		Elaine R. Mardis, PhD, discusses genomic insights into resistance mechanisms in endocrine therapy.

	Although breast cancer is among the best-characterized tumor types, continuing efforts to refine the sequencing of the human genome are opening the door to a new treatment paradigm in which oncologists will have swift access to a wealth of information that will enable more personalized therapy for patients at earlier stages of disease.

	It is a vision of the future that Elaine R. Mardis, PhD, a speaker at the 11th International Congress on the Future of Breast Cancer, not only anticipates but also helps to create.

	Mardis is co-director of the Genome Institute, director of Technology Development, and professor of Genetics and Molecular Microbiology at Washington University School of Medicine in St. Louis, Missouri. The institute is among three large-scale sequencing centers that the National Institutes of Health has enlisted nationwide to join in developing The Cancer Genome Atlas.

	One of the institute’s endeavors is to help build a database of human reference genome sequences, a more complete library of information than the initial Human Genome Project generated, which can be used to develop targeted therapies and as a comparison point for an individual patient’s genomic signature.

	While that work continues, new sequencing technologies now in development are enabling researchers “to anticipate assembling that person’s genome as opposed to aligning it back to the human reference,” thus expanding their ability to understand what is happening with the patient’s chromosomes, said Mardis.

	“It’s a brave new world out there right now, and I’m personally very excited about it because I love the technology aspects—it’s really powerful to see what the technology is going to be able to do,” she said.

	In this interview, Mardis discussed clinical applications of genomic research on the near horizon.

, “Whole-Genome Analysis Informs Breast Cancer Response to Aromatase Inhibition”

is one of the first genomic studies to demonstrate how this research can be applied in the clinical setting. You found 18 significantly mutated genes in the tumor samples. What is the clinical significance of this research?

 I was honored to recently have a publication in 

 with a large number of collaborators that studied sequencing samples from a clinical trial of aromatase inhibitors. Our overarching goal in this study was to begin to characterize the genomes of patients who were known, by virtue of the clinical trial parameters, to respond to the aromatase inhibitors compared with those who did not respond.

	In essence, what we wanted to identify in these data were signatures from the genome that will help us predict which patients will or will not respond to aromatase inhibitors so that we can be more intelligent about our choices in deciding which patients to assign to this therapy versus other types of therapy (eg, surgery, chemoradiation, or other new targeted therapies).

	We performed whole-genome sequencing of patients who were about equally stratified between those who did and did not respond based on a fundamental immunohistochemistry marker of Ki67, which provides a metric of tumor cell proliferation.

	Some of the outcomes of this study, which focused on estrogen receptor-positive tumors, included new insights into genes that were not previously known to be commonly mutated in luminal-type cancers. In particular, we identified five new genes historically thought to be only involved in hematopoietic malignancies that were clearly highly mutated, and were contributing to the disease onset or were “drivers” of the disease. This was an important finding in terms of what we typically refer to as significantly mutated genes. These significantly mutated genes are genes that, by a variety of mathematical tests, are more commonly mutated than would be typically expected.

	We also found that patients with TP53 mutation, high proliferation by Ki67, and luminal B-type tumors were the least likely patients to respond to aromatase inhibitors. By comparison, a new gene that was also identified in our study, 

, is commonly mutated in patients with luminal A-type tumors and a lower Ki67 proliferation index, and these were the patients who most commonly responded to the aromatase inhibitor therapy.

	So, in essence, what we have from this study is the very beginning of a genomic signature that’s combined with conventional pathology markers, such as Ki67 and RNA subtyping, to identify the specific intrinsic subtype of the breast tumor, and to identify patients who are likely to respond before they’re assigned to aromatase inhibitor therapy.

Please discuss the so-called “druggable targets” you found through sequencing these tumors, and the implications in identifying agents that are FDA-approved for other indications.

	We did an interesting exercise in the Nature paper that showed that for the mutational spectrum for the breast cancers we sequenced, there are many other drugs (typically small-molecule inhibitors) to which these patients were likely to respond. This raises the specter of targeted therapy in the context of breast cancer care, which is a very important consideration to have on the table.

	But what was also offered by this exercise was the fact that many of the drugs that were suggested by these patients’ genomes are not FDA-approved for a breast cancer indication. This suggests that there will be fundamental changes needed in the context of how the FDA uses clinical trial information to approve drugs for therapeutic uses, and suggests that, in many cases, off-label use will become the norm until this testing process can be rectified by the FDA.

	This, of course, raises huge issues just in terms of the high costs associated with these therapies. If they’re not FDA-approved or on-label for that patient’s use, then the patient is in a situation where her insurance company typically will not pay for these agents. So, patients have two options: (1) pay for the drugs themselves, which is pretty unlikely for most patients, or (2) appeal to the pharmaceutical company for the off-label use in compassionate care.

