CPMC’s 2016 Oncology Summit showcases the hospital’s leading cancer research expertise

California Pacific CURRENTS: The online journal of CPMC Research Institute

May 31, 2016

CPMC’s 2016 Oncology Summit showcases the hospital’s leading cancer research expertise

What are the latest advances in cancer research and patient care at California Pacific Medical Center? To understand this and more, over 200 cancer researchers, physicians and clinical research staff attended CPMC’s Oncology Summit this month in San Francisco. The congress was developed and coordinated by a planning committee that included Mohammed Kashani-Sabet, MD, Medical Director of CPMC’s Cancer Program, California Pacific Medical Center Research Institute (CPMCRI) Scientific Director Michael Rowbotham, MD, Paula Rowbury, and TJ Touran.

Topics ranged from immunotherapies to healthcare economics, precision medicine, and palliative care.

Review highlights of Oncology Summit presentations by CPMCRI investigators and leading national oncologists. 

The Melanoma Center of Excellence, and an Update on Melanoma Therapies

Kevin Kim, MD, Director of Melanoma Clinical Research for CPMC’s Center for Melanoma Research and Treatment, presented the latest advances in the management of melanoma and an overview of systemic therapy.

“As recent as five years ago, few options were available to treat our patients. But the advent of targeted and immunotherapies has greatly advanced our ability to improve survival outcomes,” said Dr. Kim, noting that progression-free and overall survival have improved with therapies targeting mutations in the BRAF and MEK pathways. 

But resistance to therapy is frequently observed within one year of treatment, despite high response rates with these newer agents. Dr. Kim explained that, to mitigate resistance, new studies are assessing the impact of combination therapy with BRAF and MEK inhibitors and other targeted therapy drugs (such as AKT inhibitors) or with checkpoint inhibitors.

Whereas targeted therapies are designed to selectively inhibit the growth and survival of cancer cells harboring genetic mutations, immunotherapy (sometimes with biologics) engages the body’s cellular defense mechanisms to fight the illness. Dr. Kim outlined the rationale behind new immunotherapies called checkpoint inhibitors such as ipilimumab, and novel PD-1 inhibitors such as nivolumab and pembrolizumab. 

“Checkpoint inhibitors block the effects of PD-1, acting as a brake on the immune system. Many tumor cells engage this brake by making the protein PD-L1, which binds to PD-1 on immune system cells. By blocking PD-1, the drugs release the brake and allow the immune system to function,” explained Dr. Kim.

He presented data from recent studies showing significantly improved progression-free survival in metastatic melanoma, with ipilimumab and nivolumab. Phase 3 studies have shown superior outcomes in previously untreated patients given nivo-ipi combination therapy, versus ipilimumab alone (e.g., Postow et al, NEJM 2015).    

“On the horizon, we may expect further studies supporting the proven survival benefit of these immunotherapies,” said Dr. Kim. “We are seeing durable disease responses and prolonged survival among the responders, potentially increasing cure rate. Ongoing studies will assess the role of combination immunotherapies as first-line treatment or as second-line after targeted therapy (for BRAF-mutated tumors).”   

Learn more about Dr. Kim’s research.

Treatment of Gynecologic Cancers: The Latest and Greatest

Approximately 100,000 Americans are diagnosed with gynecologic cancers every year. Ovarian cancer is especially challenging to diagnose and treat because most patients present with advanced disease in which the cancer has already spread to the upper abdomen or other organs.  For the majority of these patients, their cancer will recur and become chronic.

“Although the treatment can be complex, we are developing innovative approaches to care for patients with advanced ovarian and other gynecologic cancers that will significantly improve their chance of survival compared with standard chemotherapy regimens,” said John Chan, MD, Medical Director of CPMC’s Gynecologic Oncology Program and Gynecologic Oncology Lead for the Sutter West Bay Region.

Dr. Chan presented new advances in the treatment of cancers of the ovaries, cervix, and endometrium.

Focus on Ovarian Cancer

Approximately 21,000 Americans are diagnosed with ovarian cancer every year, and about 67% of them will eventually die from the illness.

Dr. Chan reviewed treatment options such as anti-angiogenic therapy with bevacizumab (combined with taxol/carboplatin); newer agents called PARP inhibitors as maintenance therapy; new regimens of taxanes given in smaller, more frequent doses; and novel approaches to administering chemotherapy, with intraperitoneal (IP) therapy.

