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Breast Cancer TRDG: Meetings and Minutes

Agenda:

  1. 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.
  2. Opportunities for collaboration based on existing ongoing activities or through knowledge of developments in the field.
  3. To exchange information regarding funding opportunities.
  4. To consider multidisciplinary programmatic efforts that may be supported by P01s or SPOREs.
  5. To discuss progress that is being made through more focused presentations by specific investigators or subgroups.
  6. 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.
  7. 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

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

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