	This is a huge area that needs to be addressed at the regulatory level, at the clinical trials level, and at many other levels. I can assure you that it’s not just specific to breast cancer. We’re seeing this across all cancer types, in that cancer is a disease of the genome. When the genome is altered, it has relatively little to do with the tissue type in which the cancer is occurring, but has much more to do with the genes that are actually driving the onset and progression of that cancer.

	This is the fundamental truth that’s coming out of all the genomic studies and is exemplified by our finding in breast cancer: Genes that were thought to be essentially restricted to the hematopoietic malignancies are actually very prominent players in the development of estrogen receptor-positive breast cancer.

How can community oncologists apply genomic information in their practice today?

	Breast cancer is one of the predominant tumor types, and so from a discovery standpoint, we’re fortunate in that regard. But we do have a very large amount of information now to coalesce and distill down for the oncologist who is actively seeing patients every day in clinic. In particular, what I think genomics can contribute to that daily practice regimen is a more specific description of the disease from a molecular standpoint. Although breast cancer is already one of the best- characterized tumor types, genomics will now add some richness to that data and distill out much more information that can be used on a day-to-day basis.

	I think the role of the community oncologist in treating patients with breast cancer becomes more well-informed. Obviously, it’s a lot of information to take in, and we’re going to have to develop systems that deliver that information in a much more cogent and hands-on, facile way. At the end of the day, the idea is to begin to treat the disease as early as possible with these new methodologies and this new information, so that we begin to alleviate the transition from primary to metastatic disease.

	In that regard, by treating primary tumors up front with the best mechanisms possible, whether it be with combinations of chemotherapy, targeted or small-molecule therapies, or immunotherapies, we can begin to understand how to decrease the number of patients who are progressing to metastatic disease.

How do you see the roles of the oncologist, geneticist, and other healthcare professionals changing in light of these genomic advances?

	Genomics has the potential to change the spectrum of care from the standpoint of those who provide care on a daily basis. There will be an onus on the community oncologist and the oncology nurse to provide genomic consent to patients who decide to pursue genomic testing because these patients will have either their full genome or a portion of their genome sequenced, and they’re going to need to understand what that return of information might reveal about their breast cancer, and possibly other aspects of their genomic makeup. This will also elicit, at a much higher level than ever before, the need for genetic counselors to be involved to deliver that information. It will require a very concerted effort of all healthcare providers across the spectrum of care to help breast cancer, patients understand the information, and more importantly, to help patients understand how the information is going to help them be more successful in their fight against the disease.

How will genome sequencing affect the way oncologists stage tumors and evaluate patients for therapy?

	Genomic information is very interesting in the context of traditional pathology. For example, by looking at RNA gene expression signatures we can already subtype, but we can also confirm what immunohistochemistry from conventional pathology tells us. Namely, is a patient estrogen receptor-positive or -negative, progesterone receptor-positive or -negative? Is that patient HER2- positive or HER2-negative? So, in essence, the genomics recapitulates the pathology.

	This is not to suggest that conventional pathology will fall by the wayside, but what genomics brings to the table is additional granularity or resolution to that patient’s mutational spectrum. Genomics identifies targeted therapies or immunotherapies that may be helpful to that patient above and beyond what we can predict from traditional pathology right now.

	What we know from sequencing breast cancer is that it’s a complicated disease, and that inherently, based on the complications in the genomes of these patients, we will need to have a more specific regimen for each patient to ensure success in that patient’s disease. While genomics is complicated, we need to embrace the information and try to understand what its base meaning is so that the oncologist will be more successful in treating that patient moving forward.

How can oncologists determine the right sequencing technology to use for evaluating their patients?

	There are a variety of next-generation sequencing instruments available from different manufacturers. Most of them produce short-reads that need to be aligned back to the human genome to make sense of them. Most of these instruments are relatively easy to operate, but the bioinformatic analysis of the data is what’s complex. Once you have the data in hand, interpreting it—both from the standpoint of where the mutations are, and then from an aspect that I call “medical interpretation,” that is, deciding which drugs are indicated by that patient’s genome&mdash;is a highly complex operation.

	In terms of how this can be applied in practice, there are limited gene panels being used for patient diagnosis at some of the larger teaching hospitals. In limiting the scope of the gene panel, you have an easier time in the analysis because you’re looking at a small number of genes in the bioinformatics, which is not as daunting as a whole-genome approach. That said, we know from sequencing whole genomes of many cancer patients that these targeted panels will often miss some information that would be germane to the patient’s therapy. So there’s a delicate balance here, but what will likely get implemented into the clinic first are the targeted panels. And that’s fine because they’re going to help a large number of patients, just not all.

	Then what will emerge over time, as the bioinformatics becomes more refined and more plug-and-play, if you will, will be whole-genome tests that will be much more comprehensive and will most likely tie into information from RNA, which we already know from a discovery or a basic science standpoint is important to cancer and cancer care. At the same time, from a technology standpoint, there are new instruments in development that will sequence an entire genome worth of data overnight.