In one of his published studies, Dr. Chan and researchers at leading cancer centers across the US under the Gynecologic Oncology Group provided 10-year data demonstrating long-term advantages of IP therapy over standard intravenous therapy. Their findings included new strategies for personalized treatments for selected patients.

Dr. Chan and colleagues investigated survival outcomes of 876 advanced ovarian cancer patients undergoing intraperitoneal versus intravenous chemotherapy, and evaluated prognostic factors predicting treatment success.

After an overall median follow-up of over 10 years, IP therapy was associated with a 23% decreased risk of death even after adjusting for age, performance status, cell type, tumor grade and residual disease. The risk of death decreased by 12% for each cycle of intraperitoneal chemotherapy completed.

“The long-term results of these trials are encouraging and show that overall survival endpoints can be achieved in advanced ovarian cancer,” says Dr. Chan. “Selecting patients who are more likely to benefit from therapy moves the field toward individualized approaches to treating cancers.”

Dr. Chan also presented a new approach to treating ovarian cancer that provides similar benefits with less toxicity compared to a standard taxane-based chemotherapy dosing regimen. He published findings earlier this year in The New England Journal of Medicine of an open-label, phase 3 randomized study of 692 women with newly diagnosed stage II-IV epithelial ovarian, fallopian tube, or primary peritoneal cancer who had received no prior treatment. Participants were prospectively stratified by whether they elected to receive bevacizumab, and then randomly allocated to receive either paclitaxel every three weeks plus carboplatin, or weekly paclitaxel plus carboplatin. The primary study endpoint was PFS.

After a median follow-up of 28 months, weekly paclitaxel did not significantly prolong PFS, over its administration every three weeks in the overall intent-to-treat group (14.7 versus 14 months respectively; p=0.18). Of those who did not receive bevacizumab (16% of the total group of patients), weekly paclitaxel was associated with an almost four-month improvement in PFS over giving the chemotherapy every three weeks (14.2 vs. 10.3 months; p=0.03). But in patients who received bevacizumab (85% of the study group), weekly paclitaxel did not prolong PFS over dosing every three weeks (14.9 vs. 14.7 months; p=0.6).

“We suspect that the dose of an anti-vascular drug such as paclitaxel may affect tumor vascular normalization: lower doses might improve drug delivery, while higher doses can impede drug delivery and increase metastasis,” said Dr. Chan. “Clearly, the dosing of taxanes including paclitaxel combined with biologic therapy warrants further investigation, including comparative effectiveness studies with consideration of cost.”

Other recent advances in gynecologic cancers research, screening and treatment:

  • The UK Collaborative Trial of Ovarian Cancer Screening showed that multimodal screening detects significantly more earlier stage ovarian/peritoneal cancers than no screening. However, there was a non-significant reduction in mortality, undetermined magnitude of benefit, and uncertainty of cost-effectiveness. 
  • The new hypothesis of ‘seed and soil’ may implicate the fallopian tubes in the development of ovarian cancer
  • Ovarian cancer treatment has advanced with the introduction of anti-angiogenic therapies such as bevacizumab (e.g., AURELIA study) and PARP inhibitors
  • Genetic testing and risk-reducing surgeries may lower the incidence of ovarian cancer
  • As the use of vaccines targeting HPV increases, the incidence of cervical cancer is decreasing
  • Cervical cancer incidence and mortality is increasing, but advances in robotic and minimally invasive surgeries have improved patients’ quality of life   

CPMC's Gynecologic Cancer Program offers patients upwards of 18 clinical studies led by Dr. Chan. The number of gyn-onc studies exceeds those at peer medical centers and greatly increases treatment options for women with these cancers.

Learn more about Dr. Chan’s research.

Novel Therapeutic Approaches for Brain and Spinal Tumors

Approximately 23,000 Americans are diagnosed with a primary brain and other nervous system tumor every year, and almost 60% of them will eventually die from the illness.

Lewis Leng, MD, a leading CPMC neurosurgeon, presented novel therapeutic approaches for treating brain and spinal tumors. He discussed the application and role of new therapies including endoscopic skull base and intraventricular surgery, fluorescence aided surgery, and minimally invasive spine surgery.

“These techniques—which have arisen thanks to advances in high-definition endoscopes, fluorescent compounds and fluorescence-enabled microscopes, and GPS-like intraoperative navigation—allow surgeons to treat tumors more effectively, safer, and less invasively,” said Dr. Leng.

