Breast Cancer TRDG: Meetings and Minutes

Agenda:

The current status of translational research efforts at FCCC and Temple in the particular disease site including the status of Investigator-initiated trials and opportunities based on science and feasibility.
Opportunities for collaboration based on existing ongoing activities or through knowledge of developments in the field.
To exchange information regarding funding opportunities.
To consider multidisciplinary programmatic efforts that may be supported by P01s or SPOREs.
To discuss progress that is being made through more focused presentations by specific investigators or subgroups.
To take full advantage of institutional capabilities and resources in terms of genomics, tissues, CTO, and to integrate across programmatic efforts, basic or clinical research activities and tumor boards.
To bring in additional investigators including lab members/trainees involved in translational research.

The TRDGs strive to recognize and develop opportunities for collaborative translational research directions by providing a focused forum for exchange of information among a diverse group of stake-holders interested in a particular disease site. Before each meeting, depending on the particular expertise, participants are asked to review/be prepared to discuss the current disease site early phase investigational protocols at FCCC, the potential opportunities in industry with available targeted agents, potential collaborations with other institutions that have activated protocols with novel agents, specific molecular targets or signaling pathways for the disease site at FCCC, resistance mechanisms, potential biomarkers that can be incorporated into protocols, and the major open questions for the disease site or other more general questions in the field that could be addressed for the disease site.

10-21-16

Kathy Alpaugh spoke about “Utility of Circulating Tumor Cells to Follow Both Response to Therapy and/or to Detect Early Progression from Primary to Metastatic Disease. Presentation of Specific Cases and the Early Data from an Ongoing ECOG Trial.” There was description of the utility of CTCs in various cancer types. In metastatic breast or prostate cancer >5 CTCs/7.5 mL of peripheral blood is associated with a worse prognoses and in metatstatic CRC >3 CTCs/7.5 mL of blood is associated with a poor outcome. CTCs are highly predictive of metastatic disease and can be used to monitor response to therapy. It was noted that in the SWOG 0500 trial CTCs didn’t make any difference in switching therapy. It was mentioned that CTCs are more common in prostate than other tumors such as pancreas and CRC and don’t necessarily correlate with tumor burden. It was mentioned that GI CTCs are more fragile and that CTCs get into lymphatics on the way to blood. There was discussion of some specific cases as well as ongoing studies evaluating the impact of elevated CTCs in different clinical settings as they relate to patient outcomes. There was a discussion about potentially innovative directions with ctDNA and other measurements in blood that could inform about the status of a tumor or its therapy.
5-13-16

Jeff Peterson spoke about “Targeting Glutathione Addiction in TNBC.” There was an introduction about cancer metabolism as different from normal cell and tissue metabolism with efforts at Fox Chase Cancer Center to examine different breast cancer cell lines TNBC versus mammary epithelial cells. Dr. Peterson described that a subset of TNBC lines have an addiction to glutathione that may be exploited in breast cancer therapy. This work has been awarded a grant from the Pennsylvania Breast Cancer Coalition (https://www.foxchase.org/news/2015-12-21-peterson-PBCC-research-grant). Dr. Peterson described different TNBC subtypes and discussed the glutathione pathway and observed ferroptosis that can occur during its therapeutic targeting. He further described ferroptosis and the possibility of targeting vulnerabilities in TNBC. He described in vivo studies and directions including drug combinations. There was discussion about approaches to translate the preclinical findings including in the neoadjuvant setting versus as a therapy for advanced TNBC.
2-26-16