	Consider the practical implications of this: If the sequencing can happen overnight and the bioinformatics that I just described takes on the order of several days, you could be returning genomic information to the oncologist and to the patient in a timeframe that would impact the treatment paradigms for most patients. This would give the oncologists time to till through the information, really get a grasp on what’s being suggested, and come up with a very personalized plan for that patient in a three-week period between her initial diagnosis and when she comes back to clinic to discuss treatment plans.

Can you discuss some of the challenges and future implications you see on the horizon for genomics?

	Whole-genome sequencing in particular brings on a number of challenges that are unique to whole-genome sequencing, and not so much to just specific panels of genes. In particular, there are a variety of ethical challenges. They include a decision on what information to return to the patient, and this takes on a very important form and flavor in the context of cancer of any type. For example, fundamental or “constitutional” mutations, as we call them (eg, inherited susceptibility to diseases like Alzheimer or Huntington), may not be so important in the context of a patient who’s fighting for their life against cancer, but may become important later if that fight is successful. As a result, there are inherent challenges in terms of the ethics of returning this information to the patient.

	Should the return of information be constrained just to the information that is germane to that patient’s cancer care, or should all information across the full spectrum of the genome be returned to the patient? This is a decision that has to be included in the documents that are used in the patient’s consenting process, and then if there are “constitutional defects” that need to be revealed at some point, there has to be a decision about how to do that. And this is really where genetic counselors need to become involved.

	We actually published a unique case that described a patient who was consented onto a research protocol for AML [acute myeloid leukemia] therapy [

. 2011;305(15):1568-1576]. Unfortunately, the patient died during the research project, but she had living children. This presented a dilemma because we had identified in her genome a cancer susceptibility defect that had a possibility of being transitioned to her offspring. However, we were able to deal with it by consenting her living relatives, and thereby were able to bring them in for testing.

	In returning information on the genome to the patient, there is also the concern about the ramifications of identifying or disclosing a constitutional defect in the genome to private insurers. Because people have children, this genomic data is also informative about the patient’s children’s potential for developing disease later in life. So, there are a multitude of ethical ramifications that don’t only apply to the individual, but extend to the individual’s family members as well.

	Ultimately, there will need to be regulation and genome legislation that encompasses the potential for discrimination in the workplace or in insurance situations.

		Table. "Druggable" Targets in Luminal Breast Cancers

					Myeloproliferative disease, psoriasis

					Prostate, colorectal, glioblastoma, endometrial

		CML indicates chronic myeloid leukemia; GIST, gastrointestinal stromal tumor; NSCLC, non-small cell lung cancer.

		Mardis ER. Targeting resistance to endocrine therapy—genomic insights. Presented at: 11th International Congress on the Future of Breast Cancer; July 26-28, 2012; Coronado, CA.

Articles

An interview with Elaine R. Mardis, PhD, discussing the clinical applications of genomic research on the near horizon that will enable more personalized therapy for patients at earlier stages of breast cancer.

Putting the Genome to Work in Breast Cancer

		Scrape cytology illustrating features of papillary carcinoma of the thyroid.

	A blanket approach to the use of radioactive iodine (RAI) may not be necessary in many patients with papillary thyroid cancer (PTC) provided they undergo expert total thyroidectomy first, Memorial Sloan-Kettering Cancer Center (MSKCC) investigators have shown. Findings were presented at the annual meeting of the American Thyroid Association (ATA).

	Iain Nixon, MD, and MSKCC colleagues retrospectively reviewed outcomes for 1129 PTC patients who had undergone total extracapsular thyroidectomy between 1986 and 2005. As Nixon emphasized, there was no evidence of macroscopic residual disease following surgery, and it was assumed patients were disease-free at the time of risk stratification.

	The median age of the cohort was 46 years; 39% overall had T3/T4 disease and more than 40% had nodal disease. “Overall, these patients did well,” Nixon observed, “as disease-specific mortality was only 1% and our recurrence rate at 5 years was 8%.” They subsequently analyzed a subgroup of 490 patients whose disease was confined to the thyroid, approximately two-thirds of whom were selected not to receive RAI.

	“At a median follow-up of 63 months, select patients with early primary disease (pT1/T2) and low-volume metastatic disease in the neck (pT1/T2 N1) managed without RAI had excellent outcomes,” investigators report. None of the patients died during follow-up, as Nixon noted. At 5 years, regional and distant recurrence rates of only 2% and 1%, respectively, were not statistically different between those selected not to undergo RAI and those who did, he added.

	Another 193 patients had limited local disease but with evidence of nodal metastasis, approximately one-quarter of whom were selected not to receive RAI. Again, those selected not to receive RAI had “excellent outcomes,” as Nixon noted, with virtually no local or distal recurrences observed over the 5 years of follow-up.

	The majority of another group of 444 patients with more aggressive local disease—T3/T4&mdash;did receive RAI. Of the 16% who did not, there were again no deaths at 5 years. At 2% and 7% for regional and distant recurrence rates respectively, outcomes were again very acceptable, as Nixon suggested.

