S, Lane D, Santiago L, Arribas E, Hess KR, Valero V, Thompson A, Helgason T, Ravenberg E, Yang W, Rauch GM. Early ultrasound evaluation for prediction of treatment response to neoadjuvant chemotherapy in triple negative breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-02-10.

Background Estrogen receptor-positive (ER+) primary inflammatory breast cancer (IBC) has a poorer prognosis than ER+ primary non-IBC. Our objective was to determine the association between ER positivity and survival outcome in order to elucidate the biological reason that ER+ IBC is more aggressive than non-IBC. Methods We retrospectively determined the relationship between ER expression by immunohistochemistry staining and neoadjuvant chemotherapy response as well as survival outcome for 189 patients with ER+ and HER2-negative (HER2-) IBC and 896 case-matched patients with stage III non-IBC seen at MD Anderson Cancer Center between January 1989 and April 2015. We performed gene expression (GE) analysis for 39 patients with ER+/HER2- IBC and 40 patients with non-IBC to detect genes that are specifically overexpressed in IBC. Logistic regression and Cox proportional hazards model were used to determine the predictive and prognostic value of percentages of cells positive for ER and progesterone receptor (PR) among the patients with ER+/HER2- IBC and non-IBC. Recursive partitioning analysis (RPA) was used to determine the optimal cutoff points for ER% and progesterone receptor (PR) % that maximized differences in survival. The identified cutoff points were tested in an external cohort of 192 ER+/HER2- IBC patients from Institut Paoli-Calmettes in France. Results The median values for ER% for IBC and non-IBC were 85 (range, 1-100) and 90 (range, 1-100), respectively. The logistic regression model demonstrated a lack of a relationship of ER% with pathological complete response rate to neoadjuvant chemotherapy both in IBC (P=0.29) and non-IBC (P=0.14). Expression of ER was significantly associated with distant disease-free survival (DDFS); hazard ratio (HR), 0.56 [95% CI, 0.37-0.83] per 50% increase in ER%; P Conclusions Increased ER positivity was significantly associated with improved survival in ER+/HER- IBC patients. ER+/HER- IBC had several activated pathways with MYC upregulation compared to non-IBC. MYC upregulation was associated with a poor survival outcome for ER+/HER- IBC. The results indicate that MYC is a key gene for understanding the aggressive biological behavior of ER+/HER- IBC. Citation Format: Iwase T, Harano K, Masuda H, Kida K, Espinosa Fernandez JR, Hess KR, Wang Y, Woodward WA, Layman RM, Dirix L, Van Laere SJ, Bertucci F, Ueno NT. Myc as a poor prognostic marker for ER+ inflammatory breast cancer (IBC): Quantitative estrogen receptor (ER) expression analysis and gene expression analysis in ER+ IBC vs non-IBC [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-05-04.

Background: ARTEMIS (A Randomized, TNBC Enrolling trial to confirm Molecular profiling Improves Survival) is a randomized trial to determine if precision guided neoadjuvant chemotherapy (NAC) impacts rates of pathologic complete response in the breast and axillary nodes (pCR). We hypothesized that CTCs in peripheral blood after completion of NAC would provide prognostic information beyond pCR alone in TNBC patients. Methods: Blood was assessed for CTCs after NAC as part of two IRB approved studies, ARTEMIS (2014 – 0185/PA15-1050), and LAB04-0698. CTCs were identified using the Cell Search® System (Menarini Silicon Biosystems). Samples with one or more cells, also having morphologic criteria for malignancy, were deemed CTC positive. Log-rank test and Cox regression analysis were applied to evaluate associations between CTC positive, pCR, and overall survival. Results: pCR was achieved in 24/68 (35%) patients with TNBC. Twenty four patients (35%) were CTC positive. Three year overall survival was evaluated in 4 groups of patients: pCR and no CTCs (n=20), pCR and CTC positive (n=4), non-pCR and no CTCs (n=24) and non-pCR and CTC positive (n=20). Three year overall survival was higher in the pCR and no CTCs cohort (100%), compared to pCR and CTC positive (50%), non-pCR and no CTCs (83%), non-pCR and CTC positive (19%); log rank p Conclusion: The identification of CTCs after NAC has prognostic significance beyond that of pCR, and should be considered in evaluation of patients for clinical trials of adjuvant therapies. Citation Format: Lucci A, Hall C, Hess K, Ravenberg E, Clayborn A, Mittendorf E, Rauch G, Candelaria R, Moulder S, Thompson A. Circulating tumor cells (CTCs) after neoadjuvant chemotherapy for triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-01-01.