He discussed a landmark study by Stummer et al (Lancet Oncology 2006) which demonstrated improved extent of resection and survival for patients with glioblastomas (GBMs), a deadly malignant tumor, using fluorescence-guided surgery. Dr. Leng cited research by Coburger et al (PLOS ONE 2015) that showed a synergistic benefit of 5-ALA fluorescence guided surgery with intraoperative MRI compared with intraoperative MRI alone.

Improvements in surgical techniques have also advanced the treatment of spinal tumors, especially as an adjunct to radiation therapy. Dr. Leng summarized a landmark study by Patchell et al (Lancet 2005) of direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer.

In the randomized, multi-center, non-blinded trial, patients with spinal cord compression caused by metastatic cancer were randomized to either surgery followed by radiotherapy, or radiotherapy alone. The primary endpoint was the ability to walk.

“Direct decompressive surgery plus postoperative radiotherapy was shown to be superior to treatment with radiotherapy alone for patients with spinal cord compression caused by metastatic cancer,” said Dr. Leng. “Significantly more patients in the surgery group regained the ability to walk than patients in the radiation group.  Dr. Leng discussed critical research by Laufer et al (Journal of Neurosurgery: Spine 2013) that demonstrated the effectiveness of ‘separation surgery’ for the treatment of metastatic spine tumors.

The approach stresses the adjunctive role of surgery in enabling patients to undergo more effective high-dose stereotactic radiation therapy treatments for the control of metastatic spine tumors.  At CPMC, “we are using this approach along with innovative minimally invasive surgical techniques to enable faster recovery and transition to the next stages of treatment for our patients,” said Dr. Leng.

Dr. Leng summarized additional innovative therapies including MRI-guided laser thermal therapy, tumor treating fields, and immunotherapy.  He discussed a recent groundbreaking study by Stupp et al (JAMA 2015) of combined tumor treating fields with standard-of-care chemotherapy and radiation therapy. Results showed improved overall and progression-free survival for patients with primary GBM. Tumor treating fields use low-dose alternating electric fields to slow tumor growth without causing any significant side effects.

Learn more about Dr. Leng’s research.

Lung Cancer Screening and Lung Nodule Evaluation

Lung Cancer Screening and Lung Nodule Evaluation Lung cancer is the leading cause of cancer-related deaths in the US. Non-small cell lung cancer (NSCLC) is the most common type of the disease and accounts for 85% of lung cancer cases, with the majority being adenocarcinomas.

If detected when the cancer is still localized, the five-year survival rate is 54%. However, only 15% of cases are diagnosed at an early stage; most patients present with advanced disease in which the cancer has already spread to the lymph nodes and/or metastasized to the other lung and distant sites.

“Increasing evidence points to the value of low-dose radiation CT (computerized tomography) scans to help detect lung cancer early, when it’s more treatable,” said Tze-Ming Benson Chen, MD, a pulmonologist who leads CPMC’s new Lung Cancer Screening Program. “Even when patients have stopped smoking, their risk remains elevated decades later. Without screening, lung cancer is usually detected when already at advanced stages.”

Studies have shown that CT scans are more effective than chest X-rays in detecting lung cancers, especially early stage cancers that are more treatable. With low-dose CT scans, even the smallest nodules are easily detected, as shown in the National Lung Screening Trial of over 50,000 adult patients with a history of smoking (New England Journal of Medicine 2011).

“The NLST demonstrated that low-dose CT imaging increased detection of lung cancer, and decreased lung cancer-related mortality by 20%,” said Dr. Chen. “Low-dose CT is an effective screening tool for people at high risk for lung cancer, however the technique is associated with a high rate of false positives and exposes patients to potentially harmful levels of radiation.” Dr. Chen suggested that additional risk assessment models such as the Swensen model, Lung RADS, and Fleischner Society Recommendations for detecting small nodules may be especially helpful.

Dr. Chen presented additional examples of advances in the diagnosis and treatment of lung cancer. These include improvements in therapy provided by stereotactic radiation therapy, biomarker-based therapies that target mutations in the ALK and EGFR pathways, and less invasive diagnostic tools.

His team is well known for their expertise in the use of endobronchial ultrasound (EBUS) and electromagnetic navigational bronchoscopy, tools used to assist in staging lung cancer and diagnosing lung nodules, respectively.

