bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiac safety of the trastuzumab biosimilar ABP 980 in women with HER2-positive early breast cancer in the LILAC study.
Authors: Kolberg Hans-Christian , Colleoni Marco , Demetriou Georgia , Santi Patricia Xavier , Tesch Hans , Fujiwara Yasuhiro , Tomasevic Zorica , Hanes Vladimir
Published: May 2019

557

Background: Although trastuzumab is generally well-tolerated, cardiotoxicity is the main limitation in its use, leading to a severe heart failure in 2-4% of patients in adjuvant trials. In the phase 3 LILAC trial, trastuzumab biosimilar ABP 980 demonstrated similar efficacy, safety, and immunogenicity to trastuzumab reference product (RP) in women with HER2-positive early breast cancer. Here we report analyses comparing cardiac safety of ABP 980 and RP. Methods: In the neoadjuvant phase, all 725 patients received 4 cycles of chemotherapy with epirubicin + cyclophosphamide Q3W and were then randomized 1:1 to ABP 980 (n = 364) or RP (n = 361) with a loading dose of 8 mg/kg, then 6 mg/kg IV Q3W for 3 cycles plus paclitaxel Q3W (4 cycles) or QW (12 cycles). After surgery, patients received investigational product (IP) Q3W for up to 1 year; ABP 980-treated patients continued ABP 980, and RP-treated patients either continued RP (n = 190) or switched to ABP 980 (RP/ABP 980; n = 171). AEs were assessed every 3 weeks and cardiac safety every 3 months. Cardiac safety was monitored by computerized 12-lead ECG; LVEF was assessed by 2D ECHO. LVEF decline was defined as LVEF value decrease from study baseline by ≥10 percentage points and to < 50%. Results: Treatment groups were well balanced with regard to IP disposition. Over the entire study, 22 (3.1%) patients had LVEF decline by ≥10 percentage points compared to baseline and to < 50%; no meaningful between-group differences were observed (ABP 980:10/359 [2.8%], RP: 6/184 [3.3%], RP/ABP 980: 6/171 [3.5%]). The incidence of cardiac AEs was low and comparable in treatment groups. One grade 3 cardiac failure event was reported in the RP/ABP 980 arm; another in the RP arm was coincident with LVEF decline. No patient discontinued IP during adjuvant phase because of cardiac failure. Conclusions: These pre-specified analyses confirm the tolerability of ABP 980 and demonstrate clinical similarity of ABP 980 and RP with respect to cardiac safety. The incidence of LVEF decline was consistent with the known cardiac safety profile of the RP. No new cardiac safety signals were observed whether patients were on ABP 980 or switched from RP to ABP 980. Clinical trial information: NCT01901146.
T cell trafficking within the peritoneal tumor environment and ovarian cancer progression.
Authors: Desai Sharina Palencia , Bahmani Maryam , Adams Sarah Foster
Published: May 2019

5573

Background: Ovarian cancer is associated with high mortality due to detection at late stages with widespread peritoneal metastases at diagnosis in a majority of patients. Ovarian cancer recurrences are primarily found in the peritoneal cavity, and peritoneal disease is the primary cause of morbidity and mortality in this disease. This pattern of tumor engraftment and recurrence indicates that the peritoneal tumor environment is distinct from other niches. Our data indicate that selective peritoneal dissemination is immunologically mediated, based on functional differences in peritoneal and systemic T cells during ovarian cancer progression. This is consistent with data in other solid tumors demonstrating that tumor immunity is driven by regional lymphocyte populations. However, less is known about the mechanisms that establish a permissive immune environment in the peritoneal cavity. We hypothesize that pathways regulating T cell recruitment and retention in the peritoneal cavity (PC) are co-opted by ovarian cancer cells to enable intraperitoneal cancer dissemination and recurrence. Methods: We have developed a novel model that uses direct in vivo labeling of peritoneal cells in an established immune-competent high grade serous murine cancer model. This functional approach enables us to identify T cell subsets retained in the PC with tumor engraftment and progression. Results: We identified high expression of CD49d (a4 integrin) as the most prevalent cell surface marker on T cells retained in the peritoneal cavity, consistent with prior published data in healthy mice and people. We demonstrated a functional role for CD49dhi in T cell retention by showing preferential binding to VCAM. A role for tumor cells mediating this interaction was observed based on enhanced binding affinity in vitro with tumor monolayers. The importance of this mechanism is supported by high VCAM expression in multiple murine and human ovarian cancer cell lines, and T cell localization to VCAM rich areas within ovarian cancer tumors in vivo. Conclusions: CD49d not only defines a lymphocyte subset with a significant role in tumor immunity but presents itself as an important potential therapeutic target to modulate T cell trafficking.
The Circulating Cell-free Genome Atlas (CCGA) Study: Follow-up (F/U) on non-cancer participants with cancer-like cell-free DNA signals.
Authors: Cohn Allen Lee , Seiden Michael , Kurtzman Kathryn N. , Hubbell Earl , Gross Samuel , Venn Oliver , Fung Eric T. , Liu Minetta C. , Klein Eric A. , Oxnard Geoffrey R. , Hartman Anne-Renee , Waterhouse David Michael
Published: May 2019