Purpose: To report preliminary data in a pilot study evaluating the ability of Tc99m sestamibi Molecular Breast Imaging (MBI) to predict response and assess residual disease at the completion of neoadjuvant chemotherapy (NAC) in breast cancer patients. Materials and Methods: Patients with localized, invasive breast cancer (T1-T4, N0-N3, M0) planned for NAC were enrolled in this prospective IRB approved clinical trial. All patients had digital mammography (DM), ultrasound (US), and MBI at baseline (T0), after 2 NAC cycles (T1), and at after NAC completion (T2). Tumor size and volume changes were compared with residual disease at surgery. MBI images were corrected for scatter and attenuation using a novel approach and regions of interest (ROI) were drawn over tumors to compute three quantitative MBI uptake metrics for correlation with pathologic response: tumor to background ratio (TBR), fractional activity uptake (FAU), and MBI-specific standardized uptake value (SUV). ROC analysis was performed. Results: Patients (n=25) who completed NAC, had 75 imaging time points and had surgery, were included in this analysis. Median age was 49 years (range 31 -77). Eleven patients (11/25, 44%) had complete pathologic response (pCR). Absolute TBR values after 2 cycles (T1) and before surgery (T2) had highest correlation with pCR (AUC 0.81; 95% CI 0.63 to 0.99, p=0.01, and AUC 0.78; 95% CI 0.59 to 0.97, p=0.015, respectively). Change in SUV after 2 cycles, Δ SUV1 (T1-T0), (AUC 0.84; 95% CI 0.66 to 1.00, p=0.01) and change in SUV prior to surgery, Δ SUV2 (T2-T0) (AUC 0.80; 95% CI 0.60 to 1.00, p=0.02), were most predictive of pCR. Tumor size and volume showed modest specificity for detecting residual disease, and was highest for MBI (79%), followed by MMG (64%), and lowest for US (55%). Conclusion: Quantitative MBI metrics show promise for the prediction of pCR in breast cancer patients undergoing NAC. Establishment of quantitative metrics for the early prediction of tumor response during NAC of breast cancer patients may provide an alternate to influencing NAC choice early in the management algorithm. Further investigation with a larger sample size is warranted. Citation Format: Rauch GM, Adrada BE, Kappadath C, Candelaria RP, Huang ML, Santiago L, Moseley T, Scoggins ME, Knudtson JD, Lopez BP, Hess KR, Krishnamurthy S, Moulder S, Valero V, Yang W. Quantitative assessment of tumor response to neoadjuvant chemotherapy in women with locoregional invasive breast cancer using Tc99m sestamibi molecular breast imaging - preliminary results [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 P5-01-02.

Background: Image-guided percutaneous needle biopsy of the breast is a common procedure. In breast cancer patients (pts) undergoing core biopsies and surgical resection on the same day, the rate of tumor cell displacement along the needle track has been reported to be up to 50%. However, the clinical significance of this finding in triple negative breast cancer (TNBC) patients (pts) undergoing serial biopsies while receiving neoadjuvant chemotherapy (NACT) is unknown. Here we report the incidence of needle-track seeding (NTS) in a cohort of TNBC pts enrolled on a molecular triaging protocol involving serial biopsies of the index breast lesion. Methods: We reviewed the clinical records of 144 consecutive TNBC pts enrolled on a molecular triaging protocol at MD Anderson Cancer Center. Per protocol, all pts underwent a pre-treatment research biopsy and were initiated on anthracycline based NACT (AC). Pts with inadequate response to front-line NACT were encouraged to undergo additional biopsies of the index breast lesion prior to switching therapies. Serial breast ultrasound (US) was performed to monitor therapeutic response and incidental evidence of needle-track seeding noted on US was documented. Results: Clinicopathological characteristics of the pts are summarized in Table 1. 89% (128/144) of pts had a diagnostic breast biopsy done at another center prior to presenting at MDACC. To date, we have performed 209 US guided biopsies of index breast lesions in 144 pts. 92% (193/209) of these biopsies were done mainly for research purposes. 1.4% (2/144) of pts were found to have evidence of NTS on follow up US. The first pt had a T1N0 (1.9cm), grade 3, invasive ductal carcinoma (IDC) at diagnosis. She underwent a diagnostic biopsy followed by a research biopsy before initiating AC. She was found to have NTS as well as progression of disease (PD) on follow up US after 2 cycles of AC. The second pt had a T2N0 (3cm), grade 3 IDC at diagnosis. She underwent a diagnostic biopsy at another center, followed by a research biopsy before initiating AC. Like the first pt, she was found to have NTS and PD on follow up US after 2 cycles of AC. Both pts are currently on neoadjuvant clinical trials of novel agents. Conclusion: The rate of NTS detected on US in TNBC pts undergoing serial biopsies of index breast lesions while receiving NACT is low and further studies are needed to determine the impact of serial biopsies on long term outcomes in TNBC. Table 1: Patient CharacteristicsCharacteristicN=144Age - Median (years, interquartile range)55 (46-62)Tumor Size Mean (cm, standard deviation)3.4 (2.2)T1 – n(%)35 (24)T2 – n(%)89 (62)T3 – n(%)19 (13)T4 – n(%)1 (1)Clinical Nodal Status Negative – n(%)74 (51)Positive – n(%)70 (49)Grade 1 – n(%)1 (1)2 – n(%)17 (12)3 – n(%)124 (86)Unknown – n(%)2 (1)Histologic Subtype Invasive ductal carcinoma – n(%)121 (84)Invasive lobular carcinoma – n(%)2 (1)Mixed ductal and lobular carcinoma – n(%)3 (2)Metaplastic carcinoma – n(%)13 (9)Not specified – n(%)5 (3)Laterality Right – n(%)72 (50)Left – n(%)72 (50) Citation Format: Yam C, Santiago L, Candelaria RP, Adrada BE, Rauch GM, Hess KR, Litton JK, Piwnica-Worms H, Mittendorf EA, Ueno NT, Lim B, Murthy RK, Damodaran S, Helgason T, Huo L, Thompson AM, Gilcrease MZ, Symmans WF, Moulder SL, Yang W. Risk of needle-track seeding with serial ultrasound guided biopsies in triple negative breast cancer [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 P6-03-05.