Elias Obeid spoke about “Immune predictors of response to PD-1 blockade with carboplatin in metastatic TNBC.” He gave an introduction about breast cancer emphasizing that the disease is heterogeneous with about 15% being triple negative breast cancer (TNBC). He previously worked with Dr. Olopade at U. Chicago as a clinical fellow and focused on the breast cancer tumor microenvironment. He has been interested in how the immune system might impact the TME and how therapeutic modulation might impact on breast cancer’s aggressive behavior. Dr. Obeid is interested in various components of the immune response including what their activities might be in different types of breast cancers. There was discussion of TNBC subtypes including the immune-modulatory subtype, and of stromal TILs associated with better outcomes of TNBCs treated by anthracycline-based chemotherapy. There was discussion of the phase 2 clinical trial design using Pembrolizumab/carboplatin/gemcitabine versus carboplatin/gemcitabine. He presented preclinical data with anti-PD1 and paclitaxel in a mouse model with 4T1 breast cancer. Dr. Obeid discussed SABCS 2015 data with atezolizumab plus nab-paclitaxel in a metastatic TNBC trial that showed ORR of 89% in 9 patients in first line with lower % ORR in second or third line. There was discussion about potential effects of chemotherapy in combination with immune checkpoint therapy although clinical data does seem to suggest antagonism but certainly an opportunity of further study. There was some discussion about ongoing activities at Fox Chase looking at immune markers from patients (Kerry Campbell) and mention of Matt Zibelman’s trial using IFN. In the TNBC trial, there is a 2:1 randomization for the Pembrolizumab arm and this trial includes pretreatment biopsy and second biopsy before cycle #3. The hypothesis for Dr. Obeid’s trial is that the combination therapy will stimulate local and systemic immune changes that may correlate with patient responses. There was some discussion about high costs of the immune and stromal analyses associated with the trials and some discussion of additional molecular correlates being examined by Dr. Obeid in the TNBC trial.
12-4-15

Marie Baumeister, an MD/PhD student in the El-Deiry Lab spoke about ONC201 and breast cancer. She mentioned that breast cancer is in need for novel targeted therapy and spoke about the TRAIL pathway and TRAIL as a target for cancer therapy. TRAIL is made by NK cells as well as tumor cells and is selective for killing transformed and tumor cells but not normal cells. She described the extrinsic and intrinsic pathways of cell death and that TRAIL has been in trials as have death receptor agonist antibodies. The majority of breast cancers are resistant to TRAIL but TNBC are sensitive. Clinical trial TBCRC 019, a phase II trial with paclitaxel plus tigatuzumab published in Clinical Cancer Research showed some prolonged responses with the combination versus paclitaxel alone in TNBC patients. She spoke about the discovery of TIC10/ONC201 as a TRAIL inducing compound published in Science Translational Medicine in 2013 and spoke about the range of anti-cancer activities and then focused on effects in breast cancer. She showed results in various breast cancer subtypes and showed some effects on breast cancer stem cells. There was discussion that it would be useful to evaluate combinations of ONC201 -/+ PARP inhibitors using breast cancer mammospheres. Various other research directions were discussed including plans for in vivo studies.
10-2-15

Matt Robinson spoke about antibodies in oncology and an interest in why some patients fail trastuzumab. ERBB3 represents an escape mechanism. ErbB3 partners with Her2 and so lapatinib can inhibit ErbB3 initially. Pertuzumab inhibits the partnering between Her2 and ErbB3. ErbB3 can confer resistance to cetuximab in Head & Neck cancer. Dr. Robinson described therapeutic antibodies targeting ERBB2/ERBB3 and a related trial MM111 and MM131 (with Crystal Denlinger). Activity was seen in gastric cancer. Trials stopped after phase II and were pre-pertuzumab. There was no patient selection based on tumor ligand levels. He has been working on mechanism and combinations with candidate therapeutic antibodies. He described other efforts using siRNA screening to understand resistance to trastuzumab with some promising hits that are being further evaluated.
6-15-15

There was a general discussion that breast and ovarian cancer were part of women’s cancer program and that historically at FCCC there was a formal breast cancer research program as part of the CCSG. Now breast cancer research is housed within several programs and spans the whole spectrum from prevention to survivorship, including behavioral research, genetics, survivorship. Xiaowei Chen spoke about intra-individual heterogeneity in breast cancer. Genome-wide allele specific expression to ID novel alleles including non-coding regions. He uses surgical samples to enrich and get ds-cDNA and gDNA for microarrays and applies the DASE technology looking at differential allele-specific expression and how this contributes to phenotypic variability and cancer risk. He has published several papers in this area of research. He discussed several examples of ongoing work. Dr. Goldstein mentioned an important clinical question which is to figure out who with DCIS will progress. Whether a test might predict and that might keep patients from going to surgery. LCIS patients usually don’t get preventive surgery and generally decline tamoxifen and so a predictive test might be helpful.
4-23-15