5574

Background: A noninvasive cell-free DNA (cfDNA)-based cancer detection assay offers the hope of a blood test that might reduce morbidity and mortality of cancers, particularly those without recommended screening tests (eg, some gynecologic cancers). CCGA (NCT02889978) is a prospective, multi-center, longitudinal, case-control study evaluating models for discriminating cancer versus non-cancer. Here, we report F/U of control participants (pts) who demonstrated a cancer-signal in CCGA. Methods: Clinically evaluable samples (N = 2508) from pts enrolled without a cancer diagnosis (dx; NC) and treatment-naive pts with newly diagnosed cancer (C) were divided into training (n = 1564; 580 NC, 984 C) and test (n = 944; 368 NC, 576 C) sets. Classification performance (cancer/non-cancer) was assessed via 3 prototype assays: whole-genome bisulfite (WGBS), whole-genome (WGS), and targeted (507 gene) sequencing. Notable outlier NC pts were identified with cancer-like scores in either ≥2 assay classification results or by the presence of known cancer drivers with ≥1 assay classification result suggesting cancer. All pts are currently in F/U in accordance with study protocol (to date: 80% with > 10 mo and 15% with > 22 mo F/U). Results: Among training and test sets, 8 ( < 1%) NC pts were identified with a cancer-like signal. To-date, 2 have been diagnosed with a gynecologic malignancy: 1 stage IIIc clear cell endometrial carcinoma and 1 stage IIIc ovarian cancer, 3 and 2 months (mo) post-enrollment [PE], respectively. Among C pts in the study, sensitivity (at 98% specificity; WGBS) in these cancer types was: uterine/endometrial: 11% (n = 27 train) and 22% (n = 9 test); ovarian: 82% (n = 17) and 71% (n = 7). In addition, a third NC pt was diagnosed with a stage IV lung cancer 15 mo PE. Conclusions: This cfDNA-based assay detected a cancer-like signal that anticipated a clinical presentation of cancer in undiagnosed pts as early as 15 months prior to the actual dx. High specificity ( > 99%) requires accounting for undiagnosed cancers in study design and analysis. Together, these data suggest that this prototype assay may have high performance detecting a variety of gynecological and other cancers. Clinical trial information: NCT02889978.
DPX-Survivac and intermittent low-dose cyclophosphamide (CPA) with or without epacadostat (E) in the treatment of subjects with advanced recurrent epithelial ovarian cancer (DeCidE1 trial): T cell responses and tumor infiltration correlate with tumor regression.
Authors: Tanyi Janos Laszlo , Dorigo Oliver , Oza Amit M. , Strauss James Fredric , Pejovic Tanja , Ghamande Sharad A. , Ghatage Prafull , Villella Jeannine A. , Fiset Stephan , MacDonald Lisa Diana , Hrytsenko Olga , Stanford Marianne , Newton Robert C , Leopold Lance , Rosu Gabriela Nicola
Published: May 2019

5576

Background: DPX-Survivac is a novel T cell activating therapy designed to elicit an effective immune response against recurrent ovarian cancers that express the survivin protein. The survivin specific T cells induced by DPX-Survivac can infiltrate the tumors and are associated with clinical responses. It is likely that achieving an anti-tumor effect requires a favorable ratio of T cells to tumor cells. Epacadostat (E) is an IDO1 enzyme inhibitor that may enhance effector T cell proliferation, shifting the tumor microenvironment (TME) away from an immunosuppressive state toward one supporting productive immune response. Methods: Recurrent ovarian cancer patients with advanced and metastatic progressive disease were treated with DPX-Survivac, intermittent low dose CPA with or without E. In the Phase 1b, 53 subjects were enrolled to receive DPX-Survivac, low dose CPA and E BID. In the Phase 2, 12 subjects were randomized to receive DPX-Survivac and low dose CPA with or without E. The data on immunological responses, biomarkers, and clinical responses were analyzed in relation to the baseline sum of target lesions per RECIST 1.1. Results: The study showed that DPX-Survivac and intermittent low dose CPA with or without E can generate strong T cell responses. The infiltration of tumors with survivin-specific T cells correlates with the observed tumor regression. The sum of target tumor measurements at baseline by RECIST 1.1 correlated with observed clinical benefits. In the group of 15 patients with the baseline sum of target lesions less than 5 cm, all subjects have shown clinical benefits. Four of these subjects reached partial response and remained without progression over a prolonged period. Conclusions: The treatment studied leads to strong survivin-specific T cell responses. Infiltration of tumors by survivin-specific T cells correlated with clinical benefit in treated subjects. A predictive model based on tumor size to improve response to DPX-Survivac in recurrent ovarian cancer is being prospectively explored. Clinical trial information: NCT02785250.
Clinical outcome of sequential chemotherapy after immune checkpoint inhibitors in advanced ovarian cancer.
Authors: Bonilla Luisa , Oza Amit M. , Lheureux Stephanie , Saibil Sam , Chen Shiyi , Lee Yeh Chen , Gray Diana , Colombo Ilaria , Madariaga Ainhoa , Dhani Neesha C. , Bhat Gita , Bowering Valerie , Garg Swati , Yokom Daniel , Cyriac Sunu Lazar , Butler Marcus O.
Published: May 2019

5580

Background: Immunomodulation through check point inhibition is an important treatment strategy in many cancers. In ovarian cancer (OC) response rates with immune checkpoint inhibitors (ICI) alone are around 10%. Chemotherapy antitumoural effect is driven by cytotoxicity and immunomodulatory effect. ICI treatment reduces tumour induced immune-tolerance improving immunocompetence, essential for chemotherapy effect. We chose to investigate clinical outcomes of chemotherapy post ICI in women with OC. Methods: The Tumor Immunotherapy Program (TIP) database at the Princess Margaret Cancer Centre identified patients with OC treated with chemotherapy after ICI from 2011 to 2018. Evaluation of clinical outcomes including response rate (RR), progression free survival (PFS) and overall survival (OS) was assessed for pre ICI, ICI and post ICI. Results: 40 women with OC were treated with chemotherapy after ICI. 90% had high grade serous histology, 7.5% carcinosarcoma and 2.5% low grade serous. Median number of pre ICI treatment lines was 3 (1-8) and 2 (1-6) in the post ICI setting. Median time of ICI initiation from diagnosis was 3 years. At ICI all patients had PS 0-1 and treated in clinical trials. 2% of the patients had platinum refractory disease, 88% had platinum resistant disease and 10% platinum sensitive disease. 50% were treated with ICI single agent, 16% were treated with ICI combined with chemotherapy, 14% ICI combo and 17% ICI in combination with other agents. Patients were treated for a median of 3 cycles (1-26). 8% experienced PR, 18% SD, no CR were seen. 67% of the patients discontinued treatment due to PD, 25% due to toxicity. Last treatment in pre ICI RR was 35%. First treatment in post ICI RR was 30%. RR for each treatment used in post ICI was 9% for liposomal doxorubicin, 25% for single agent platinum, 29% for weekly paclitaxel and 67% for chemotherapy with bevacizumab. Median PFS in the last pre ICI treatment was 6.5m and 5m in the first post ICI treatment. Median PFS and OS for all the population was 53m and 54m respectively. Conclusions: ICI are associated with modest activity in OC, planned clinical trials exploring systematic sequential therapy integrating ICI, targeted agents and chemotherapy are needed.
A phase II, open labeled, single-arm study of dose-dense paclitaxel plus carboplatin in advanced or recurrent uterine corpus cancer: KCOGG1303 study.
Authors: Hori Kensuke , Nishio Shin , Ushijima Kimio , Kasamatsu Yuka , Kondo Eiji , Takehara Kazuhiro , Kakubari Reisa , Ito Kimihiko
Published: May 2019