Background This retrospective study aims to investigate the activity of retreatment with anti-EGFR-based therapies in order to explore the concept of clonal evolution by evaluating the impact of prior activity and intervening time interval. Methods Eighty-nine KRAS exon 2-wild-type metastatic colorectal patients were retreated on phase I/II clinical trials containing anti-EGFR therapies after progressing on prior cetuximab or panitumumab. Response on prior anti-EGFR therapy was defined retrospectively per physician-records as response or stable disease ≥6 months. Multivariable statistical methods included a multiple logistic regression model for response, and Cox proportional hazards model for progression-free survival. Results Retreatment anti-EGFR agents were cetuximab (n = 76) or cetuximab plus erlotinib (n = 13). The median interval time between prior and retreatment regimens was 4.57 months (range: 0.46-58.7). Patients who responded to the prior cetuximab or panitumumab were more likely to obtain clinical benefit to the retreatment compared to the non-responders in both univariate (p = 0.007) and multivariate analyses (OR: 3.38, 95 % CI: 1.27, 9.31, p = 0.019). The clinical benefit rate on retreatment also showed a marginally significant association with interval time between the two anti-EGFR based therapies (p = 0.053). Median progression-free survival on retreatment was increased in prior responders (4.9 months, 95 % CI: 3.6, 6.2) compared to prior non-responders (2.5 months, 95 % CI, 1.58, 3.42) in univariate (p = 0.064) and multivariate analysis (HR: 0.70, 95 % CI: 0.43-1.15, p = 0.156). Conclusion Our data lends support to the concept of clonal evolution, though the clinical impact appears less robust than previously reported. Further work to determine which patients benefit from retreatment post progression is needed. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1701-3) contains supplementary material, which is available to authorized users.

The potential role of oncogenic viruses mediating development of proliferative skin lesions in patients treated with RAF inhibitors is poorly understood. The objective of this study was to investigate human papilloma virus (HPV) and Merkel cell polyomavirus (MCPyV) in skin lesions among patients treated with RAF inhibitors with the help of a case series describing prevalence of HPV, MCPyV, and RAS mutations in skin biopsies obtained from patients receiving RAF inhibitors and developing cutaneous lesions. HPV-DNA was amplified by PCR utilizing multiple nested primer systems designed for detection of a broad range of HPV types. MCPyV copy number determination with real time PCR technology was performed by a "Quantification of MCPyV, small t region" kit. Thirty-six patients were tested (squamous cell carcinoma (SCC) = 14; verruca vulgaris = 15; other = 11). Nine of 12 SCCs (75 %) and eight of 13 verruca vulgaris lesions (62 %) tested positive for MCPyV whereas none of the normal skin biopsies obtained from nine of these patients tested positive for MCPyV (p = 0.0007). HPV incidence in cutaneous SCCs was not different compared to normal skin (50 vs. 56 %, p = 0.86). The association between MCPyV and proliferative skin lesions after RAF inhibitor therapy merits further investigation.