There was discussion of recent literature using PI3K inhibitor plus CDK4 inhibitor therapy in ER+ metastatic breast cancer. There was also some mention of recent immunotherapy results in melanoma with pembrolizumab plus ipilumumab. Dr. Edna Cukierman spoke about stroma results at AACR: normalize stroma stop alpha-SMAD, FAP, etc There was discussion of tumors that resist immunotherapy. Dr. Cukierman spoke about desmoplasia in general and with regard to breast cancer. Cancers are wounds that never heal. She discussed the WHFC triad: wound healing fibrosis cancer triad; with acute wound healing there is resolution but in chronic wounds there is fibrosis with mesenchymal components. In cancers investigators have generally focused on epithelial components but now the mesenchymal components are under study as well. Stromagenesis (aka desmoplasia) occurs during tumorigenesis and the components interact after basement membrane breakdown. The stroma can intermingle with the cancer and the cell types can be differentiated by marker expression. Early during tumorigenesis the stroma is repressive but the stroma evolves to an activated state that promotes tumor growth. Lineage tracing showed that EMT does not contribute to stroma but rather cells come from host or are bone marrow derived. Dr. Cukierman spoke about visualization of collagen with two photon showing changing appearance in the invasive front of a tumor. Dr. Cukierman gets normal and tumor tissue to create an in vivo 3D stroma system to study matrix effects with a goal is to renormalize the cells. She is using PDX models and spontaneous models. There was discussion about epigenetics and cytokines as impacting on the evolution of the stroma and about targeting TGF-beta. There was some discussion about making clinical correlations with stroma components. Dr. Neil Johnson spoke about BRCA1 mutation specific therapy resistance. BRCA1/2 mutation carriers have better Overall Survival than non-carriers. This is believed to be due to inefficient repair in the BRCA-deficient breast and ovarian tumors. Olaparib was approved in Dec 2014 with brief extension of survival. Dr. Johnson has been asking how do the BRCA1-mutant cancers become resistant to PARP inhibitors or cisplatin. Dr. Johnson described results that have been recently published (http://cancerres.aacrjournals.org/content/76/9/2778.abstract).
2-12-15