5584

Background: We studied the effectiveness and safety of dose-dense paclitaxel plus carboplatin in advanced or recurrent uterine corpus cancer. Methods: The patient eligibility criteria were women aged 20–75 years with histologically confirmed uterine corpus ; FIGO stage III who had residual tumors, FIGO stage IV, and recurrence after first-line radical treatment, or second-line chemotherapy or radiotherapy. They received paclitaxel (80 mg/m2, days 1, 8, 15) + carboplatin (area under the curve 5, day 1 every 3 weeks). The primary endpoint was the response rate (RR). The secondary endpoints were feasibility, progression-free survival, overall survival, and adverse effects. The threshold RR was set to 40%. The expected RR of this treatment was set to 60%; the number of necessary cases calculated with a type I error of 5% and power of 80% was 44. Considering the existence of dropped cases, we set the target number of cases in this study to 48. Results: Forty-eight patients were registered, and 45 were eligible to receive the treatment. The median age of the patients was 61 years (43–76). Twenty-two patients had recurrence; the others had primary advanced corpus cancer. On histology, there were 10 cases of serous carcinoma, 3 cases of endometrioid carcinoma G3, 2 cases of carcinosarcoma, and 2 cases of clear cell carcinoma. Twenty-eight patients (62%) could receive 6 or more cycles of chemotherapy. The RR (complete, 13 cases; partial, 20 cases) was 73.3% (60.7–86.0 95% confidence interval). Conclusions: Dose-dense paclitaxel plus carboplatin was safe and effective for advanced or recurrent uterine corpus cancer. Clinical trial information: R000019874 UMIN000017138.
Identifying a potential biomarker for anti-PD-1 immunotherapy in patients with advanced stage, surgically-resectable endometrial cancer.
Authors: Fuh Katherine Cynthia , Lomonosova Elena , Guo Lei , Fantl Wendy , Pachynski Russell Kent , Malkova Olga , Oh Stephen T. , Hagemann Andrea R. , McCourt Carolyn K. , Powell Matthew A. , Thaker Premal H.
Published: May 2019

5590

Background: The FDA approval of pembrolizumab for patients with MSI-H or dMMR tumors has led to the treatment of a select cohort of endometrial cancer (EC) patients. We sought to ascertain tumor immune modulatory effects in the front-line setting for advanced stage III/IV EC patients regardless of MSI-H or dMMR. The primary objective was to determine the safety of preoperative and maintenance pembrolizumab. The secondary objective was to examine pembrolizumab-induced changes in peripheral immune effector phenotype in order to identify potential biomarkers of clinical response. Methods: In an open label, single-arm Phase I trial, 8 EC patients were treated with 2 doses of preoperative pembrolizumab IV prior to surgery followed by chemotherapy and 4 doses of pembrolizumab IV. As an initial study, pre- and post-treatment (on the day of surgery) peripheral blood was collected from 3 patients as well as a healthy control and processed for high-dimensional single-cell mass cytometry (CyTOF) using an optimized antibody panel. Results: Six of 8 patients completed the treatment. One patient had rapid cancer progression and another had an exacerbation of comorbidities. Peripheral blood from 3 patients with pathological response were then immunoprofiled using CyTOF. Data analysis revealed that the frequencies of CD8+ T cells, B cells and CD56hiCD16- NK cells were lower, whereas the frequency of CD14+CD16-HLA-DRhi classical monocytes was higher in the cancer patients compared to controls. Cancer patients had lower frequencies of circulating CD4+ and CD8+ naïve T cells but higher frequencies of effector CD8+ and CD4+ T cells. Notably, the median expression of Granzyme B in CD8+ and CD4+ T cells was higher and median expression of signal regulatory protein (SIRP), CD172a-b on monocytes was lower for cancer patients compared to control. The frequencies of NK and myeloid cells expressing CD137(4-1BB), PD-1+NK cells, and PD-L1+DCs were greater in post-compared to pre-pembrolizumab. Conclusions: This is the first trial to evaluate the use of neoadjuvant pembrolizumab in advanced stage EC patients. Here, we present peripheral immune correlative data and show an increase in markers of activation in patients with pathologic responses to pembrolizumab. Additional data from this ongoing study will help us to identify candidate predictive biomarkers. Clinical trial information: NCT02630823.
Use of nivolumab as salvage therapy in heavily pretreated patients with gynecologic malignancies.
Authors: Williams Heather , Wang Jennifer , Tran Lynn , Mobley Sara , Rungruang Bunja Jane , Ghamande Sharad A.
Published: May 2019

