The Breast Cancer Symposium Clinical Conversations series discusses some of the unanswered eQ&A questions posed by attendees of the 2015 Breast Cancer Symposium during panel discussions.

Julie Gralow, MD, of the University of Washington/Seattle Cancer Care Alliance, helped moderate a General Session during the 2015 Symposium on “Genomics and Personalized/Precision Medicine.” Other speakers included:

• Adrian V. Lee, PhD, University of Pittsburgh
• Daniel F. Hayes, MD, University of Michigan Comprehensive Cancer Center
• Nancy E. Davidson, MD, University of Pittsburgh Cancer Institute
• Anne Schott, MD, University of Michigan Comprehensive Cancer Center

Dr. Gralow and these speakers collaborated to answer some of the questions that did not get addressed during the panel discussion due to time limitations. ASCO Connection also spoke with Chief Medical Officer Richard L. Schilsky, MD, FASCO, regarding ASCO's first clinical trial. 

Should we be biopsying multiple metastatic sites?

JG: Ideally, yes, but it is usually not feasible as part of standard practice. In studies that have looked across the cancer spectrum by time and location—comparing the primary tumor to various metastatic sites—many of the distant sites show distinct clones with different genetic mutations and changes. Metastatic biopsies of multiple liver lymph node and lung metastases can show different kinds of genomic and molecular profiles.

Ongoing trials are trying to look at biopsying multiple sites. In clinical practice right now, it’s frequently not practical (or safe) to biopsy beyond one site. I think we will move toward trying to get as much information about the various sites of metastatic disease as possible. In my clinical practice, I try to always biopsy at least one metastatic site, primarily for estrogen receptor (ER) and HER2 testing. If I’m giving a therapy and the bulk of the tumor is responding, but there is an area of the tumor not responding or actually progressing, that is when I would suggest going after different sites. Also, rebiospy at the time of disease progression should be considered if we think the markers might have changed.

ND: Early data suggests that circulating cell-free DNA may someday help us sample multiple metastases simultaneously. While this is investigational at present, emerging technology may make it more practical.

AL: As Dr. Davidson mentioned, tumors shed DNA into the circulation and these can be detected in both blood and urine.  Research studies and early clinical studies suggest that detection of mutations in blood and/or urine may be a non-invasive method to monitor tumor burden and also identify targets for therapy—although more clinical work is required to determine the sensitivity and specificity of these assays and whether liquid biopsies are equivalent to, or any better than, current practice.

How should a molecular tumor board be structured? Who should be on it? What should it say about potentially actionable mutations? How should it report recommendations to physicians and patients?

JG: Clearly, a molecular tumor board needs a pathologist and a genomic or molecular scientist to help explain the findings. We generally have geneticists and ethicists on the committee because of the potential for finding inherited mutations and the need to then relay that information. A molecular tumor board also needs the input of oncologists and bioinformaticians to put the findings in perspective.

The primary goal of the tumor board is centered on the patient, with discussion about whether the information obtained from comprehensive genomic and molecular profiling can and should impact treatment recommendations. You need somebody who represents the clinical end of things to discuss whether mutations/findings are actionable, and what drugs are available, and the clinical research team to advise whether are there any trials available. It may be helpful to have patient advocates advise these tumor boards to help put this in perspective and ensure that the language that comes out of it is digestible, not just for the treating clinician but also for the patient.

We must be careful at this point that we don’t oversell the targeted therapies. In breast cancer, there are very few therapies that we’ve proven have identified targets, mutations, or variations with respect to benefit from treatment. Certainly drugs that target ER and HER2 have been available for a long time. We can find these receptors, however, through immunohistochemistry; we don’t need a costly and complex molecular profile to find the targets. Right now, we may find a PIK3CA mutation, for example, but that doesn’t necessarily tell us that we know this tumor is going to respond to a PI3 kinase inhibitor. Such targeting is certainly of interest but we need clinical trials to sort that out.