Dr. Lori Goldstein described an interest in molecular phenotyping. She has been collaborating with Dr. Elias Obeid on translational directions including immune checkpoint therapy. She mentioned 3 conceptss that were submitted. Dr. Goldstein is looking at TILs that are prognostic in TNBC and Her2+ tumors. She is collaborating with NYU and ECOG-ACRIN and Dr. Telli at Stanford on a neoadjuvant trial of PARP inhibitor plus chemotherapy; looked at TILs and showed they were prognostic in TNBC. Dr. Goldstein mentioned having productive meetings at the SABCS to develop collaborations. Genentech has a PD-1 inhibitor for clinical testing in the Her2+ space. She mentioned Raparixin, a stem cell inhibitor, completed phase II testing in combination with taxol in metastatic breast cancer that has been presented in abstract form. She mentioned interest in a neoadjuvant trial in the window of opportunity 21 days before surgery but said it is difficult to accrue to TNBC because patients often don’t want to wait 21 days with experimental agent alone. Dr. Goldstein is involved with cooperative group trials and mentoring investigators. She is interested in novel approaches using HDAC inhibitors for metastatic breast cancer and mTOR inhibitors in the adjuvant setting... Expand
She spoke about a homologous recombination assay that may not be so promising but suggested a need for such an assay that may be useful to incorporate as correlative in trials. She is interested in national effort for a BASKET trial like the lung cancer MAP trial and wants to get low mutation carriers and direct them towards specific drugs starting with TNBC. The MATCH is phase II based on pathways and crosses all diseases that is opening at Fox Chase. Dr. Goldstein mentioned that if a Fox Chase Cancer Center lab develops a test or an early phase agent and want to bring to phase II, she can help. Dr. Paul Cairns is interested in early detection and risk assessment and is involved as Fox Chase Cancer Center co-PI with EDRN. He mentioned he started years ago by working with Dr. Ed Sauter who provided nipple aspirated samples. There were breast tumor cells in the cytology slides and he found tumor specific methylation. He went on to do assays in plasma and serum although mentioned these still have technical difficulties and he has been working with tissue looking for markers of who may develop breast cancer. There was discussion about sample collection at surgery including several vials of blood that historically were sent to biorepository. There was discussion of CTCs and markers and their current use in breast cancer oncology. Dr. Goldstein mentioned that current use of CTCs in breast cancer patient care is limited because of a clinical trial that could not demonstrate impact on outcomes due to earlier detection of lack of response or disease progression versus later detection through CT scans. Dr. Richard Bleicher spoke about the OncoType Dx assay and when it is most helpful. There was discussion by Dr. Russo that at one time there was a plan at Fox Chase Cancer Center to do next gen sequencing on all breast cancer patients and it isn’t clear what happened to those plans although it was mentioned that outside companies were doing clinical testing of various tumor types using latest technologies. Dr. El-Deiry mentioned Guardant was Fox Chase today for preliminary discussions. This is a company started out of Stanford and is doing a panel of genes that are being sequenced from serum. Currently reports are being sent about actionable targets, drugs on NCCN compendium, off-label and clinical trials that are available. There was discussion that Nanostring can diagnose breast cancer subtypes and that Fox Chase is bringing in the technology and that it would be good for the group to learn more and think about uses in clinical studies. Dr. Elias Obeid spoke about his translational breast cancer research efforts. He mentioned that TNBC is heterogeneous and affects 15-20% of breast cancer patients. TNBC currently lacks effective targeted therapy. Outcomes are dependent on chemotherapy with median survival of one year. TNBC has 6 molecular sub-types determined from 587 TNBC’s that were profiled. Basal-like 1, basal-like 2, mesenchymal-like, immunomodulatory, mesenchymal stem-like and luminal AR with increased expression of certain genes. Dr. Obeid mentioned two types of breast cancer non-inflammed and inflamed per Gajewski, 2011 with macrophages and T-reg cells in the inflamed type. There is recent interest in what lymphocytes are doing in breast cancer. Loi et al., JCO, 2013 looked at degree of tumor infiltration with lymphocytes vs. outcomes. Lymphocyte predominant tumors did better than those not highly infiltrated by lymphocytes in terms of DFS or OS. Adams JCO 2014 looked at prognostic value of stromal TILs in TNBC and provided a validated data set. A German group looked at neoadjuvant therapy with standard chemotherapy -/+ additional carboplatin. TNBC patients who received carboplatin did better if they had more TILs prior to therapy. Patients with residual disease who also had TILs did better per another study Dr. Obeid mentioned as compared to patients with residual disease who did not have TILs. He mentioned mouse models using platinum + PD1 inhibitor showed better efficacy in TNBC tumors. Dr. Obeid described the rationale for trial of MK-3475 (pembrolizumab, humanized IgG4 anti-PD-1) in metastatic TNBC. It is not yet known if the immunomodulatory TNBC sub-group might be sensitive to such therapy. He spoke about T-cell exhaustion as a protective mechanism to protect vs. autoimmunity, but in cancer its blocks anti-tumor immunity. Pembrolizumab was recently approved for certain indications in melanoma and lung cancer. There are 3-4 different anti-PD1 antibodies including from BMS, Merck, Genentech, AstraZeneca. BMS has an anti-PD-L1 antibody. The Phase I/IB trial with Merck planned for FCCC uses Pembrolizumab in combination with carboplatin/gemcitabine. In phase I there will be a pre-treatment biopsy and as few as 6 patients will be included in phase I if no toxicity. Likely will also enroll lung and bladder so very few may have TNBC. In phase II there is a randomization to gemcitabine/carboplatin + PD-1 or placebo. Fox Chase Cancer Center is the lead site on the phase II study. Dr. Obeid spoke about the KEYNOTE-012 study that was led by Dr. Plimack at Fox Chase Cancer Center and included a TNBC cohort that he spoke about. Pembrolizumab was given as a single agent at 10 mg/kg Q 2 wks. A significant response rate was seen in KEYNOTE-012 that will be confirmed in the trial of pembrolizumab plus chemotherapy. Despite observed response rate, ~44% with TNBC had progressive disease in KEYNOTE. Dr. Obeid spoke about planned correlative studies with a grant submitted to AACR-BCRF. He described his hypothesis and aims looking at local and systemic immunity and correlations with clinical responses. He spoke in more details about the experimental plan for IHC looking for PD-L1 and TILs in pre-treatment biopsy as well as in the biopsy after 2 cycles. There were questions about cytokines, gene expression profiling and CTLA4 that were suggested as additional markers (some were already planned). He is collaborating with Dr. Kerry Campbell on circulating immune cells to be analyzed by flow cytometry and is collecting DNA to use in the future. He discussed details of immune cell markers analysis and is planning to make correlations between immune changes and clinical outcomes. Collapse
12-17-14