5593

Background: There are limited effective treatments for gynecologic cancer patients who have been previously treated with multiple lines of chemotherapy. Immune checkpoint inhibitor (ICI) therapy has demonstrated significant activity in certain cancers but has been inconclusive in most gynecologic malignancies. The objective of this study was to determine the impact of salvage ICI therapy in heavily pretreated gynecologic oncology patients. Methods: An IRB approved retrospective study was performed of women with gynecologic cancer treated with nivolumab on a compassionate use program between October 2015 and January 2018. Patient demographics, disease characteristics, pathology and treatment history were collected. Survival probabilities were calculated. Results: Twenty-eight women were identified. Median age at start of treatment was 63 years with a median of 4 prior lines of chemotherapy. Median ECOG status was 2. Disease site was evenly distributed among uterus, ovary and cervix. 67.9% of patients completed 3 or more cycles of treatment. Median PFS of all patients was only 2.6 months however when comparing patients who received 2-3 cycles (n = 13) with those who received 4 or more (n = 9), median PFS was statistically significant 2.4 months vs 6.4 months (p = 0.0005). When looking at treatment response, 7 patients had partial response/stable disease after 3 cycles (25%). Median PFS of the 7 “responders” was 6.6 months vs 2.5 months of the non-responders (p < 0.001). Only 1 of 9 patients with uterine cancer had a disease response and that patient’s tumor was MSI high. Five patients had low grade serous ovarian cancer. Four of them had a treatment response with a median PFS of 6.1 months (range 3.8 – 25 months). Adverse events were experienced by 68% of patients; most commonly being fatigue (46.4%), arthralgia (25%), and anemia (21.4%). Only 1 patient experienced a grade 3-4 event (a diffuse maculopapular rash). Conclusions: In patients with heavily pretreated gynecologic malignancies with suboptimal performance status, immune checkpoint inhibitor therapy may prolong survival without significant toxicity. Also, there may be a role for ICI in patients with historically chemo resistant low grade serous ovarian cancers.
Screening for cancer-related distress among women with newly diagnosed breast cancer (BC).
Authors: Rynar Lauren Z. , Wendell Kristen B. , Mumby Patricia B. , Albain Kathy S. , Robinson Patricia A. , Mai Hanh P. , Grace-Louthen Cathy , Lo Shelly S.
Published: May 2019

567

Background: The Loyola University Chicago Cardinal Bernardin Cancer Center multidisciplinary Breast Oncology Center evaluates new patients (pts) for cancer-related distress using a needs-based screening tool, in accordance with Commission on Cancer (CoC) Standard 3.2. Identifying distress among newly diagnosed pre-surgical and pre-neoadjuvant pts allows for comprehensive treatment planning and establishment of a baseline for repeated assessments. Methods: Pts with newly diagnosed BC between May 2017 and June 2018 completed the “Patient Screening Questions for Supportive Care” (Coleman Supportive Oncology Collaborative, 2017), a consolidated screening tool based on validated instruments (NCCN Distress, PHQ-4, PROMIS), prior to initial provider visit. Cancer staging, demographics, and supportive oncology referrals were obtained from medical records. Descriptive statistics and chi-square were used. Results: 100 pts aged 30-94 (mean(SD) = 61.56(12.03)) completed the screening tool; 14.9% had Stage 0, 43.6% Stage I, 34.0% Stage II, 3.2% Stage III, and 4.3% Stage IV disease. 39% of pts screened positive for anxiety on the PHQ-4, and over 20% for depression. Anxiety was associated with cancer stage ( X2(df) = 12.20(4), p = .016). The most common practical concerns included living alone (19%), issues with work/school (16%), and paying for medical care (12%). Common physical concerns included difficulty with sleep (40%) and concentration/memory (17%), and tingling hands or feet (14%). Poor sleep was associated with depression ( X2(df) = 6.50(1), p = .011) and anxiety ( X2(df) = 7.17(1), p < .01). 57.7% reported at least "a little bit" of fatigue and 17.7% reported moderate to very severe pain. Nearly all pts wanted to better understand their diagnosis (87.8%), prognosis (87.8%), or treatment (91.8%). Conclusions: Pts with newly diagnosed, early stage BC experience high levels of physical and emotional distress at the earliest point in the treatment trajectory. This study captures BC patients at a unique time point and provides support for conducting routine screening for supportive oncology needs at initiation of care. Further studies should reassess needs sequentially to determine changes across the care continuum.
Biomarker analysis of PALLET: A neoadjuvant trial of letrozole (L) ± palbociclib (P).
Authors: Martins Vera , Kilburn Lucy , Dodson Andrew , Modi Arjun , Pogue-Geile Katherine L. , Rimawi Mothaffar F. , Huggins-Puhalla Shannon Leigh , Bartlett Cynthia Huang , Perry Sophie , Batten Leona , Osborne C. Kent , Jacobs Samuel A. , Johnston Stephen R. D. , Bliss Judith , Dowsett Mitchell ,   On behalf of the PALLET investigators
Published: May 2019

