OncologyLive® is the flagship publication of OncLive®. Each issue delivers expert insights and clinical oncology news and updates, which impact the day-to-day clinical practice of oncology professionals who work tirelessly to help improve patient outcomes.

	Advances in the understanding of tumor biology and a robust drug development pipeline are combining to form a “perfect storm” of opportunity for personalized cancer research to make a leap forward, according to Gordon B. Mills, MD, PhD.

	Mills, however, said researchers are going to have to develop strategies for overcoming resistance to targeted therapeutics, which he said have had “an unexpected high rate of failure.”

	Mills, the keynote speaker on the opening day of the conference, is co-director of the Institute for Personalized Cancer Therapy and chair of the Department of Systems Biology at MD Anderson Cancer Center in Houston, Texas.

	He said scientists are now able to understand tumors “with a breadth and depth” previously unavailable, and that a “wonderful toolbox” of nearly 900 cancer drugs, including 125 in breast cancer alone, is in various stages of investigation.

	“We have an opportunity now of capitalizing on our new ability to characterize patients’ tumors and this toolkit to hopefully engender a perfect storm that is going to make a change in how we manage patients and move forward,” he said.		

	Mills, however, said the oncology community is “entering an era of information overload.” Researchers have to make sense of the flood of data generated by high-throughput technology, which now enables genome sequencing for $1000 to $2000, he said.

	“It is generating data but not knowledge, and certainly not the wisdom to manage patients. It’s noise until we know what to do with it,” he said.

	Overall, Mills said, targeted therapies have had limited success in fighting tumors, often achieving a benefit for specific populations of patients for a short time before recurrence. “We need to understand who will benefit and who will not,” he said.

	Mills said a key step lies in understanding resistance mechanisms in cancer cells, and listed 3 major types of resistance: intrinsic resistance, or genetic aberrations; selected resistance, engendered at a genetic level by the therapy itself; and adaptive homeostatic mechanisms by which the cells stay alive in other ways after therapy.

	He is working to build mathematical models that can define “emergent properties” in complex cell signaling pathways and, for example, predict such effects of targeting a particular node as the loops that are activated and the unexpected reactions.

	Mills said single drugs will not be able to achieve results. Instead, he said rational combinatorial adaptive resistance therapy (CART) is needed to attack resistance in different ways.

	“Many of the drugs that we are using, particularly in targeted therapies, when they hit their targets turn off the pathways that they are supposed to, but because the cells attempt to come back into homeostatic equilibrium, you turn off pathways that have been activated [while] you turn on others,” Mills said.

	He said that activity “could represent or identify synthetic lethality or optional targets, or targets that you could combine together rationally and in an efficient manner, to come forward and find the system where you can make all of the cells die.”

		Mathematical modeling, left, is used to analyze cell lines exclusive interviews treated with a PI3K inhibitor. Schematic depiction is at right. From research by Taru Muranen, Laura Selfors, and Yiling Lu.

	Using reverse phase protein arrays, his research team is starting to build a human proteomics atlas. The Cancer Genome Atlas has contracted with the team to analyze 11,000 samples across 22 diseases.

	“We are beginning to capture new information at the protein level that was not captured at the RNA level, and amplifying on the previous clustering system,” he said.

	One particularly promising strategy under study is the combination of BEZ235, a novel oral agent from Novartis that inhibits both the PI3K and mTOR pathways. Since other pathways become activated, the team added a BCL2 inhibitor.

	“You put the two together and you have complete wipeout,” Mills said. “I’ve spent many years trying to do synthetic lethality screens. We’ve never seen anything like this.”

	He noted, however, that the concept of CART as an anticancer strategy extends beyond any specific therapy under study.

Articles

Advances in the understanding of tumor biology and a robust drug development pipeline are combining to form a 'perfect storm' of opportunity for personalized cancer research to make a leap forward.

Resistance Strategies in Focus: Combinations Target Multiple Pathways

	Although cystoscopy is a mainstay in diagnosing bladder cancer and monitoring its recurrence, researchers have been seeking to improve upon its ability to detect early evidence of cancer, particularly flat lesions and small papillary tumors.

	Last year, the FDA approved the optical imaging agent Cysview™ for use with photodynamic blue light cystoscopy in conjunction with the standard white light cystoscopy.

	The agent, which contains hexaminolevulinate hydrochloride, is injected into the bladder through a catheter. It enters the bladder mucosa, where it accumulates preferentially in malignant cells. When illuminated with blue light from the cystoscope, the diseased cells emit red fluorescence, improving the clinician’s ability to see potentially troublesome growths.