BACKGROUND: Approximately 50% of TNBC pts treated with standard taxane/anthracycline-based NACT will have chemo-insensitive disease (CID) manifested as extensive residual disease (RCB-II or III) at the time of surgery. 40-80% of these pts will develop recurrence within 3 years of initial diagnosis. Recent advances in molecular profiling have identified subsets of TNBC with distinct, targetable molecular features. We developed a clinical trial to identify and characterize CID (ARTEMIS: A Randomized, TNBC Enrolling trial to confirm Molecular profiling Improves Survival). In the ARTEMIS trial, treatment naïve pts with localized TNBC undergo a pretreatment biopsy and then immediately start their initial phase of anthracycline-based chemotherapy so that the results of the molecular characterization are used in combination with response assessment (clinical exam/diagnostic imaging) to identify CID and inform the second phase of NACT, thus using a 'second hit' strategy in the middle of NACT to overcome drug resistance. The mesenchymal subtypes of TNBC have a high incidence of PI3K pathway activation. Preclinical models demonstrated response to PI3K inhibitors in this subtype. Metaplastic breast cancers make up ∼30% of tumors characterized as 'claudin-low/mesenchymal' by gene signature and are also associated with a high rate of PI3K activating molecular aberrations. A combination regimen of liposomal doxorubicin, bevacizumab and the mTOR inhibitors temsirolimus or everolimus (DAT or DAE) demonstrated response (including durable complete responses) in metastatic metaplastic breast cancer. PRIMARY OBJECTIVE: Determine the rate of pathologic complete response (pCR/RCB-0) or minimal residual disease (RCB-I) after 4 cycles of DAE for treatment of mesenchymal TNBC deemed to be CID through the ARTEMIS trial TRIAL DESIGN AND STATISTICAL METHODS: Only pts deemed to have mesenchymal CID on the ARTEMIS trial can enter this non-randomized phase II study. Realizing that pts without response to their initial cycles of chemotherapy have very low chance (5%) of achieving pCR with additional cycles of chemotherapy, it would be clinically meaningful to see pCR in this pt population improved to 20%. Counting pCR (RCB-0) or RCB-I as response, a two-stage Gehan-type design will be employed with 14 pts in the first stage. If at least one pt responds, 23 more pts will be added for a total of 37 pts. This design has a 49% chance of terminating after the first stage if the true response rate is 0.05, 23% chance if the true rate is 0.10, 10% if the true rate is 0.15 and 4% if the true rate is 0.20. If accrual continues to the second stage and a total of 37 pts are enrolled, the 95% confidence interval for a 0.20 response rate will extend from 0.10 to 0.35. BRIEF ELIGIBILITY CRITERIA: Inclusion: localized TNBC enrolled onto ARTEMIS trial, adequate organ, bone marrow and cardiac parameters Exclusion: metastatic disease, pregnant or lactating pts, medical illness that increases chance of moderate to severe toxicity CORRELATIVE SCIENCE: Correlate vimentin expression by IHC, mesenchymal signatures and PI3K pathway aberrations with response. Citation Format: Moulder S, Hess K, Rauch M, Astrada B, Litton J, Mittendorf E, Ueno N, Tripathy D, Lim B, Piwnica-Worms H, Thompson A, Symmans WF. NCT02456857: A phase II trial of liposomal doxorubicin, bevacizumab and everolimus (DAE) in patients (pts) with localized triple-negative breast cancer (TNBC) with tumors predicted insensitive to standard neoadjuvant chemotherapy (NACT) [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 OT2-01-22.