570

Background: PALLET randomized 307 postmenopausal women with ER+ primary breast cancer to one of 4 treatment groups (3:2:2:2 ratio): A: L for 14wks; B: L for 2wks then L+P to 14wks; C: P for 2wks then L+P to 14wks; D: L+P for 14wks. This allowed a randomized 1:2 comparison of L (Group A) vs L+P (Groups B+C+D) at 14wks. P was given 125mg/d PO (21 days on, 7 days off). Adding P to L markedly enhanced Ki67 suppression and Complete Cell Cycle Arrest (CCCA, Ki67 < 2.7%) by 14wks but did not substantially increase clinical response. We now report exploratory analysis of the association of baseline expression of 6 pre-specified biomarkers involved in estrogen and CDK4/6 signaling with CCCA at 14wks and changes in their expression during therapy. Methods: Estrogen receptor (ER), progesterone receptor (PgR), RB and CCNE1 were measured by IHC and CCND1 by IHC and FISH (CCND1/CEP11 ratio≥2.0 amplified). Baseline biomarker values were available with 14wk Ki67 values in up to 64 patients for L alone and up to 124 patients for L+P. Of these 59% and 90%, respectively, achieved CCCA. Results: With L alone CCCA was significantly less frequent (indicating relative resistance) with low baseline PgR (odds ratio [OR] 0.22, 95%CI 0.05-0.96, p = 0.04) or high CCNE1 levels (OR 10.39, 95%CI 1.19-90.48, p = 0.03). With L+P CCCA was also significantly less frequent with high CCNE1 (OR 50.34 95%CI 5.12-495.34, p = 0.001) or with low baseline ER (OR 0.21 95%CI 0.08-0.60, p = 0.004). CCCA was not significantly different with either treatment according to CCND1 amplification status or expression overall. However, CCCA showed a tendency to being less frequent in non-amplified cases with low baseline cyclin-D1 expression when treated with L+P (p = 0.10). There were no significant changes in ER levels or CCND1 amplification over 14wks. By 14 wks PgR, RB, CCND1 and CCNE1 levels were significantly suppressed by L or L+P (geomeans PgR: -96.4% vs -94.9%; CCND1: -79.9% vs -70.7%; CCNE1: -68.2% vs -74.7%; RB: -23.5% vs 26.1%, respectively) and there was no significant difference between the treatments. Conclusions: These data support low ER, possibly indicating limited luminal status, and high CCNE1 as markers of poor Ki67 response to L+P in primary disease and are consistent with findings in studies in advanced disease. Clinical trial information: NCT02296801.
Role of anthracyclines in neoadjuvant anti-HER2 regimens for HER2+ breast cancer (BC): A network meta-analysis (NMA).
Authors: Pelizzari Giacomo , Gerratana Lorenzo , Basile Debora , Bartoletti Michele , Lisanti Camilla , Garattini Silvio Ken , Bortot Lucia , Corvaja Carla , Buriolla Silvia , Curtolo Gianluca , Garutti Mattia , Di Nardo Paola , Torrisi Elena , Da Ros Lucia , Freschi Andrea , Saracchini Silvana , Bolzonello Silvia , Miolo Gianmaria , Spazzapan Simon , Puglisi Fabio
Published: May 2019

577

Background: It is matter of current debate which would be the best chemotherapy backbone of neoadjuvant HER2-targeted therapy for HER2+ BC. The TRAIN 2 trial showed no significant difference in terms of pathological complete response (pCR) when anthracyclines–based (CTA) or anthracyclines–free regimens (CT) were combined with dual HER2 blockade. However, it remains unclear how anthracyclines may influence the relative benefit across different anti-HER2 treatments. Methods: A systematic review was conducted which included all phase II/III randomized clinical trials (RCTs) comparing different neoadjuvant regimens for HER2+ BC. pCR (yT0/isN0) was the outcome of interest. Indirect comparisons of all combination of anti-HER2 agents with CTA or CT were estimated with a random-effects frequentist NMA. Estimated pCR rates were inferred adopting a Bayesian NMA. Results: 17 RCTs (3933 patients) were included. Overall, 8 arms were identified, comprising all possible combinations of CTA and CT with trastuzumab (H), lapatinib (L) and dual HER2 blockade (D) but also CTA and D only. Odds ratios (OR) for pCR and 95% confidence interval (CI) of selected NMA comparisons are shown in the table. Estimated rates of pCR for each treatment and 95% credible interval (CrI) are reported in the table. Conclusions: Through indirect comparisons, no significant pCR gain was found for CTA vs CT when combined to D, H and L. In particular, considering double vs single-agent anti-HER2 regimens, D-CT remains superior to H-CTA, supporting a possible omission of anthracyclines when dual anti-HER2 block is used. On the contrary, our pooled estimate suggests a more relevant role for anthracyclines when comparing H-CT/A vs CTA. Moreover, we estimated a 4% pCR gain for D-CTA vs D-CT, and an 8% higher pCR rate for H-CTA vs H-CT. [Table: see text]
Correlation between mutation landscape and clinical outcomes of neoadjuvant therapy in HER2-positive breast cancer patients.
Authors: Liao Ning , Wang Yulei , Li Kai , Chen Bo , Zhang Guo-Chun , Li XueRui , Guo Liping , Cao Li , Ren Chong-Yang , Wen Ling-Zhu , Jia Minghan , Li Cheukfai , Mok Hsiaopei , Chen Xiaoqing , Wei Guangnan , Lin Jiali , Hou Ting , Han-Zhang Han , Zhang Zhou , Liu Jing
Published: May 2019

579

Background: The standard management of early stage human epidermal growth factor receptor 2 (HER2) positive (+) breast cancer (BC) involves neoadjuvant therapy with combination of chemotherapy and HER2-targeted therapy followed by surgery. However, diverse pathologic responses were observed. We interrogated whether baseline genomic heterogeneity contributes to the varied therapeutic responses. Methods: Capture-based targeted sequencing using a panel consisting of 520 cancer-related genes, spanning 1.6MB of human genome, was performed on tissue biopsy samples, obtained prior to neoadjuvant therapy, of 33 HER2+ women with stage I-III BC. The median age of the cohort was 53. The correlation between genomic alterations and pathologic response were analyzed by multivariate analysis. Results: A majority of them was diagnosed with stage II (67%, 22/33), while 30% (10/33) had stage III and 3% (1/33) had stage I disease. 58% (19/33) were HR+ and 42% (14/33) were HR-. Mutation profiling of baseline samples revealed 349 mutations spanning 145 genes, with TP53, CDK12 and PIK3CA being the top 3 most frequently mutated genes. Neoadjuvant regimen was comprised of trastuzumab and HER2 inhibitor (i.e. pertuzumab or lapatinib). 15 patients used single HER2 inhibitor;18 used dual HER2 inhibitors. Endocrine therapy was also administered to HR+ patients (19/33) in combination with trastuzumab and HER2 inhibitor. Complete pathologic response (pCR) was observed in 45.5% (15/33) of patients. Interestingly, ROS1 copy number amplifications (CANs) were only identified in patients achieved pCR (p = 0.033). In contrast, missense mutations in PIK3CA and CNAs in CCND1, FGF19, FGF3, FGF4, SPOP, HNF1B and BRIP1 showed a trend of being less likely to mutate in pCR patients (p values between 0.05-0.1). Previous reports have suggested that pCR rates in HER2+ patients are associated with HR status. However, our data revealed comparable pathologic response of patients based on either HR status or neoadjuvant regimen. Conclusions: Our data revealed a distinct mutational profile between patients achieved pCR vs patients did not. Further studies with a larger cohort are required to confirm these findings.
Tumor immune microenvironment (TiME) changes by multiplex IF staining in a pilot study of neoadjuvant talazoparib for early-stage breast cancer patients with a BRCA mutation.
Authors: Hobbs Evthokia , Yang Fei , Kumar Tapsi , Contreras Alejandro , Parra Cuentas Edwin Roger , Garber Haven , Scoggins Marion , Adrada Beatriz E , Whitman Gary J , Arun Banu , Mittendorf Elizabeth A. , Litton Jennifer Keating
Published: May 2019