	“I should make it clear that in our institution we still use RAI in low, intermediate, and high-risk groups on an individually selective basis,” Nixon said. “But we know treatment is not without side effects in terms of salivary and lacrimal dysfunction and increased rates of dysphagia, and there is a risk of secondary malignancy as well. Our findings suggest that most patients whose disease is limited to the thyroid and even selected patients with low-risk, local disease and limited nodal disease have good outcomes following management without RAI.”

	ATA guidelines on the management of well-differentiated thyroid cancer currently recommend the routine use of radioactive iodine for the treatment of tumors >4 cm and selective use of radioactive iodine in patients with intrathyroidal disease that is <1 cm. RAI is also recommended for patients who have evidence of nodal metastases.

	The guidelines acknowledge, however, that data upon which to make firm recommendations for most patients are both conflicting and inadequate.

View coverage from the 2012 ATA Annual Meeting

A blanket approach to the use of radioactive iodine may not be necessary in many patients with papillary thyroid cancer provided they undergo expert total thyroidectomy first.

Blanket Approach to RAI in PTC Patients May Not Be Necessary

The 10th International Congress on the Future of Breast Cancer was held in Coronado, California, August 4-7, 2011. The 4-day, interactive program was developed and chaired by leading breast cancer researcher Joyce A. O’Shaughnessy, MD, a medical oncologist with Texas Oncology-Baylor Charles A. Sammons Cancer Center in Dallas.

	Our editors had a unique opportunity to sit down with Dr O’Shaughnessy to discuss the goals of the meeting—namely, to increase our understanding of the biologic subtypes of breast cancer&mdash;and to get her perspective on how the hypotheses and data are evolving in this dynamic field.

	OBTN: This 2011 meeting marks the tenth year of The International Congress on the Future of Breast Cancer. The 10th anniversary is typically associated with tin or aluminum, signifying pliability and durability—the ability to bend, but not break. Looking back on the past 10 years, there have certainly been a few bends in the road. Can you talk a little about how the field of breast cancer research&mdash;and this meeting specifically&mdash;has evolved over the past decade?

 As I remember back to the very first meeting, I think the main thing I recall is that Carlos L. Arteaga, MD, gave a very good talk about the role of the HER (ERBB) family in breast cancer and the interconnectedness between the HER receptors and downstream proteins. There was an incredible sense of excitement at that time about us being able to start to tease out resistance mechanisms to therapy and really have a handle on what some of the deadly pathways were for patients who had aggressive breast cancer.

	That’s the kind of information that I try to bring to this meeting—the cutting edge, new mechanistic, pathogenetic mechanisms&mdash;because that’s what physicians are so eager to learn about. This area has just grown over the years as we’ve become increasingly mechanistic in our understanding of the various subtypes of breast cancer. So, this meeting focuses primarily on the various biologic subtypes of breast cancer; our understanding of these subtypes has increased significantly since we first started meeting 10 years ago.

	The meeting draws an international and an interdisciplinary audience. How does this year’s program manage to address this level of diversity in the attendees?

	We really focus more on what all breast cancer practitioners need around the world: a better biologic understanding of the disease, better diagnostics, and better therapeutics. So, we don’t focus on the clinical needs of the international audience, per se. The informational needs in breast cancer are universal, that is to really understand this disease and make better therapeutics. We have experts from around the world who are as interested in breast cancer as people in the United States, and so they come to this meeting because it’s a way to get a focused update on all the important clinical information, and to see how the hypotheses and data are evolving with regard to the patients they’re taking care of right now.

	You participated in the FDA hearings on Avastin. In a nutshell, the real issue seemed to be that the drug showed improvement in progression-free survival but was unable to demonstrate a benefit in overall survival. In your opinion, what is the most meaningful endpoint to demonstrate an unequivocal benefit to the patient? How much improvement/benefit is enough? What should be the standard going forward?

	The front-line Avastin trials in metastatic breast cancer—3 large, randomized trials&mdash;all met their primary endpoint of progression-free survival. They did not meet the endpoint of overall survival, but that wasn’t their primary endpoint. Nor were these trials really powered for survival in terms of picking up small benefits. So, I think that the primary endpoint for approval for Avastin and other first-line therapies should be progression-free survival.

	I think that if you have a statistically significant finding and you meet your primary endpoint, the drug should be approved. Then it’s up to the oncology community to decide whether the magnitude of benefit is large enough to warrant the risks versus the benefits. I think Avastin in first-line therapy for metastatic breast cancer is very safe, as physicians are now accustomed to avoiding Avastin use in patients who have the possibility of complications (ie, patients with recent surgery, diverticulitis, any kind of active wound in the body, or with baseline uncontrolled hypertension).

It’s all hands on deck in the worldwide race to understand this disease. The Cancer Genome Atlas Project for breast cancer will be completed by the end of this year. So, we will soon have a full catalog of all of the mutations in breast cancer by subtype.”