BACKGROUND: Approximately 50% of patients with TNBC treatedwithstandardtaxane/anthracycline-based neoadjuvant chemotherapy (NACT)have chemo-insensitive disease (CID), i.e., residual disease burden (RCB)-II/III at the time of surgery, and 40-80% of patients develop recurrence within 3 years. Recent developments in molecular profiling have identified subsets of TNBC with distinct, targetable molecular features. We developed a clinical trial to identify and characterize CID (ARTEMIS: A Randomized, TNBC-Enrolling trial to confirm Molecular profiling Improves Survival). In ARTEMIS, patients with localized TNBC will undergo a pretreatment biopsy, then begin anthracycline-based NACT. During NACT, we use molecular profiling and response assessment to identify CID and allocate patients to alternative therapies to overcome CID. Epidermal growth factor receptor (EGFR) is overexpressed in 25-30% of TNBC. In preclinical studies, suppression of EGFR signaling has shown efficacy in controlling cancers through suppression of the stem cell population, enhanced apoptosis via MAPK/PI3K signaling, and modulation of epithelial-mesenchymal transition (EMT). Moreover, in a phase II trial of triple negative inflammatory breast cancer, neoadjuvant PaCT yielded significantly higher pathologic complete response (pCR) rates than historic control. Taken together, we hypothesize that using PaCT to suppress EGFR in TNBC will enhance the pCR rate. OBJECTIVES: Primary objective: determine pCR and RCB-0/I rates in TNBC patients with CID given PaCT. Secondary objective: determine the benefit of using baseline genomic signatures to develop an alternative second phase of NACT. TRIAL DESIGN AND STATISTICAL METHODS: Patients with >10% volume reduction for non-CID or BRIEF ELIGIBILITY CRITERIA: Inclusion: localized TNBC; enrolled in ARTEMIS trial; adequate organ, bone marrow, and cardiac parameters; Exclusion: pregnant or lactating, known or suspected metastasis. CORRELATIVE SCIENCE: Circulating tumor cells (CTCs) and cell free (cf) DNA in baseline and subsequent blood samples, EGFR expression (immunohistochemistry), stem cell/EMT/apoptosis marker changes in tissue and CTCs, PD-L1 glycosylation for EGFR sensitivity. Citation Format: Lim B, Helgason T, Hess KR, Piwnica-Worms H, Yang W, Adrada BE, Rauch GM, Gilcrease M, Symmans FW, Huo L, Mittendorf EA, Thompson A, Stacy M-TL, Debu T, Ueno NT. Phase IIB study of neoadjuvant panitumumab combined with carboplatin and paclitaxel (PaCT) for anthracycline-resistant triple-negative breast cancer (TNBC) [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 OT2-01-20.

BACKGROUND: TNBC has an especially poor prognosis in patients (pts) whose tumor does not respond to anthracycline and taxane-based chemotherapy. Approximately 50% will have chemo-insensitive disease (CID) resulting in extensive residual disease at the time of surgery. 40-80% of these pts will recur < 3 years. Recently developed molecular profiling techniques to identify TNBC subsets detect distinct molecular hallmarks. We designed a clinical trial to identify and characterize CID (ARTEMIS: A Randomized, TNBC Enrolling trial to confirm Molecular profiling Improves Survival). Treatment naïve pts with localized TNBC undergo a pretreatment biopsy followed by anthracycline-based chemotherapy (AC). During AC the molecular profile is determined; these results along with the response assessment (clinical exam/diagnostic imaging) will identify CID and guide the second phase of neoadjuvant chemotherapy. Tumor-infiltrating lymphocytes (TIL) have been identified as having prognostic and predictive significance in TNBC pts leading to higher pCR rates post NACT. However, the tumor microenvironment also contains regulatory T cells and myeloid-derived suppressor cells that are immunosuppressive. Programmed death ligand 1 (PD-L1) is expressed in 20% TNBC. Targeting this may lead to a more durable response as compared to chemotherapy alone. PRIMARY OBJECTIVE: Evaluate the rate of pathologic complete response (pCR)/RCB-0 + residual cancer burden (RCB)-I responses in TNBC pts, determined to have CID after anthracycline-based chemotherapy, then treat with atezolizumab + nab-paclitaxel preoperatively. TRIAL DESIGN AND STATISITCAL METHODS: Pts deemed to have CID on the ARTEMIS trial can enter this non-randomized phase II study. Pts without response to their initial chemotherapy cycles have a low likelihood (5%) of achieving pCR with additional cycles of chemotherapy. It would be clinically meaningful for pCR to improve to 20%. Counting pCR (RCB-0) or RCB-I as response given similar survival outcomes, a two-stage Gehan-type design will be employed with 14 pts in the first stage. If at least one pt responds, 23 more will be added. This design has a 49% chance of terminating after the first stage if the true response rate is 0.05, 23% chance if the true rate is 0.10, 10% if the true rate is 0.15 and 4% if the true rate is 0.20. If accrual continues to the second stage, the 95% confidence interval for a 0.20 response rate will extend from 0.10 to 0.35. BRIEF ELIGIBILITY CRITERIA: Inclusion: localized TNBC enrolled onto ARTEMIS and determined to have CID at the time of response assessment after anthracycline chemotherapy, adequate organ, bone marrow and cardiac parameters. Exclusion: prior immunotherapy, IBC, history of autoimmune disease, HIV, Hep-B, Hep-C, active tuberculosis, pregnant. CORRELATIVE SCIENCE: Evaluate the presence and phenotype of TIL and other immune cell populations in tumor tissue pre/post treatment; determine changes in expression of co-stimulatory and co-inhibitory molecules on tumor cells and immune cells in the microenvironment; evaluate the immune repertoire and cytokine responses in serially collected peripheral blood mononuclear cells and serum respectively. Citation Format: Litton JK, Moulder S, Helgason T, Clayborn AR, Rauch GM, Gilcrease M, Adrada BE, Huo L, Hess KR, Symmans WF, Thompson A, Tripathy D, Mittendorf EA. Triple-negative first-line study: Neoadjuvant trial of nab-paclitaxel and atezolizumab, a PD-L1 inhibitor, in patients with triple negative breast cancer (TNBC) (NCT02530489) [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 OT2-01-14.