We saw very interesting results for palbociclib, the CDK4/6 inhibitor, that was FDA-approved in February in combination with letrozole for ER+ metastatic breast cancer. The trial that led to its initial approval had two parts. One part enrolled patients with ER+ cancers who were selected for molecular changes that we believed would make them more sensitive to a CDK4/6 inhibitor (CCND1 amplification and loss of p16). The other group consisted of patients who were ER+. We found through that trial that we did not better select those patients who would respond to a CDK4/6 inhibitor—both groups had equal benefit. We have to prove through trials that using molecular information will actually lead us to a therapy that is better than standard of care, and/or a population more likely to respond to a targeted therapy.

DH: It’s worthwhile to discuss the content of the molecular tumor board, which will depend on what type of assays have been performed. The type of somatic assays performed on the tumor will determine the required expertise of the molecular tumor board members. Is it comprehensive genomic (DNA) and/or transcriptomic (RNA), or is it a panel assay of commonly found abnormalities? If so, what? Just DNA mutations/copy number variations, or RNA and/or protein abnormalities as well? If total genomic germline DNA analysis has been performed, then the board needs to consider whether any germline abnormalities known to be associated with susceptibility to cancer, or any other disease, exist. There are many nuances to these discussions, especially regarding the levels of evidence that support application of the findings to either the patient’s, or their family’s, medical care. This discussion absolutely requires genetic counselors and experts in bioethics.

When reviewing somatic tumor assays there are basically 4 questions of interest.

1. Was an abnormality found that is known to be an important prognostic or predictive factor for that patient’s disease that was not previously identified in prior biopsies? For example, some breast cancers are HER2 negative but develop HER2 positivity in subsequent metastases, and if so, these patients should be treated with anti-HER2 therapies.
2. Was an abnormality found that is an eligibility criterion for an ongoing clinical trial at that institution, or otherwise? This is the point of the ongoing MATCH trial.
3. Was an abnormality found that is known to be a predictor of benefit from a targeted therapy in another disease, but not proven in the patient’s disease? For example, as Dr. Davidson discussed in her presentation in this session, a BRAF V600e mutation predicts benefit from vemurafenib in melanoma and non-small cell lung cancer, but not other cancer types.  This consideration is the basis of the TAPUR trial.
4. Was an abnormality found that is of biological interest and might raise new hypotheses, but is of no value for the care of the individual patient at present. For example, as discussed by Dr. Matthew Ellis in his Gianni Bonadonna Breast Cancer Award Lecture at the 2015 Breast Cancer Sympsium,  the observation of ESR1 mutations in ER+ metastatic breast cancer has resurrected the hypothesis that these mutations may result in absolute resistance to aromatase inhibitors, and relative, dose-dependent resistance to selective estrogen receptor modulators and downregulators.

Can you provide an overview of the SHIVA trial and explain the importance?

JG: This was a randomized trial of personalized cancer care versus physician’s choice that was published in Lancet Oncology in September and presented at the ASCO Annual Meeting in 2015. The trial was not just for breast cancer; it enrolled approximately 200 patients with any solid tumor that was metastatic and refractory to standard care. Patients were assigned to receive either targeted agents chosen on the basis of their cancer’s molecular profiling or physician’s choice of therapy.

For the group as a whole, progression-free survival (PFS) was not longer for the group that received targeted therapies versus physician’s choice. PFS was approximately 2.3 months versus 2.0 months—in both cases quite short. The SHIVA trial is important because it shows feasibility for conducting such trials, and is the first randomized trial reported in this era of massive growth of genomic profiles. It showed that we need to keep performing research in this area. The study authors concluded that these findings suggest that off-label use of molecularly targeted agents outside their indications should be discouraged, and enrollment into clinical trials encouraged.

Can you give brief overview of the ASCO-led TAPUR trial with initial sites, as well as the NCI-MATCH trial (both ongoing or about to start)?

JG: NCI-Molecular Analysis for Therapy Choice (NCI-MATCH) is a clinical trial that analyzes patients’ cancers to determine whether they contain genetic abnormalities for which a targeted drug exists and assigns treatment based on the abnormality. NCI-MATCH seeks to determine whether treating cancers according to their molecular abnormalities will result in tumor response.