585

Background: We previously reported a median tumor volume loss of 88% (range 30-98%) in 13 patients with early stage BRCA1/2 mutant breast cancer treated on a neoadjuvant trial of the PARP inhibitor talazoparib. The effects of PARP inhibition on immune aspects of the TiME in early-stage breast cancer has not been well described. The goal of this study was to evaluate the TiME in pre and post-treatment core biopsies from enrolled patients. Methods: Eleven paired core biopsies were available for examination. Tumor infiltrating lymphocytes (TILs) were quantified by H&E stained slides by a central pathologist. Specimens were assessed by multiplex immunofluorescence (mIF) using a panel of 6 biomarkers (PD-1, PD-L1, CD3, CD8, CD68 and CK) with the Opal 7-color Kit in LEICA BOND auto stainer, Vectra automated quantitative pathology imaging system and inForm software (PerkinElmer). Results: In the analyzed core biopsies, there was an increase in TILs evaluated by H&E in post-treatment compared to baseline (mean 36 vs 11%). By mIF there was an increase in CD3+ T cell and CD3+CD8+ cytotoxic T cell density in post-treatment samples compared to baseline, summarized in table. PD-L1 expression in tumor cells was rare in the cohort. There was no difference in CD3+PD-1+ or CD3+CD8+ PD-1+ lymphocytes in pre and post-treatment specimens. There was also no differences in macrophages (CD68+). Evaluation of immune phenotype and imaging response will be presented in the final analysis. Conclusions: This is the first study phenotyping the immune response to neoadjuvant talazoparib in BRCA-mutant breast cancer patients. In this small cohort, intratumoral and stromal CD3+ T cells and CD3+CD8+ cytotoxic T cells increased after two months of talazoparib. Clinical trial information: NCT02282345. [Table: see text]
Evidence that neoadjuvant anthracycline based combination chemotherapy (NACT) in breast cancer (BC) induces phenotypical changes which guides the optimal adjuvant therapy.
Authors: Abdel-Fatah Tarek Mohamed Ahmed , Webb Rebekah , Li Ruizhe , Chen Xin , Giannotti Elisabetta , Auer Dorothee , Walker Jennifer , Moseley Paul M , Pockley A. Graham , Ball Graham , Ellis Ian O. , Rakhah Emad , Hodi Zsolt , Lee Andrew , Chan Arlene , Chan Stephen
Published: May 2019

590

Background: We hereby evaluated the histopathological and radiological alterations of tumor characteristics after receiving NACT and the clinical significance of the changes of adjuvant therapy based on these findings. Methods: A pathological assessment of tumor features including ER, PR, HER2 and proliferation markers (Ki67 and SPAG5) status in pre and post NACT tumors tissue have been centrally evaluated in two cohorts [Nottingham University Hospital (NUH; n=850) and Australian cohort (n=250 patients)]. Since 2013 any change in the ER and HER2 status from negative (-) [in the pre NACT biopsies] to positive (+) [in the post NACT surgical specimens] received additional adjuvant therapy (Endocrine therapy (ET) for ER+ and Trastuzumab for HER2+ cases) in NUH. MRI volumetric and texture changes have been assessed in 400 cases. The primary end point was disease free survival (DFS; median follow-up = 62 months). Results: 10% of pre NACT HER2- cases had been converted to post NACT HER2+ and those cases who subsequently received adjuvant Trastuzumab had achieved 92% 5-year DFS compared to those who remained HER- in post NACT specimens (58% 5-year DFS); (HR (95% CI)= 0.25 (0.08-0.80); p=0.016). While 13% of pre NACT HER2+ tumors were converted into HER2- in post NACT surgical specimens and had similar 5-year DFS to those who remained post NACT HER2+ (5-year DFS= 94% vs., 87%; p=0.613). Loss of PR in the residual disease of pre NACT ER+ BC was associated with shorter 5-year DFS after ET compared to those who remained post NACT PR+ (HR (95% CI)=2.1 (1.25-3.46); p=0.005). After NACT, 40% of pre NACT SPAG5+ cases were converted into post NACT SPAG5- and these patients had prolonged DFS compared to those who remained SPAG5+ in post NACT specimens (27%) [5-year DFS=84% vs 49%; (HR (95% CI)= 3.8 (2.1-6.9); p<0.0001). A prognostic model has been generated including factors in table (AUC = 0.854 (95% CI) = 0.777-.0.931; p= 0.00000001]. Conclusions: We hereby showed evidences a change of treatment strategy based on the changes in the tumor post NACT phenotype gives the optimal choice of treatment eg., the introduction of HER2 targeting therapy for the conversion of HER2– to HER2+ phenotype after NACT improved DFS. Multivariate Cox regression model for 5-year DFS. [Table: see text]
CALGB (Alliance) 40603: Long-term outcomes (LTOs) after neoadjuvant chemotherapy (NACT) +/- carboplatin (Cb) and bevacizumab (Bev) in triple-negative breast cancer (TNBC).
Authors: Sikov William M. , Polley Mei-Yin , Twohy Erin , Perou Charles M. , Singh Baljit , Berry Donald A. , Tolaney Sara M. , Somlo George , Port Elisa R. , Ma Cynthia X. , Kuzma Charles S. , Mamounas Eleftherios P. , Golshan Mehra , Bellon Jennifer Ruth , Collyar Deborah E. , Hahn Olwen Mary , Hudis Clifford A. , Winer Eric P. , Partridge Ann H. , Carey Lisa A.
Published: May 2019