BACKGROUND: Approximately 50% of TNBC expresses AR by immunohistochemical (IHC) staining. Luminal androgen receptor (LAR) subtype is heavily enriched in hormonally regulated genes, yet negative for ER by IHC. LAR is associated with low pCR rates and long survival. Preclinical data have shown that taxanes inhibit translocation of AR from the cytoplasm to the nucleus where AR is activated. Combining paclitaxel with enzalutamide may inhibit the AR pathway synergistically thereby increasing pCR rates. We hypothesized that patients with AR-positive TNBC who have chemo-insensitive disease (CID) after initial anthracycline-based chemotherapy treated with ZT would have higher RCB-0 and RCB-I rates than those who receive conventional taxane-based chemotherapy. Our team developed a clinical trial to identify patients with CID (ARTEMIS: A Randomized, TNBC Enrolling trial to confirm Molecular profiling Improves Survival). In the ARTEMIS trial, treatment-naïve patients with localized TNBC undergo a pretreatment biopsy and then begin anthracycline-based chemotherapy. Molecular testing results and radiographic response assessment are used to identify CID and will guide the second phase of neoadjuvant chemotherapy (NACT) to overcome CID. PRIMARY OBJECTIVE: To determine RCB-0 and RCB-I rates of patients with TNBC who have CID to initial anthracycline-based chemotherapy and who received ZT. TRIAL DESIGN AND STATISTICAL METHODS: Patients with CID from the ARTEMIS trial can enroll in the 12-week ZT (paclitaxel, 80 mg/m2 intravenously per week; enzalutamide, 160 mg orally per day). We will define pCR (RCB-0) or RCB-I as a response, using a Simon optimal 2-stage design with alpha=beta=10% and then setting the threshold for an acceptable pCR or RCB-I rate at 20%. We will enroll 12 patients into the first stage. If no patients experience pCR or RCB-I, we will stop the study after the first stage. If at least 1 patient experiences pCR or RCB-I, we will enroll 25 more patients for a total of 37 patients. We would declare the treatment worthy of further study if at least 4 of the 37 patients experience pCR or RCB-I. This design has a 54% probability of early termination after the first stage if the true pCR or RCB-I probability is 5%. Because patients with CID have a very low chance (5%) of achieving pCR with additional chemotherapy, improving pCR rates to 20% in this patient population would be clinically meaningful. BRIEF ELIGIBILITY CRITERIA: Inclusion criteria: Primary invasive TNBC patients who have CID under the ARTEMIS trial; AR+ ≥1% nuclear staining by IHC; and adequate physical, organ, bone marrow, and cardiac functions. Exclusion criteria: Pregnant or lactating patients, history of colitis or absorption abnormality, known or suspected brain metastasis or leptomeningeal disease, or history of seizure. CORRELATIVE SCIENCE: Enumeration of circulating tumor cells (CTCs) and expression of CTC-related gene transcripts will be measured to correlate CTC characteristics and/or gene profiles related to the AR pathway and treatment response to ZT. Citation Format: Fujii T, Lim B, Helgason T, Hess KR, Gilcrease MZ, Willey JS, Tripathy D, Litton JK, Moulder S, Krishnamurthy S, Yang W, Reuben JM, Symmans WF, Ueno NT. NCI-2016-00367: A phase IIB study of neoadjuvant ZT regimen (enzalutamide therapy in combination with weekly paclitaxel) for androgen receptor (AR)-positive triple-negative breast cancer (TNBC) [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 OT3-02-05.