	Avastin remains my standard of care for aggressive metastatic breast cancer that requires the use of 2 agents for optimal control of the disease. The choice is using either 2 chemotherapy agents or using Taxol with Avastin. The Taxol/Avastin combination allows you to continue the treatment for metastatic breast cancer without having to decrease the dose or stop one of the drugs. So, you’re able to continue with doublet therapy for a longer period of time to improve progression-free survival, as opposed to using a doublet of chemotherapy that you have to reduce the dose or stop one agent over time, thereby losing the effectiveness of the 2 agents in combination. I believe Taxol/Avastin is an excellent treatment for patients with aggressive breast cancer.

	In the triple-negative subset of patients—many of whom are quite refractory to chemotherapy&mdash; where we have fewer options, I especially think that this is the area where Avastin fills its greatest unmet medical need.

	It must have been pretty powerful and emotional to hear all the patient testimony at the hearings. How do you reconcile the widely varying opinions on the contributions of Avastin in breast cancer treatment? How do you anticipate this will net out from the varying stakeholders’ perspectives: the FDA, the patient, the insurer, and the community oncologist?

	I don’t know. To tell you the truth, I don’t think a lot about that. I really think about what I need to do in my practice to take care of patients. I think that the good news is that after the FDA’s Notice of Opportunity for Hearing, Medicare said that it would continue to pay for the drug. That was fabulous news. All I want is access. I feel strongly that patients and physicians should continue to have access to this agent. Because Avastin is approved for so many other cancers and approved in Europe for 2 indications as first-line therapy with Taxol and with capecitabine, there’s plenty of information out there to guide the practicing doctor.

	I firmly believe in the confirmatory trial that will look at VEGF-A levels as a predictive biomarker. I think that’s very important. But I think we have to focus on having the few agents like Avastin that are non-cross-resistant with chemotherapy available for patients who have very limited options.

	We hear a lot about personalized medicine— finding specific subsets of patients who respond to particular drugs. Consider the differences between Herceptin and Avastin. Herceptin uses HER2 as a prognostic marker; Avastin came to market without a biomarker signature, but some suggest perhaps there is one that would explain why some people seem to be “super responders.” Should all new products be required to have this type of biomarker signature?

	I don’t think so. I think it’s very difficult to define these signatures given the complexity of the cell. I think the recent information on pertuzumab in the CLEOPATRA (CLinical Evaluation Of Pertuzumab And TRAstuzumab) trial is a good example. This trial evaluated taxane/Herceptin with or without the antibody pertuzumab also against HER2. Although I’ve not yet seen the data, I’ve heard that it’s a very positive trial. Even so, we still don’t know which of the HER2-positive cancers will benefit the most from pertuzumab. It may take us years to figure that out. Meanwhile, there’s apparently a very nice incremental benefit. I think going into the adjuvant setting with a mixed population of triple-negatives and indolent ER-positive breast cancer is a thing of the past, and we really can’t be doing that kind of “all-comer” trials any longer.

	Even though I think we need to do some selection, I don’t think it will be feasible to come up with the “ALK story” for each and every drug we’re developing. Because as we’ve heard from this meeting, a lot of what determines sensitivity or resistance is systems biology. We may not be able to really know all of the operative pathways and microenvironment issues, but at least if we can get some understanding of the biology of these tumors and—importantly&mdash;not enroll subsets of patients in clinical trials who we think have very little possibility of benefit. That’s a way of selecting too&mdash;rather than a positive selection, a negative selection by not enrolling those who may not benefit. I think that this is something we will strive to do, but I think it will be very challenging to identify very narrow molecular subsets. There will be some successes, no doubt, but I think for the most part it’s going to come down to more broadly defined biological subsets.

	In light of the data you presented at ASCO on iniparib, PARP inhibitors may not be the magic bullet people were expecting. What can we learn from these negative results? Where do you see the class of PARP inhibitors going?

	Well, it turns out that iniparib is not a PARP inhibitor at the physiologic concentrations that are achieved in women. The mechanism of action is under intensive study. Of course, there had been a lot of work done on this mechanism from the time it was first discovered, and I’ve been told about some of the new hypotheses coming out, and they’re very interesting. So, I think that the iniparib story will be interesting once again, in terms of its mechanism of action at physiologic concentrations. If you give enough of it, you do inhibit PARP-1. But the levels that are achieved with a dose of 5.6 mg per kilogram, you’re not inhibiting PARP-1. That’s really clear.

	In terms of crossover in the setting of a trial that has survival as an endpoint, I think we’re back to being more cautious about that. With the phase II results being so robustly positive, even with a crossover, I think people felt that it was reasonable to go ahead with a crossover in the phase III study. With survival as a primary endpoint, you can muddy the waters with crossover.