“EBUS and endoscopic ultrasound (EUS) have revolutionized the management of lung cancer by providing real-time images of mediastinal and hilar lymph nodes permitting accurate minimally invasive non-surgical biopsy of these lesions to determine whether cancer has spread to these areas,” said Dr. Chen.

Learn more about Dr. Chen’s research and the Lung Cancer Screening Program.

Precision Medicine and CPMCRI’s Cancer Avatar Project
CPMCRI Senior Scientist Liliana Soroceanu, MD, PhD, introduced the Cancer Avatar Project and the use of patient-derived xenografts (PDXs) or tumor tissues to better predict response to cancer therapies. PDX models are mouse avatars. When transplanted from a human patient with cancer into an immunodeficient mouse, tumors retain the characteristics of the original specimen and provide an unlimited resource for genetic and drug testing. PDX models can also be used to generate patient-derived cell (PDC) cultures for high-throughput drug screening.

“Using a living biology approach, the goal of the project is to provide rapid and comprehensive molecular and functional analyses. We aim to enable oncologists to make more accurate predictions of response to available treatment options,” said Dr. Soroceanu.

She explained that CPMC/Sutter is ideally positioned to lead advances in cancer precision medicine through the avatar project. “Sutter has as many new cancer cases each year as UCSF and Stanford combined. The patients, physicians and infrastructure are in place at CPMC to advance this growing area of research. We anticipate the Cancer Avatar Project will enhance clinical care, attract and retain patients, and foster sustainability of Sutter’s biobank and precision medicine translational research efforts,” said Dr. Soroceanu.

The goal is to create a repository with over 100 fully evaluated examples of each of eight poor prognosis cancers (melanoma, and cancers of the breast, colorectum, pancreas, brain, lung, ovary, and liver). Each case will have genomic analyses, conventional biomarker testing, mouse avatars and related cell cultures (including circulating tumor cells and cell free DNA), and pharmacologic testing of available treatment options. Blood, tissue specimens, and avatar-derived materials will be biobanked.

“We will develop validated prediction tools through an integrative bioinformatics-driven approach,” said Dr. Soroceanu. She noted this will comprise a comprehensive list of drugs to test in each cancer (single and multi-drug combinations) plus relevant drug target concentration ranges for humans. An initial platform to enable high-throughput screening has been created and validated, as well as a drug response scoring system. 

“By integrating pharmacological scoring data with genomics/proteomics data, we aim to refine the predictive value of the PDXs and provide screening results to oncologists in time for new treatment decisions to be made,” said Dr. Soroceanu. Foundation Medicine reports will be used to refine Cancer Avatar Project screens and when meeting with CPMC/Sutter oncologists and surgeons at tumor board meetings.

Learn more about Dr. Soroceanu’s research.

Senior Scientist Greg Tranah, PhD, presented methods for linking cellular and molecular ‘omics’ data (e.g., genomics, transciptomics, proteomics, metabolomics) with clinical information to drive the discovery of novel cancer targets and personalized treatments.

“Precision medicine is the research that leads to new strategies for identifying who will experience disease progression and what interventions work best for an individual,” said Dr. Tranah.

He explained that the Cancer Avatar Project sequencing pipeline is being used to identify genetic mutations (i.e., point mutations, insertions/deletions, copy number variations) underlying cancer progression. Identification is followed by annotation, interpretation, and the generation of clinical reports that can be used to help guide treatment decisions.

“With this project, our aim is to move past the ‘single mutation, single treatment’ model toward a better understanding of genomic complexity and the combinations of mutations that drive cancers. This approach will enable the discovery of new diagnostics, and targeted, pathway-based interventions,” said Dr. Tranah.  Each patient participating in the CPMC Cancer Precision Medicine program will undergo tumor genomic profiling (i.e., sequencing of DNA and RNA samples) and biomarker analysis, using the Foundation Medicine DNA sequencing platform that identifies genetic alterations in cancer-related genes. The test utilizes next-generation sequencing to identify alterations in all genes known to be somatically altered in human solid tumor cancers.             

“We will analyze the raw DNA sequence data produced via Foundation Medicine tumor profiling and use bioinformatics to create an integrated system. This will include relevant data and tools to analyze and translate a wealth of diverse molecular and clinical data,” said Dr. Tranah. He noted that the Cancer Avatar Project team is already advancing the science of gene expression in numerous cancers and is at the forefront of developing novel drug targets and treatments. Integrating these large genomic and clinical data sets requires massive computing and data storage capabilities.