Background: Cancer stem cells (CSCs) in bone marrow (BM) are epithelial tumor cells that express CD44+CD24−/lo. CSCs can be further divided into those that have ALDH activity (Aldefluor+) and those that do not. We hypothesized that if CSCs are responsible for tumor dissemination, their presence in BM would be prognostic in early stages of breast cancer (EBC) patients. Therefore, using multiparameter flow cytometry (FACS), we assessed epithelial cells for expression of CD44+CD24−/low and Aldefluor in BM of EBC patients and correlated these findings with circulating tumor cells (CTC), disseminated tumor cells (DTC) and clinical outcome. Methods: This is a prospective laboratory study (Protocol 04–0657) conducted in the Departments of Surgical Oncology and Hematopathology, at The University of Texas MD Anderson Cancer Center in Houston, TX, USA, and was approved by the institutional review board. BM aspirates were collected at the time of surgery from 108 patients with EBC. BM was analyzed for CSCs and ALDH activity by FACS analysis. Ten cytospin slides of the bone marrow mononuclear cells were prepared from each BM aspirate and reacted with a cocktail of antibodies, including AE1/AE3, CAM5.2, MNF116, CK8 and CK18, to identify epithelial cells (DTC) by immunohistochemistry (IHC). In addition, the CellSearch system (Veridex, Raritan, NJ) was used to enumerate CTCs in each of 3 tubes of 7.5 mL of peripheral blood per patient. Overall survival (OS) and disease-free survival (DFS) were calculated from the date of diagnosis and analyzed with Kaplan-Meier survival plots. Cox multivariate proportional hazards model was also performed. Results: Of the 103 evaluable patients, 45 patients received neoadjuvant chemotherapy, 35 adjuvant chemotherapy and 23 no chemotherapy. The median follow-up was 40 months (range 7–66 months). Patients with CSCs in BM had a hazard ratio (HR) of 8.8 for DFS (p = 0.002); patients with Aldefluor+ CSCs had a HR of 5.9 (p = 0.052) for DFS. Seven patients have expired and all of them had CSCs in BM. Moreover, we evaluated the presence of DTCs by FACS (CD326+CD45−) in 104 patients. Sixty-one (75%) of patients had positive BM samples for DTC (CD326+CD45- BM cells ≥ 0.53%). No association was shown between DTC in BM as determined by FACS and CTCs in PB. In a multivariate model, after adjusting for age (< 45 years old), clinical T stage, N stage, ER, PR, HER2 status, and nuclear grading, the presence of CSCs was found to be an independent predictor of DFS (HR = 15.8, P = 0.017) as was the presence of CTCs (HR = 13.9, P = 0.007). In this subset of patients, the presence of Aldefluor+ CSCs and DTCs was not found to be predictive of DFS in the multivariate model including the same factors as listed above. Conclusions: Our data indicate that the presence of BM metastasis is correlated to CSCs, and CSCs irrespective of ALDH activity are independent adverse prognostic factors in EBC patients. Moreover, the presence of CTCs was a strong independent predictor of DFS. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-03-01.

Purpose: To conduct a Phase II one-arm study to evaluate the long-term efficacy and safety of accelerated fractionated radiotherapy combined with i.v. carboplatin for patients with previously untreated anaplastic gliomas. Methods and Materials: Between 1988 and 1992, 90 patients received 1.9–2.0-Gy radiation 3 times a day with 2-h infusions of 33 g/m 2 carboplatin for two 5-day cycles separated by 2 weeks. After radiotherapy, patients received procarbazine, lomustine (CCNU), and vincristine (PCV) for 1 year or until the tumor progressed. Results: Ninety patients were evaluable for analysis. Histologically, 69 had anaplastic astrocytoma; 14, anaplastic oligoastrocytoma; and 7, anaplastic oligodendroglioma. Gross total resection was performed in 20 (22%), subtotal resection in 45 (50%), and biopsy in 25 (28%); reoperation (total or subtotal resection) was performed in 50 (56%) patients. A multivariate analysis showed that a younger age ( p = 0.026), Karnofsky performance score (KPS; p = 0.009), and brain necrosis ( p = 0.0002) were predictive of a better survival. Results from analysis of extent of surgery (biopsy, subtotal resection, gross total resection) approached significance ( p = 0.058). Radiation dose, irradiated tumor volume, and techniques used (boost and fields) were not significant variables. The median survival (MS) of all anaplastic glioma patients was 28.1 months; for anaplastic astrocytoma patients, MS was 28.7 months and 40.8 months for the combined anaplastic oligodendroglioma/oligoastrocytoma patients. Long-term survival occurred in 25% of anaplastic glioma patients who were alive 8.6 years after treatment was initiated. Treatment-induced necrosis was documented by surgery or autopsy in 19 (21%) patients; 21 (23%) had a mixed pattern of necrosis and tumor; and an additional 13 (14%) patients who did not have surgical or autopsy demonstration of predominant radiation necrosis had magnetic resonance imaging (MRI) evidence of radiation necrosis. Serious clinical neurologic deterioration and/or dementia requiring full-time caregiver attention were observed in 9 (10%) patients. Conclusion: When comparable selection criteria are applied, the rate of MS in this study is inferior to results attainable with current radiation and chemotherapy approaches, although the rates of long-term survival are comparable. Theoretically, patients failing therapy and dying earlier than anticipated may be because of excessive central nervous system (CNS) toxicity resulting from the combination of accelerated fractionated irradiation, intensive carboplatin chemotherapy before each radiation fraction, and postirradiation PCV chemotherapy. On the other hand, patients with treatment-induced necrosis survived significantly longer than patients who did not demonstrate MRI or histologic evidence of necrosis (MS, 106 months vs. 18–33 months).