	Sanofi has gone back to phase I to continue to increase the dose of iniparib because the drug has such a low toxicity profile. It may be that they will get to a point where they’re able to inhibit PARP-1 with higher doses, but at the current physiologic concentrations, the drug is biologically active. It does cause DNA damage, and there is a case of an excellent response in BRCA2—mutated pancreatic cancer. We need to better understand its mechanism of action, and to parse triple-negative breast cancers into biologic subsets because there’s a signal of activity in the phase III trial.

	Although the iniparib phase III trial didn’t meet its primary endpoint, this negative trial tells us that focusing on treatments for triplenegative breast cancers is still too broad. We need to get more granular in our focus with DNA-damaging agents like iniparib regarding which triple-negative patients benefit. So, in terms of lessons learned, I think going forward we need to better understand the biologic subsets of triple-negative breast cancer and to select subtypes of triple-negative breast cancer for future trials.

		I also think that doing serial biopsies of metastatic disease— real-time monitoring of disease&mdash;will be important over the next 5 years. For example, monitoring circulating tumor cell changes over time and redoing biopsies at multiple time points in metastatic disease for patients with longer natural histories will become increasingly important.”

	Moving forward with research on iniparib, how will future studies deal with the issue of heterogeneity in triple-negative breast cancer tumors? Would testing for BRCA mutation status be required?

	Because iniparib is not a PARP inhibitor, the BRCA story becomes less relevant. One could consider doing a study of basal breast cancers, for example, or basal triple-negatives versus non-basal triple-negatives if your hypothesis was about DNA-damaging agents and DNA repair. However, I think that what we’ll find is that investigators will be looking for specific mutations such as loss of PTEN or activating mutations in phosphoinositide-3 kinase (PI3K) to determine which patients to enroll in studies. For PI3K pathway inhibitors, investigators will be looking for mutations that lead to RAS/ MAP kinase activation, for example. So, I think there will increasingly be selection for pathway activation and microenvironment cytokines. I think what we’re going to see are many smaller, randomized phase II hypothesis-generating studies over the next 5 years.

	How do you see the landscape of breast cancer treatment changing over the next 10 years? What trends in breast cancer research seem really exciting to you? Are there new areas that are just beginning to be explored that sound very promising even in the early stages?

	In one of the presentations at the meeting, Matthew Ellis, MD, PhD, described the concept of using “genome-forward” approaches to patient selection, as opposed to doing studies where we collect tissue and then retrospectively look at the molecular characteristics of the patients who responded versus not. I think that this is an exciting concept that we can apply in areas where we need better patient selection tools. However, with regard to some of these targeted therapeutics, we do need to make our very best hypotheses about which patients are likely to benefit and build that into the trial. You may also evaluate and treat a broader population, but you have to have a prospective hypothesis within your proof-ofconcept trial looking at particular subsets. I think the genome-forward concept is one of the things we will be focusing on in the future.

	I also think that doing serial biopsies of metastatic disease—real-time monitoring of disease&mdash;will be important over the next 5 years. For example, monitoring circulating tumor cell changes over time and redoing biopsies at multiple time points in metastatic disease for patients with longer natural histories will become increasingly important.

	I think that the future is very bright for HER2-positive disease, with all the new agents available, and I think that there will be a deeper understanding of the subtypes of HER2-positive disease, possibly through the evaluation of phosphoprotein signaling in the cell.

	For ER-positive disease, I think we will gain a better understanding of the biology—the molecular pathogenesis&mdash;with regard to which of the indolent cancers just can’t die. Patients with these cancers may need prolonged endocrine therapy. We’ll have a better understanding of the molecular abnormalities of the aggressive ER-positive tumors, in terms of which amplicons and deletions are driving the cancers, and where the dominant pathway abnormalities are. The BOLERO-2 trial with everolimus is a good step in this direction. We also have the entinostat data that were mentioned at this meeting that may be very promising for the more aggressive ER-positive cancers.

	The triple-negative breast cancers remain our greatest challenge because we still have a relative dearth of sound, clinically testable hypotheses at this time. I think we’re going to see some breakthroughs soon with excellent hypotheses emerging, so I am optimistic. It’s all hands on deck in the worldwide race to understand this disease. The Cancer Genome Atlas Project for breast cancer will be completed by the end of this year. So, we will soon have a full catalog of all of the mutations in breast cancer by subtype. I think these data will be very important in subtyping triple-negative disease and will spur a lot of hypothesisgenerating studies that will ultimately lead to some breakthrough therapies.

Leading breast cancer researcher Joyce A. O'Shaughnessy, MD, developed and chaired the 10th International Congress on the Future of Breast Cancer, a 4-day interactive program.

A Look Into the Future of Breast Cancer: A Conversation With Joyce A. O'Shaughnessy, MD

After 2 days of emotional pleas from patients and a wealth of clinical data from scientists, an FDA advisory committee unanimously recommended Wednesday that the agency withdraw the breast cancer indication for Avastin.

