This post was written by three NICB cancer researchers: Neil Conlon, Alex Eustace & Denis Collins, with equal contributions from each
Texas is known for big cars, big hats and big steaks but for five days each year one particular corner of the Lone Star state is known for big research. The CTRC-AACR San Antonio Breast Cancer Symposium is in its 40th year and remains one of the premier global meetings for clinicians and scientists focussed on breast cancer research. Breaking clinical trial results and the latest scientific findings are presented to an international audience of around 7,500. After 40 years, the Symposium is a well-oiled machine, now with a helpful phone app to organise the talks you want to attend. The Henry B. González Convention Center buzzes with activity as medics, scientists, patient advocates and industry representatives move between talks from 8am to 7pm (and beyond) in auditoria that hold a thousand or more. Strong coffee and occasional food are the order of the day.[embedyt] https://www.youtube.com/watch?v=XVcvEk6xU2M[/embedyt]
Neil: My poster was titled “Targeting Src kinase blocks development of afatinib resistance in HER2-positive breast cancer”. An afatinib-resistant HER2-positive breast cancer cell line was produced and analysed for changes in key oncogenic pathways. Src kinase was shown to be activated in the afatinib-resistant cells and the cells were highly sensitive to the combination of afatinib and the Src inhibitor dasatinib. Interestingly, the combination of afatinib and dasatinib was not just effective in afatinib-resistant breast cancer cells, it also prevented the development of afatinib resistance in cancer cells that had never received afatinib treatment.
My SABCS highlight was related to HER2-positive breast cancer and new treatments for those patients whose cancers no longer respond to HER2-targeted therapy. Immunotherapies such as pembrolizumab have revolutionised the treatment of several cancer types, including melanoma, gastric, and lung cancer, and there has been particular interest in the potential of these drugs in treatment-resistant HER2-positive breast cancer. Pembrolizumab targets the protein PD-L1, which dampens the anti-cancer immune response and PD-L1 over-expression has been associated with resistance to HER2-targeted therapies such as trastuzumab in pre-clinical studies. The PANACEA phase I/II clinical trial examined the potential of trastuzumab and pembrolizumab in the treatment of trastuzumab-resistant HER2-positive breast cancer. The results of this trial were presented at the SABCS conference and showed that the combination of pembrolizumab and trastuzumab are safe, tolerable, and effective in a sub-population of patients. Patients that had PD-L1-positive cancers and/or had higher levels of immune cells infiltrating their tumours responded best to the drug combination. These results show that the combination of HER2-targeted therapies and immunotherapy may be effective for a sub-population in the treatment of HER2-positive breast cancers.
Alex: I am the research lead for Molecular Therapeutics for Cancer in Ireland and am funded by Cancer Clinical Research Trust. My highlight of the San Antonio Breast Cancer Symposium 2017 meeting was the talk given by Prof Dennis Slamon, from the UCLA Jonsson Comprehensive Cancer Centre, when he received the Susan G. Komen Brinker award for Scientific Distinction in clinical research. Prof Slamon has been a pioneer for the treatment of women with breast cancer. His discovery that over expression of the HER2 protein or amplification of the HER2 gene in breast cancer cells results in those cells being more aggressive and harder to treat, and became the distinguishing feature of HER2-positive breast cancer. During Prof Slamon’s talk he over-viewed how his lab experimentally confirmed HER2 over-expression in breast cancer cells and how they determined the impact of HER2 over-expression on how a cancer cell grew and responded to chemotherapy. Prof Slamon was also one of the first scientists to identify and test the humanised monoclonal antibody Herceptin in HER2 over-expressing breast cancer. His talk reviewed the advances in the treatment of women with HER2-positive breast cancer and how combining chemotherapy with Herceptin has led to over 90% of women with the disease responding to their therapy.[embedyt] https://www.youtube.com/watch?v=vsa7oTsYaEE[/embedyt]
Prof Slamons lab has also identified a novel treatment for women with oestrogen (ER) positive breast cancer which accounts for nearly 70% of all breast cancers. ER+ breast cancers are dependant on the cyclin dependant kinases which are required to allow the cancer cells divide. Prof Slamon took the CDK 4/6 inhibitor palbociclib (IBRANCE) which had not been previously shown to have any benefit in breast cancer, and demonstrated that ER+ breast cancer cells were sensitive to its treatment. His expansion of this work into clinical trials demonstrated its clinical use and its inclusion as a treatment for women with ER+ breast cancer has resulted in the improved survival of many women with this disease.