591

Background: Both Cb and Bev demonstrate activity when combined with standard chemotherapy in TNBC. CALGB 40603 is a 2x2 randomized trial that previously demonstrated that adding Cb to NACT significantly increased pathologic complete responses in the breast/axilla (pCR), while adding Bev did not (Sikov, JCO 2015). Here we report 5-year LTOs and assess factors that influenced them. Methods: 443 patients with clinical stage II-III previously untreated TNBC received 12 weeks of paclitaxel (wP) +/- Cb then dose-dense AC, +/- Bev before surgery. The primary endpoint was pCR. Analyses of LTOs (event-free survival (EFS), distant recurrence-free interval (DRFI) and overall survival (OS)), impact of residual cancer burden and other variables were secondary. Results: Median follow-up was 5.7 years (y); 5y EFS was 70.9% (95% CI; 66.7%-75.4%), DRFI 76.3% (72.3%-80.5%) and OS 76.9% (72.9%-81.2%). Pretreatment clinical stage and achieving pCR correlated with LTOs, while age, race, subtype (basal-like vs. not) and tumor grade did not. Among pCR 5y EFS was 86.4% vs. 57.5% for non-pCR (HR 0.28, 0.19-0.43), OS was 88.7% vs 66.5% (HR = 0.28, 0.17-0.44). This relationship was similar in all trial arms. Any residual disease conferred poorer outcome; compared with pCR/Residual Cancer Burden (RCB) 0, EFS HRs were 2.29 (1.32-3.97), 3.01 (1.90-4.74), and 9.67 (5.66-16.51) for RCBI, II and III, respectively. There were no improvements in LTOs with Cb (EFS HR 0.99, 0.70-1.40) or Bev (EFS HR 0.91, 0.64-1.29). In an exploratory analysis, receipt of ≥11 doses of wP was associated with better EFS (HR 1.92, 1.33-2.77); this was particularly notable in Cb-treated arms. Conclusions: As expected, regardless of treatment arm pCR was associated with markedly better LTOs, and pts with any residual disease had significantly worse outcomes. The addition of Cb or Bev to standard NACT for TNBC did not improve LTOs in this trial, although it should be noted that the trial was not powered for this endpoint. Omission of chemotherapy doses may result in poorer outcomes, especially among Cb-treated pts, which may warrant further evaluation. Support: U10CA180821; U10CA180882; Genentech; https://acknowledgments.alliancefound.org ; NCT00861705 Clinical trial information: NCT00861705.
Preoperative checkpoint inhibition (CPI) and cryoablation (Cryo) in women with early-stage breast cancer (ESBC).
Authors: Comen Elizabeth Anne , Bryce Yolanda , Page David B. , Solomon Stephen Barnett , Rodine Micaela , Abaya Christina DiLauro , Morris Elizabeth Anne , Plitas George , El-Tamer Mahmoud , Gemignani Mary , Sclafani Lisa M. , Morrow Monica , Brogi Edi , Patil Sujata , Ho Teresa , Wong Phillip , Budhu Sadna , Merghoub Taha , Norton Larry , McArthur Heather L.
Published: May 2019

592

Background: Checkpoint inhibition (CPI) combined with local strategies that cause local tumor destruction, such as cryo may augment tumor specific immunity and improve survival. We previously demonstrated in 18 ESBC patients (pts) that pre-operative (pre-op) cryo with ipilimumab (ipi) is not only safe but also generates robust local and systemic immune responses (NCT01502592). Given the added activity of dual CPI in other tumors, we undertook a second pilot study of pre-op ipi/nivolumab (nivo)/cryo to confirm the safety of this combination and the impact on immune biomarkers. Methods: In both pilot studies, eligible pts had operable ≥1.5cm invasive HER2 negative ESBC. CPI was administered 8-15d prior to, and cryo was performed 7-10d prior to, standard-of-care (SOC) surgery. Toxicity evaluation continued for 12wks after drug administration. Blood for immune correlates was obtained at baseline, cryo, surgery and 2-4 weeks thereafter. Tumor samples were obtained at cryo and surgery. Flow-cytometry of peripheral lymphocytes was compared to previously reported ipi/cryo responses. Results: After a median follow-up of 66 months all 18 ESBC ipi/cryo pts, including 3 TNBC pts, are recurrence free. In the ipi/nivo/cryo study, the safety primary endpoint was met when 5 pts underwent SOC surgery without delay. Ipi/nivo/cryo was well tolerated overall. One pt on an aromatase inhibitor had grade 4 liver toxicity 8 weeks after surgery. One pt, 3 weeks after her SOC surgery, developed grade 1 hyperthyroidism, preventing a secondary axillary dissection from proceeding as scheduled. Robust activation of peripheral CD4+ and CD8+ T cells peaked at week 2 post ipi/nivo with the majority of activated CD8+ T cells expressing PD1. Comparing the correlatives of the ipi/nivo/cryo study with the prior ipi/cryo study, we observed higher expression of activation markers (Ki-67, ICOS, CTLA-4, LAG-3) on peripheral T cells and downregulation of suppressor cells. Conclusions: Ipi/cryo-treated pts, including 3 TNBC pts, remain recurrence free after > 5y. Combining cryo with ipi/nivo preop is feasible, safe, and associated with greater T cell activation than ipi/cryo alone. These results informed an ongoing randomized phase 2 study of pre-op ipi/nivo/cryo versus SOC in women with residual TNBC after neoadjuvant chemotherapy (NCT03546686). Clinical trial information: NCT02833233.
Checkpoint inhibitors assessment in oropharynx cancer (CIAO): Safety and interim results.
Authors: Ferrarotto Renata , Bell Diana , Rubin M. Laura , Lee J. Jack , Johnson Jason Michael , Goepfert Ryan , Phan Jack , Elamin Yasir , Myers Jeffrey , Hessel Amy Clark , Johnson Faye M. , Gillison Maura L. , Sikora Andrew G. , Glisson Bonnie S. , Gross Neil D.
Published: May 2019