The MATCH trial opened nationally for enrollment in August 2015 with 10 arms. Each arm enrolls patients with refractory advanced solid tumors and lymphomas to a different targeted class of therapy which is assigned based on the tumor’s profiling results. There is no randomization. The trial will add new treatments or drop treatments over time. It is anticipated that more than 20 drugs will ultimately be tested. Accrual to the screening component of MATCH was very rapid, and it has been suspended pending evaluation of the tumors that have already been submitted and determination of the number of “matches,” as per protocol. It is expected to re-open to accrual in a few months.

TAPUR is the first clinical trial conducted by ASCO. It is a pragmatically designed trial to test whether application of drugs already approved for use in one type of cancer might work in other types of cancers that contain the same genetic or phenotypic changes, but in which the drug has not been tested or approved. It is a basket trial for the study of “off-label” use of already approved drugs within a phase II context. Eligibility requires that the patient’s metastases have been tested using some sort of genomic assay (commercial or academic) within a CLIA-approved laboratory. The agents will be provided by the respective pharmaceutical companies for patients who participate.

RS: ASCO’s Targeted Agent and Profiling Utilization Registry (TAPUR) study is a non-randomized clinical trial that aims to describe the performance (both safety and efficacy) of commercially available, targeted anticancer drugs prescribed for treatment of patients with advanced cancer that has a potentially actionable genomic variant. The study will provide approved targeted therapies that are contributed to the program by collaborating pharmaceutical companies, catalogue the choice of genomic profiling test by clinical oncologists and learn about the utility of registry data to develop hypotheses for additional clinical trials.

In launching the TAPUR study, ASCO aims to collect “real-world” data on clinical outcomes to help learn additional uses of molecularly targeted cancer drugs outside of indications approved by the FDA. The prospective, non-randomized clinical trial will collect information on the antitumor activity and toxicity of commercially available, targeted cancer drugs in a range of cancer types, including any advanced solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma with a genomic variation known to be a drug target or to predict sensitivity to a drug.

ASCO is organizing TAPUR to expand the clinical trial options available for patients with cancer. TAPUR has similar aims to the NCI-MATCH trial, but there are important differences that make it complementary to MATCH and other genomically based trials. The TAPUR protocol is focused on capturing efficacy and safety data within the context of clinical care, so it will help us learn how clinical data can be used to expand our understanding of FDA-approved drugs. TAPUR has slightly broader patient eligibility criteria and will not require a new biopsy or new genomic testing. We are using data that is already captured in the course of clinical care and will rely on clinician judgement for determining genomic testing and therapy administration.

TAPUR is launching in three research networks (encompassing 29 research sites) in the first quarter of 2016. We plan to expand TAPUR nationally to additional sites later in 2016. TAPUR is using a secure, web-based platform for data collection. The initial sites are helping us pilot test the platform to ensure smooth operations. ASCO is collecting information on additional sites that are interested in being involved. The interested-site questionnaire is available on the TAPUR website.

Should we resect oligomets?

JG: Most patients with metastatic breast cancer have multiple diffuse sites of disease at the point when the recurrence is diagnosed. We therefore generally proceed with, and focus on, systemic therapy because it needs to circulate to all of the sites. In the oligometastatic subset of breast cancer, the visible metastatic disease is restricted to a few distinct sites.

Should we be aggressive about resecting or radiating at a local level in that situation? In colon cancer, locoregional treatment of isolated liver metastasis can result in cure. Even though breast cancer doesn’t usually present that way, it may be that 10% to 20% of patients with metastatic recurrence have disease that is focal and limited enough that this approach could be considered. The question is whether it will help improve survival and disease control if we are aggressive locally and not just treating systemically.

We need evidence from clinical trials to know what the right answer is. NRG BR002 is an ongoing trial of standard of care therapy with or without stereotactic radiotherapy and/or surgical ablation for newly oligometastatic breast cancer that will help answer this question.