	The approval was based on pivotal study data that demonstrated blue light cystoscopy improved detection by 16% in patients with Tα and/or T1 lesions when compared with white light cystoscopy. The most common adverse event was bladder spasms, which were reported by less than 3% of participants.

	The data showed that Cysview “significantly improves detection of papillary bladder cancer, leading to a more complete resection of bladder cancer” in patients with initial and recurrent disease, H. Barton Grossman, MD, a professor in the Department of Urology at the MD Anderson Cancer Center in Houston, Texas, and lead investigator of the trial, said in a press release when the agent was approved.

	Cysview is designed for use with the Karl Storz D-Light C Photodynamic Diagnosis (PDD)™ system. GE Healthcare, a unit of General Electric Company, licensed Cysview from Photocure ASA, a Norwegian pharmaceutical and medical device company. The agent is approved in Europe and marketed as Hexvix.

	Last fall, Neal D. Shore, MD, became the first urologic oncologist in the United States to begin using Cysview.

		Dr Shore, center, explains use of Cysview during cystoscopy.

	He recently demonstrated its use in a live cystoscopy accessible through a virtual presentation from the Parkway Surgery Center, an outpatient facility in Myrtle Beach, South Carolina, that is part of Atlantic Urology Clinics. The patient was a 76-year-old woman who had several tumors resected and showed evidence of recurrence 6 months later. Using the Cysview technology, Shore confirmed 4 tumors, including 2 that he resected immediately and 2 smaller, nonmuscularly invasive tumors that he cauterized.

	Shore, who is managing partner at Atlantic Urology and director of its research arm, has participated in more than 100 clinical trials involving urinary tract cancers. After performing up to 75 cystoscopies using Cysview, he is enthusiastic about the technology.

	“If I can do a better job of performing a complete resection, I theoretically can reduce my short-term recurrence rates and then hopefully that will impact long-term recurrence rates,” Shore said in an interview with Onc

. “And if I can do that, I’m also reducing the number of times patients will require tumor resection with its associated morbidity and risks.”

		The Cysview kit contains 2 vials and a catheter adapter.

	Onc: Please explain why you feel Cysview represents an advance over white light cystoscopy.

It allows the treating urologist to identify more potential malignant tissue with greater certainty than without using it. And because of that, it also allows you to resect the tissue that is potentially malignant. It allows you to identify and resect the malignant tissue in a way that may have been missed previously. The end result is it allows any urologist who has been resecting bladder tumors for a long period of time to improve his outcomes.

	The bigger tumors you’ll see obviously with the white light. It is the smaller lesions, such as the 1- to 3-millimeter ones or those that are almost fl at that you will only see with the blue light and the fl uorescence uptake. The very obvious tumors on blue light will be obvious on white light as well.

	If you can detect and remove more tumor, then the next time you repeat—a surveillance cystoscopy three or four months later&mdash; you’ve theoretically performed a more complete resection. But if I had missed them initially, and now I visualize a previously missed lesion that has enlarged, I would conclude, ‘Oh, there’s recurrence.’ But, in reality, it wasn’t so much recurrence as that I just never treated it earlier.

	This observation is very important because, if I’m the patient, now I’m not being scheduled for a repeat anesthesia and a repeat attempt at eradicating that tumor, which I’m now calling “recurrent” as opposed to having been missed earlier.

	I think that it is well suited for patients who are undergoing an initial bladder tumor resection, and especially those who have multiple tumors. For any initial resection of someone who has more than two or three tumors, I think it could be very helpful in picking up the full margin of the tumor as well as any small, additional satellite tumors that may be otherwise missed with standard white light cystoscopy.

		Tumor area near resection tool shown with white light cystoscopy, top, compared with red fluorescence of Cysview, center and bottom.

	Where does Cysview fit in the treatment timeline?

	Once you’ve done a diagnostic cystoscopy and the patient has multiple tumors, I think then the installation of Cysview upon the first initial resection is extremely beneficial. When you then go back and you inspect the bladder and there’s no evidence of any recurrent disease, I think that one could potentially hold off on doing the Cysview. If you have concern that there is recurrent disease, then I think the Cysview has another very valuable role, specifically in the setting of an abnormal cytology or FISH [fluorescence in situ hybridization].

	The prescribing information states that Cysview is not intended for repetitive use. Do you agree with that, and what would constitute repetitive use?