In doing so, the Oncology Drugs Advisory Committee (ODAC) members voted 6-0 to uphold the panel’s controversial finding nearly a year ago that the world’s best-selling cancer drug posed a greater risk of harming breast cancer patients than benefiting them.

Genentech, whose appeal of last year’s ruling set the stage for this week’s hearing, contended that a subset of patients benefit from Avastin and that the drug should remain on the market while further studies are conducted.

The matter will now go to FDA Commissioner Margaret A. Hamburg, MD, who will make the final decision after the posthearing comment period ends July 28.

Until Hamburg makes her decision, Avastin remains an approved use for the treatment of HER2-negative metastatic breast cancer in combination with paclitaxel, according to Genentech. The outcome will not affect the drug’s other approved indications for metastatic colorectal cancer, non—small cell lung cancer, glioblastoma, and metastatic kidney cancer.

Nevertheless, the vote Wednesday is a blow to Genentech, a member of the Roche Group, which reportedly realized $7 billion in annual sales of the drug.

The FDA had granted Avastin an accelerated approval for metastatic breast cancer in 2009 based on the promising results of a single trial that showed a significant benefit in progression-free survival (PFS).

However, subsequent trials that evaluated Avastin in combination with other chemotherapeutic agents failed to confirm the original PFS results and showed no improvement in overall survival in patients receiving Avastin.

In this week’s hearing, the ODAC panel focused on 3 pivotal questions that would ultimately determine Avastin’s fate.

The first 2 questions dealt with whether the subsequent Avastin trials had produced compelling evidence to support the clinical benefit of Avastin for the breast cancer indication for which the drug received accelerated approval.

In the discussion sessions that preceded the vote, several panel members indicated that the AVADO and RIBBON1 studies, while well-executed, failed to confirm any clinical benefit of Avastin in women with breast cancer, and more importantly, most agreed that the drug has not demonstrated a clinical benefit that justifies the risks associated with its use.

“We can’t tolerate a 13% increase in toxicities,” said ODAC panel member Mikkael A. Sekeres, MD, MS, associate professor of medicine and director of the Leukemia Program at Cleveland Clinic’s Taussig Cancer Center in Ohio. Other panelists concurred, indicating that the evidence demonstrates a high risk to patients without any clinical benefit.

Serious adverse events include severe high blood pressure, hemorrhaging, heart attack or heart failure, and the development of perforations, including in the nose, stomach, and intestines, according to the National Center for Biotechnology Information.

ODAC members voted unanimously in response to the first 2 questions that the data failed to verify the clinical benefit that justifies the risk of Avastin in women with breast cancer.

Nevertheless, the third and most difficult question, according to one panelist, dealt with whether the FDA should continue the approval of the breast cancer indication while the sponsor conducts additional studies intended to verify Avastin’s clinical benefit. This question generated the most discussion between the panelists, Genentech, and members from the FDA Center for Drug Evaluation and Research (CDER) in the audience.

An industry representative and nonvoting member of the ODAC panel, Gregory Curt, MD, the US medical science lead of emerging products at AstraZeneca Oncology in Garrett Park, Maryland, asked how CDER would feel about continuing the breast cancer indication if the sponsor was able to identify a subset of patients that may benefit from therapy for additional study.

The deputy director of the division of biologic oncology products at CDER, Patricia Keegan, MD, said that CDER prefers to make decisions on a subgroup analysis based on data and that no data exist to indicate that a specific group of patients would respond differently.

In the end, the panelists voted against continuing the approval of the breast cancer indication. Despite its decision to revoke the approval, the panel encouraged Genentech to conduct additional studies to prove a clinical benefit for Avastin in these patients.

Ultimately, the panelists felt that the FDA should have the authority to reverse its decision in light of new data. Brent Logan, PhD, associate professor of biostatistics at the Medical College of Wisconsin in Milwaukee, summed it up by explaining, “The accelerated approval process should not indicate a change in the approval standard.”

An FDA advisory committee unanimously recommended Wednesday that the agency withdraw the breast cancer indication for Avastin.

ODAC Upholds Vote to Revoke Avastin's Breast Cancer Indication

A vast majority of Medicare patients with cancer are receiving appropriate surgical care that is in line with current treatment guidelines. While this is good news for most surgical oncology patients, a recent study revealed that doctors did not follow expert guidelines as closely for some gastric and colon procedures where the evidence for the “correct” treatment was less convincing.

	The research team, led by Caprice C. Greenberg, MD, MPH, Director of the Center for Surgery and Public Health at Brigham and Women’s Hospital in Boston, Massachusetts, looked at variations in surgical care in 5 types of cancer. The results were published online this week in the Archives of Surgery.

	The retrospective cohort study analyzed records from more than 100,000 fee-for-service Medicare patients aged 65 years or older who had undergone surgical resection for breast, colon, gastric, rectal, or thyroid cancer diagnosed between 2000 and 2005. The researchers compared the cancer care these patients received with established practice guidelines in surgical oncology.