Purpose/Objective(s): Systemic lymphocyte count has been established as prognostic in numerous cancer types. Of relevance is the ability of low dose radiation therapy (RT) to induce death in circulating lymphocytes despite the mitotic inactivity of this cell type. We sought to investigate the potential causes of RT-induced lymphopenia and its associations with patient outcomes in non-small cell lung cancer (NSCLC). Materials/Methods: Subjects were 711 patients who had received definitive RT for NSCLC with 2 lymphocyte measurements during RT. A lymphocyte nadir was defined as the minimum systemic lymphocyte value during RT. Associations between gross tumor volumes (GTVs) and lung dose-volume histogram (DVH) parameters with lymphocyte nadirs were assessed with Spearman’s correlations. Relationships between lymphocyte nadirs with overall survival (OS) and event free survival (EFS) were evaluated with Kaplan-Meier analysis and log-rank tests. Stepwise multivariate regression was conducted with linear and Cox regressions. All variables were analyzed as continuous if possible. Results: Analyses of lung DVH parameters revealed significant correlation with lymphocyte nadir at lower doses (lung v5-10: P 0.05). Lung v5 were lower in patients receiving proton therapy (Median: 30.4%) compared with 3D conformal (Median: 55.6%, P

Background To identify alterations in miRNA expression that occur in the early and late stages of lung cancer in smokers and non-smokers, we conducted miRNA profiling analysis. MiRNAs abnormally expressed in lung adenocarcinomas were compared in smokers vs. non-smokers as well as early stage vs. late stage disease. Materials and methods We collected 62 lung adenocarcinoma samples with paired non-neoplastic lung tissue from patients with no pre-operative therapy at Fox Chase Cancer Center and Methodist Hospital. Twenty-five patients had no history of tobacco smoking. The clinical stages were proportionally matched between smokers and non-smokers. MiRNA expression was profiled using the Human miRNA V2 Oligo Microarray Kit (Agilent Technologies, Alto, CA). The human miRNAs were background-subtracted, quantile-normalized in arrays, and log-2 transformed. The differences of mRNAs between tumor and normal tissue were examined using two-factor linear model. We assessed the local false discovery rates (FDRs) for all terms including the intercept using the Bum method (Pounds and Morris, 2003). Results We identified 63 miRNAs with FDR Table 1 . Conclusion Eighty-one percent of the altered miRNAs were observed in both smokers and non-smokers, which suggests a common epigenetic predisposition for lung adenocarcinoma development. Altered miRNAs expressed in early stage lung adenocarcinoma may be used as markers for the early detection of lung cancer. Table 1 . MiRNAs abnormally expressed in lung adenocarcinoma Patient characteristics miRNAs S/N/E/L 126, 130a, 135b, 141, 144, 145, 21, 21*, 200b, 210, 218, 30a, 30a*, 30c, 338-3p, 424, 451, 486-5p, 494, 497, 574-5p, 96, 99a S/N/E 200, 429 N/E/L 34c-5p N/L 135a*, 198 S, smoker; N, non-smoker; E, early stage; L, late stage.

Purpose: To prospectively evaluate in a randomized trial if a previously reported multigene predictor of pathologic complete response (pCR) to preoperative weekly paclitaxel and fluorouracil-doxorubicin-cyclophosphamide (T/FAC) chemotherapy can accurately predict pCR to neoadjuvant T/FAC chemotherapy, and if it also predicts pCR to FAC only chemotherapy. Furthermore, it is unknown if the T/FAC regimen is superior to 6 courses of FAC; therefore we compare the pCR rates for patients who receive T/FAC versus FACx6 preoperative chemotherapy.Materials and Methods: Patients with stage I-III breast cancer (n=273) were randomly assigned to receive either 12 courses of weekly paclitaxel followed by 4 courses of FAC (T/FAC, n=138), or 6 courses of FAC (FACx6, n=135) neoadjuvant chemotherapy. All patients underwent a pretreatment FNA biopsy of the tumor for gene expression profiling on oligonucleotide microarrays, and treatment response prediction (pCR versus residual disease, RD) was performed using the multigene predictor. Predicted and observed pathologic responses were compared independently in the two treatment arms.Results: The pCR rate was 19% with T/FAC and 9% with FACx6 (p Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 101.