Dr. El-Deiry introduced the breast cancer TRDG, welcomed the attendees at the meeting and went over the standing Agenda that was circulated in the initial invitation and in the email with the schedule for the meeting. It was discussed that various meeting formats going forward would be used including the round-table as well as more focused presentations by individuals or sub-groups. It was discussed that the membership of the group will likely evolve over time and the attendees at this first meeting were asked to suggest participation by those who may be interested. The participants of the meeting discussed their translational directions. Dr. Neil Johnson joined Fox Chase Cancer Center in March of 2013. He is interested in BRCA1 germ-line mutations and is studying the protein product. Mutations are scattered throughout the gene thereby impacting on the type of product. BRCA1 carriers are more responsive to certain chemotherapy including PARP inhibitors. Dr. Johnson studies various domain-lacking proteins and how they function in the DNA damage response and is looking at response to therapy as well. He is interested in new combination therapies in drug resistance. Dr. Johnson works with human cell lines and has PARP inhibitor sensitive and resistant clones... Expand
He collaborates with Dr. Susan Domchek at U. Penn, and collaborates in making PDX models. He mentioned particular interest in the 185delAG mutation. Dr. Edna Cukierman is not working directly on breast cancer per se but has in the past. Now in collaboration, she has a manuscript with Dr. Massimo Cristofinilli. She is interested in the tumor microenvironment. She mentioned that the history of the 3D-culture approach started with breast cancer. She uses 3D culture models of the mesenchymal component and studies how the matrix forms and also does co-cultures. Does something similar to AQUA. Can do 6 colors simultaneously on one slide. She mentioned the Biorepository bought a Vectra System. She uses paraffin-embedded tissues and said the model is adaptable to the 96-well format. There is focus on biochemistry, biomechanics and proteomics. She has a few cell lines available that show desmoplasia. Some investigators are trying to build endothelial cells into models. She mentioned a prior IRB protocol for needle biopsies from pancreas from which 6 of 10 got positive fibroblast cultures. CAFs are very heterogeneous. There was discussion that analysis of exosomes is very much in fashion. Dr. Cathy Evers is head of breast imaging and does lots of biopsy procedures and is interested in collaborations that would be helped by providing tissue samples for basic research or clinical trials. She mentioned that patients tolerate these procedures well. She further discussed an interest in the role of MRI for pre-op patients who have dense breast tissue in terms of what is the best strategy to image and manage. She mentioned that she often does 8-10 procedures a day. Dr. Evers mentioned the Reparixin trial in the neoadjuvant setting for patients with breast cancer and the involvement of Dr. Lori Goldstein at FCCC (https://www.clinicaltrials.gov/ct2/show/NCT01861054). This study evaluates the effects of orally administered reparixin on CSCs in the primary tumor and the tumoral microenvironment in an early breast cancer population. The aim is to investigate if cancer stem cells (CSCs) and pathway markers decrease in two early breast cancer subgroups (ER+ and/or progesterone receptor positive/HER-2- and ER negative/progesterone receptor negative/HER‑2-) and to compare any differences between the two subgroups to try to better identify a target population. 