Overall Prof Slamons, talk demonstrated how work in his lab, has resulted in the dramatic improvement in survival of women with breast cancer, resulting in novel treatments for nearly 90% of all breast cancer patients. He is a truly deserving recipient of the Brinker award.
Dr. Denis Collins (shown above) is the Cancer Clinical Research Trust research fellow in Cancer Biotherapeutics at the NICB, Dublin City University. Dr. Collins was invited to present his work as a poster presentation at SABCS 2017.
Denis: The role of the immune response in breast cancer is my particular area of research and the symposium had a number of sessions on this topic. Dr. Robert Vonderheide from the University of Pennsylvania gave an excellent overview of experimental approaches that aim to create a robust immune response against breast cancer (Dec 5th, 2.45pm). Immune checkpoint inhibitors are a new type of chemotherapy that have proven effective in lung cancer and melanoma. Dr. Vonderheide explained how these checkpoint inhibitors work by re-activating “exhausted” white blood cells. Once re-activated, the ability of these white blood cells to kill cancer cells is restored. Clinical trials are underway to establish if immune checkpoint inhibitors can be effective in breast cancer.
Another approach presented is known as CAR T cell therapy where a patient’s own white blood cells are removed, programmed to target the cancer and injected back in to the patient. This type of therapy was approved for the treatment of certain types of blood cancer in 2017. Dr. Vonderheide’s group are pursuing trials of this strategy in breast cancer. Quoting Benjamin Franklin’s line “An ounce of prevention is better than a pound of cure”, Dr. Vonderheide also covered the potential for vaccines to prevent cancer developing or re-emerging. Anti-cancer vaccines have long been sought. Recent advances in knowledge of the immune response in breast cancer has renewed hope in this field.
A lot of focus is now on whether cancers are “hot” (lots of white blood cells around the cancer and good response to immune checkpoint inhibitors) or “cold” (no immune cells around the cancer and do not respond to immune checkpoint inhibitors). The challenge is to find a way to convert “cold” cancers to “hot” cancers. A set of poster presentations in this general area were summarised by Prof. Elizabeth Mittendorf, UT MD Anderson Cancer Center, Houston, TX and Dr. Justin Balko, Vanderbilt-Ingram Cancer Center, Nashville, TN, during the Spotlight on Immuno-oncology session (Dec 7th, 5pm). This session highlighted the range and depth of work going on in the field of immuno-oncology at present and was another highlight for me.
My own poster presentation was on December 8th at 5 pm. It covered two proteins, CXCL16 and CXCR6, as potential indicators of response to therapy in the HER2+ breast cancer subtype.** Samples from Irish breast cancer patients enrolled in the TCHL breast cancer clinical trial were used in the study†. For those not familiar, poster presentations involve a rather large poster (2m wide X 1 m high), a poster board (in this case one of ~190) and being ready to answer questions on any aspects of your work. Formats can vary but in San Antonio, presenters are allotted a two-hour window during which they must display and stand beside their poster. Symposium attendees are familiar with the work as summaries of each poster are provided beforehand and so many approaches come pre-loaded with (hopefully not too difficult) questions. It is an opportunity to showcase your work, get advice and build collaborations. Sometimes you luck out and end up beside the canapés….
After five days of intense knowledge intake and larger than average meals in the company of a sizable Irish contingent, it was time to leave the home of The Alamo and return to the NICB to generate results for next year’s symposium.
** “Tumor CXCL16/CXCR6 expression and soluble CXCL16 in HER2+ BC.” Collins DM et al. SABCS 2017.
† The TCHL clinical trial (ICORG 10-05) tested three different types of chemotherapy in breast cancer patients that had HER2+ disease. The trial was conducted in the neo-adjuvant setting (before surgery). 88 patients were enrolled and some of the patients elected to provide blood and tissue samples for laboratory experiments. The TCHL trial is complete but work on samples provided by the patients is ongoing in laboratories in Dublin City University, RCSI and University College Dublin.