	The authors found that hospitals treating patients with adjuvant therapy adhered to established practice guidelines more than 90% of the time. Hospitals showed the highest concordance with the guidelines for breast cancer surgery, likely, the authors speculate, because those guidelines have been around for a long time and are based on solid evidence.

	However, the study showed that less than 50% of hospitals followed guidelines for lymph node removal in patients with gastric or colon cancer. The guidelines call for a minimum number of lymph nodes to be removed for examination in each case, but the evidence supporting these guidelines is more controversial.

	“When there’s really good evidence, it looks like people are pretty consistently getting that kind of care, Greenberg said in a press release. “However, if guidelines are based on a consensus of what people think might be the right thing to do, guidelines are consistently followed.”

	Despite the low concordance rates in lymph node removal in patients with colon or gastric cancer, recent studies have shown that doctors are getting better at following colon cancer guidelines. Yet Greenberg acknowledged that surgeons need to generate more data to further define appropriate care for patients with cancer and translate these evidenced-based findings into everyday practice.

	Greenberg CC, Lipsitz SR, Neville B, et al. Receipt of appropriate surgical care for Medicare beneficiaries with cancer [published online ahead of print June 20, 2011]. 

A vast majority of Medicare patients with cancer are receiving appropriate surgical care that is in line with current treatment guidelines.

Surgical Oncologists Typically Follow Treatment Guidelines

	A population-based natural experiment using a case-control study of Swedish men aged 44 to 50 years showed that prostate-specific antigen (PSA) levels can accurately predict the risk of developing metastasis or death from prostate cancer up to 30 years later. These results will be presented next month at the 47th Annual American Society of Clinical Oncology (ASCO) meeting in Chicago, Illinois.

	Often criticized for its tendency toward overtreatment and its overuse in populations that may have limited benefit, new data about PSA screening adds to the existing evidence about its use. In an interview with the lead author, Hans G. Lilja, MD, PhD, told Onc

, “The testing for the PSA in blood remains controversial despite that we actually have level 1 evidence from randomized, prospective trials in Europe [showing] that PSA-based prostate cancer screening can reduce mortality from prostate cancer.”

	Lilja, an attending research clinical chemist in the Departments of Laboratory Medicine, Surgery, and Medicine at Memorial Sloan-Kettering Cancer Center in New York City, remarked in a press release, “Doctors have urgently needed an effective PSA-testing strategy that accurately distinguishes men at high risk for prostate cancer who need aggressive monitoring from those at low risk of the disease, who can be safely spared from frequent testing.”

Dr. Pecora on the Results from the Swedish PSA Screening Study

	Lilja and a team of authors analyzed PSA in archived blood samples that were collected as part of the Swedish Malmö Preventive Project. Blood samples were drawn from an unscreened cohort of 12,090 men who provided blood between 1974 and 1986, from 4999 men who provided repeat samples 6 years later, and from an independent cohort of 1167 men who provided blood at age 60.

	The researchers then assessed the median PSA levels for men aged 44 to 50 years, 51 to 55 years, and 60 years to determine long-term risk of prostate cancer morbidity and mortality. The results showed that cancer-related deaths occurred in men aged 44 to 50 years who had PSA levels >1.6 ng/ml. The researchers found that intense surveillance of this small group of men with the highest PSA levels (top 10%) could prevent nearly half of all prostate cancer deaths.

	If PSA levels remained below the population median as the men aged, the risk of death from metastatic prostate cancer progressively declined. The researchers found that 28% of metastases or deaths from prostate cancer over the next 27 years occurred in men aged 44 to 50 years who had a PSA below the median (0.7 ng/ml). The risk of metastasis or death was only 18% for men aged 51 to 55 years with a PSA less than the median (0.8 ng/ml). At age 60, only 0.5% of metastasis or death occurred in men with a PSA less than the median for that age group (1.1 ng/ml).

Dr. Markman Discusses the Swedish PSA Screening Study

	Testing PSA levels in men aged 51 to 55 years and aged 60 years with PSAs below the median was sufficient to determine the risk of future metastasis or prostate cancer-related death decades later. Applying this strategy to screening would mean that half the population of men would need only 3 PSA tests in their lifetime (ie, at ages 45-49, 50-55, and 60).

	“Our overall approach in this paper is to look at the men who have little or nothing to benefit from prostate cancer screening because they do not develop any prostate cancer metastases or do not die from prostate cancer,” said Lilja. “So, our overall approach is basically: do no harm.”

	These findings, due to be presented in an oral abstract session at the ASCO meeting on Monday, June 6, 2011, could have a significant impact on future prostate cancer screening programs.

	Lilja HG, Savage C, Gerdtsson A, et al. Towards a rational strategy for prostate cancer screening based on long-term risk of prostate cancer metastases and death: data from a large, unscreened, population-based cohort followed for up to 30 years. 

Prostate-specific antigen (PSA) levels can accurately predict the risk of developing metastasis or death from prostate cancer up to 30 years later

Lyn Beamesderfer