“The Cancer Avatar Project will leverage informatics and computer science to maximize analysis of the complex datasets that this research will produce,” said Dr. Tranah.

Learn more about Dr. Tranah’s research.

Genomics: Know More than Your Patient
Edmund Tai, MD, a medical oncologist and hematologist at Sutter’s Mountain View Center, discussed risk assessment for cancer and the rapid advances in genetic testing.

“The advent of next-generation sequencing enables widespread availability of germ-line testing,” said Dr. Tai. “But recreational genomics may present more challenges than benefits,” he said, alluding to new areas of concern:

  • Many direct-to-consumer genetic tests only assess single-nucleotide polymorphisms (SNPs), not the whole genome; and not all single-nucleotide changes are SNPs.
  • There are substantial ‘variants of unknown significance’ (VUS) that cannot be acted upon. “Whole genome sequencing is not the best strategy. The more we test, the more VUS we will find,” said Dr. Tai.  “These VUS are mutations that are not common enough for us to classify as benign or pathologic. Some people interpret them as positive when in fact there is no evidence to support that.”
  • There are no federal standards on how tests are conducted, and various companies’ tests yield vastly different results
  • ‘Too much information’ forces physicians to work up things that may not matter

Dr. Tai emphasized the need to consider genetic mutation penetrance versus frequency, where genetic mutations are common and a small number are critical to the development of cancer. “This will govern decisions around prophylactic surgery, for example in cases of ‘actionable mutations’ in women with BRCA1/2 mutations at risk of breast cancer. In addition, some drugs are now the standard-of-care for some hereditary cancers, such as olaparib in BRCA-positive ovarian cancer.”

Multigene panels represent the future of cancer testing, and many are specific to cancers of the breast (BreastNext test), colon (ColonNext test), ovary and uterus (GynPlus test) and pancreas (PancNext test).

Dr. Tai encouraged physicians to refer patients to the Genetics Home Reference website for more information on understanding genetic conditions and hereditary cancers.

Other Highlights:

  • Michael Abel, MD, discussed critical components and a framework for developing CPMC’s Colorectal Cancer Center of Excellence (COE). “Our Center emphasizes clinical quality and comprehensive services, which result in excellent surgical outcomes. We offer a patient-focused approach while adhering to nationally recognized evidence-based guidelines,” said Dr. Abel. He discussed strengths of the COE model such as regular tumor board meetings, and close integration with CPMC’s clinical research and trials.
  • John Rabkin, MD, gave an update on surgical approaches for pancreatic cancer and presented a model of superior care that will be offered by CPMC’s Pancreatic Cancer Center of Excellence. This COE is being developed and led by Robert Osorio, MD. Learn more about the program in the 2015 Cancer Program Annual Report.
  • Ravi Salgia, MD, discussed the molecular and genetic drivers of lung cancer and new data on immunotherapies and targeted lung cancer therapies. He presented a ‘mindmap’ concept to visualize the molecular abnormalities of lung cancer and a fractal geometric approach to understand the progression of disease. Studies suggest more than half of NSCLC cases are linked to one of at least 10 known molecular biomarkers, which identify genetic mutations driving the disease. Some of these biomarkers can be treated with approved or investigational therapies that target specific oncogenic pathways.
  • Steven Hao, MD, discussed health policy, and the impact of the evolving healthcare market on physician reimbursement and incentives. ‘Back to the healthcare future’ envisions evolving trends in healthcare technologies and telemedicine to help solve healthcare challenges.
  • Bertrand Tuan, MD, presented strategies for evaluating geriatric cancer patients and discussed challenges in geriatric cancer care. By 2030, 50% of cancer patients in the US will be older than age 65. Investigating new cancer therapies in the elderly is difficult because this patient group is under-represented in cancer clinical trials and age-related organ dysfunction precludes enrollment.  Dr. Tuan offered treatment considerations for adjuvant and metastatic treatment for older cancer patients.

RELATED RESOURCES:

Review the 2015 Cancer Program Annual Report.

Find cancer clinical trials at CPMC.

Subscribe to our CPMC Cancer Clinical Trials E-newsletters for monthly updates on research and clinical studies.