20 patients will be enrolled to each subgroup at ten sites in the US. Reparixin is an inhibitor of CXCL8 receptor CXCR1 and CXCR2 activation. There was discussion about banking biopsies and the need for someone to get the consents. Dr. Jose Russo works on metastasis and prevention. He is interested in EMT and looking at epigenetic changes including the effects of HDAC inhibitors and demethylating agents in mice and whether it is possible to impact on metastasis in mice. He uses a model of tail vein injection. He mentioned working with Drs. Lori Goldstein & Jennifer Shi. In the area of prevention he is involved with a clinical trial in Belgium using high risk BRCA1/2 17-24 years treatment with HCG. Parous women have a signature with chromatin remodeling and now combining with HCG and planning a trial. He is also pursuing a 15 amino acid peptide 80-95 that binds HCG receptor and mentioned a dermal patch. Dr. Elizabeth Matthew is a Research Assistant Professor working with Dr. El-Deiry on circulating tumor cells in cancer of unknown primary. She mentioned experience with patient samples including from patients with breast cancer and various cell enrichment methods. She is interested in immunophenotyping breast cancer CTC samples and in directions that involve culture of such cells from the blood as well as biopsies, and if possible PDX models. There was some discussion about opportunities to analyze CTCs versus circulating tumor DNA. Dr. Elias Obeid came from U. Chicago where he worked on macrophages, Toll-like receptors in triple negative breast cancer. He has used a model of the interaction between inflammatory cells and tumor cells, a 2D model that is not yet published. He currently does clinical research and has an interest in cancer genetics. He mentioned a cohort of 218 patients with BRCA1 mutation in the last 20 years at FCCC but doesn’t know if we have tissue. He is involved with retrospective analyses. Dr. Obeid is also working in a prostate risk assessment program with 25 genes and looking to see if some can increase risk of breast cancer and will be collecting 1000 patients, 500 with no cancer and 500 patients with cancer some with no risk and others with risk. He is collaborating with colleagues at Jefferson, and Dr. Tim Rebbeck at Penn. He mentioned an interest in triple negative breast cancer and the tumor microenvironment. Along these lines, 3 proposals were submitted to Merck to study PD1 inhibitors and he and Dr. Goldstein recently got approval for phase 1/1b looking at MK3475 pembroluzumab anti-PD1. He mentioned that he has a role in a study with 27 patients 5 of whom had response. He is working to combine with chemotherapy and would like to move to phase II and is proposing correlative studies. There was discussion that there are TMAs through the biorepository. Dr. El-Deiry discussed prior work on BRCA1 regulation of p53 to direct DNA repair and growth arrest versus apoptotic responses, repression of the BRCA1 gene in the DNA damage response, models of BRCA1 deficiency. In particular he mentioned transformation of MCF10A with HRAS -/+ BRCA1 knockdown. With HRAS transformation, cells formed tumors in mice and exhibited features of the epithelial to mesenchymal transition. With BRCA1 knockdown in addition to HRAS, tumors were larger, more invasive, and had angiogenic features including increased VEGF expression. Dr. El-Deiry is working on analysis of BRCA1-deficient as well as TNBC tumors that have BRCAness to determine whether they have increased expression of VEGF. As avastin was not successful in breast cancer in general he believes may be in a sub-set it may be more useful. He mentioned an off-target effect of laptinib his lab described that involves upregulation of death receptor signaling and potential applications in TNBC where TRAIL receptor antibodies are in clinical trials. Finally he mentioned an interest in CTCs or circulating DNA as a way to get at resistance of tumor cells to therapy. There was discussion about possible translational directions given the recent finding in Nature (Ed Gunther at Penn State) regarding clonal cooperation in the genesis of breast cancer. This has not been demonstrated in human tumors and would seem to be important to do given implications for therapy. As such some effort could be directed at analysis of potentially cooperating pathways in human tumor specimens to see if there is compelling evidence in human tumors. Collapse

Agenda:

Share