6008

Background: Anti-PD-1/PD-L1 are active in metastatic oropharynx squamous cell carcinoma (OPC). Durvalumab (durva) and tremelimumab (tremi) target respectively PD-L1 and CTLA-4, which in combination may be synergistic. Here we report the safety and interim results of durva vs. durva+tremi prior to surgery in a window of opportunity trial in OPC. Methods: Pts were randomized 1:1 to durva 1500 mg or durva 1500 mg + tremi 75 mg IV Q4W x 2 cycles. The primary objective was to quantify pre- and post-treatment differences in CD8+ tumor infiltrating lymphocytes for the two arms. Secondary objectives included safety, toxicity, ORR by RECIST, fraction of patients undergoing surgery at 8 wks, and percentage viable tumor cells in the surgical specimen. Serial pre- and post-treatment blood and tumor specimens were collected for ongoing correlative analyses. Results: 28 pts enrolled: median age 64y, 27 (96%) male, 19 (68%) newly diagnosed, most (63%) at stage IVA (AJCC 7th Ed), 9 (32%) had locoregional recurrence, 24 (86%) p16 positive, and 22 (79%) had ≤ 10 PPY smoking history. Median follow-up was 7.6 months. The most common AEs were fatigue (36%), leukopenia/lymphopenia (25%), transaminitis (25%), and rash (21%). Grade 3 AEs occurred in 4 (14%) pts: 2 elevated lipase, 1 diarrhea, and 1 hepatitis, all were manageable. There were no grade >3 AEs. ORR was 43%: 50% had SD (including 29% tumor shrinkage in 1 pt). Treatment effect in the surgical specimen was observed in 19 (79%) of 24 evaluable pts; 2 pts had major pathologic response (≤ 10% viable tumor) at the primary site. Efficacy was equivalent in both arms. The 2 pts with PD and 1 pt with SD were switched to chemotherapy after durva +/- tremi before resection; interestingly, each achieved a pCR in the primary. Most pts (57%) didn’t receive radiotherapy after surgery. There was a statistically significant association between ORR and treatment effect (p=0.014). The median percentage of viable tumor in the primary was 37.5% in pts with PR, and 82.5% in SD (p=0.003). Conclusions: Durva +/- tremi prior to surgery was well tolerated in OPC pts. Activity is encouraging with treatment effect seen in 79% of pts. The primary endpoint and complete efficacy data will be presented. Clinical trial information: NCT03144778.
Genomic and transcriptomic landscape of oral pre-cancers (OPCs) and risk of oral cancer (OC).
Authors: William William Nassib , Lee Won-Chul , Lee J. Jack , Lin Heather Y. , Eterovic Agda Karina , El-Naggar Adel K. , Gillenwater Ann M. , Pisegna Marlese , Tong Pan , Li Lerong , Tian Xianjun , Tran Hai T. , Saintigny Pierre , Wang Jing , Papadimitrakopoulou Vassiliki , Lippman Scott Michael , Futreal Phillip Andrew , Heymach John , Zhang Jianjun
Published: May 2019

6009

Background: The molecular landscape of OPCs and its association with neoplastic progression is largely unknown. We report the results of high throughput DNA/RNA profiling of OPCs from pts in the Erlotinib Prevention of Oral Cancer trial (EPOC), with long-term prospective follow-up. Methods: We performed next generation sequencing of 201 cancer genes (MD Anderson T200 platform) in 170 OPCs from EPOC, and RNA profiling using HTG EdgeSeq Oncology Biomarker Panel containing 2,560 transcripts in a subset of 141 OPCs. 73 pts developed invasive OC during a median follow up of 7.3 years, from whom 23 paired OCs were profiled to characterize the evolutionary trajectory from OPCs to OCs. OPC molecular features were correlated with OC-free survival. Results were compared with TCGA invasive OC DNA/RNA profiles and an independent set of 86 OPCs with RNA data. Results: Similar to TCGA, C > T was the predominant substitution. The top mutated genes in OPCs were TP53 (29%), CDKN2A (15%), NOTCH1 (11%) and PIK3CA (7%), which were also frequently mutated (albeit at higher rates) in OCs from EPOC or TCGA. There was a progressive increase of tumor mutation burden (TMB, P < 0.05) and frequency of high-risk TP53 mutations (P = 0.02) from hyperplasia, to dysplasia, to invasive OCs (P < 0.05). Median TMB was higher in OPCs from pts who developed OC (2.45 mut/Mb) vs those who did not (1.22 mut/Mb) (P < 0.01). Pts with TP53 mutated OPCs had shorter OC-free survival compared to TP53 wild-type (HR 1.81, 95% CI 1.13-2.90, P = 0.01). A prognostic score was derived from a Cox regression model which identified 12 mRNA transcripts associated with OC risk (HR 4.72, 95% CI 2.51-8.86, P < 0.01), and which was validated in the independent set of 86 OPCs (HR 2.68, P < 0.01). This score was also associated with shorter overall survival when applied to invasive OCs from TCGA pts (HR 2.72, P < 0.01). Conclusions: This is the first large-scale cohort of OPC pts with long-term, prospective follow up and comprehensive RNA/DNA profiling. We demonstrated an association between TMB, TP53 mutations, a 12-gene RNA signature score in OPCs, and OC risk. This study may provide a framework for similar efforts of pre-cancer molecular profiling in the oral cavity and other sites, such as the PreCancer Atlas of the NCI.