	That’s a good question. You don’t want to use Cysview in the setting within three months of significant infection, or anything that can cause an inflammatory change, such as prior intravesical therapy or a recent resection. So, to me, the answer is that it is not for repetitive use within three months of any one of those things, the setting within three months of a bladder tumor resection, or within three months of intravesical installation of therapy, be it BCG [bacillus Calmette-Guérin] or mitomycin, or three months of a recent infection because it creates too much false—positive pickup of the fluorescence in the tissue.

	In your experience, have there been adverse events among the patients with whom you’ve used this agent?

	We haven’t seen any adverse events related to the installation of the Cysview. Zero. We’ve seen no one complain of any discomfort upon installation of the medication, and we’ve seen no change in anything related to the installation of the medication itself. We’ve had no systemic reactions. We’ve had no irritative voiding symptom reactions different from the mere fact of instrumenting somebody with a cystoscope, resecting a tumor, or biopsying the bladder wall.

	How do you integrate Cysview into your practice?

	Prior to using Cysview, we weren’t using anything comparable. There’s no comparable workfl ow for this therapeutic application or this diagnostic application. So, essentially, all we had to do for this is have the patients come in at the usual expected time for checking in.

	But immediately upon check-in, we want to make sure we are set up in our framework to have them catheterized to place the medication because we’re aiming for a bladder dwell time of about 60 minutes.

	The change was getting the patients when they came in, not really trying to have them come in too much earlier but early enough so they can have the medication instilled in their bladder, do their normal paperwork, preoperative preparation, talk to the nurses, fill out preoperative information, and meet with the anesthesiologist. All that’s going on, but prior to any of that we have the medication instilled.

	You have to use Karl Storz D-Light C PDD System equipment, including a light cord that gives you the blue light wavelength in conjunction with the white light wavelength. And, of course, that light cord needs to be adaptable to the Storz cystoscopic equipment.

	If you already have the Storz white light equipment, it’s not a significant step to upgrade. If you don’t have any Storz equipment, then it would be more involved in making sure you had their cystoscopes in addition to the ability to have the blue light with the white light capability.

An interview with Neal D. Shore, MD, discussing expanding the scope of cystoscopy and the optical imaging agent Cysview.

Expanding the Scope of Cystoscopy: Imaging Agent Illuminates More Lesions

	The movement to improve the accuracy and predictive value of tumor marker testing in patients with breast cancer has resulted in a dramatic upswing in the number of accredited laboratories, as well as a continuing effort to clarify definitions that guide therapy decisions.

	Antonio C. Wolff, MD, who has helped lead such efforts, reviewed several of the key controversies that have surrounded guidelines research. He is an associate professor of Oncology and a research scientist in the Breast Cancer Program at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, Maryland.

	Wolff co-chaired the cooperative panel of the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) that issued guidelines in 2007 for testing for the human epidermal growth factor receptor 2 (HER2) in invasive breast cancer. The marker guides decisions for trastuzumab (Herceptin) and lapatinib (Tykerb), and possibly in other therapies.

	“We wanted to standardize methodology, making sure that the same test done in the same tissue with the same patient anywhere would as much as possible yield the same information,” Wolff said. “The panel never set out to change the eligibility for trastuzumab. This has been a huge source of confusion.”

Table 1. Key Points in 2011 Clinical Notice

					Document time between tissue removal and start of fixation

					Fixation time in neutral buffered formalin

					6-48 hours in NBF; less fixation time permissible for needle biopsy specimens

					Pathologist discretion in selecting sample for testing

		ER indicates estrogen receptor; HER2, human epidermal growth factor receptor 2; NBF, neutral buffered formalin; PgR, progesterone receptor.

		ASCO Guidelines Clinical Notice, American Society of Clinical Oncology Website. 

. Updated January 13, 2011. Accessed August 22, 2011.

	In 2005, researchers believed that up to approximately 20% of all HER2 testing worldwide yielded false positives. Wolff said the picture for false negatives was not as clear, with estimates ranging from 5% to 10%.

	While researchers set out to compare results from local laboratories with central facilities, the issues turned on broader questions of testing protocols. “It’s not an issue of whether the test was done centrally or locally, but whether the test was done correctly,” Wolff said.

	Today, there are indications that the frequency of HER2 false positives has dropped to less than 6% in the United States, Wolff said in an interview.

	Meanwhile, the number of HER2- testing laboratories participating in the CAP accreditation program has risen markedly for both immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) methods. There were 1120 IHC and 316 FISH laboratories participating in the program this year, up from 125 IHC and 174 FISH facilities in 2004, according to a CAP survey. Likewise, more laboratories are becoming accredited for estrogen receptor (ER) testing, with the numbers rising from 97 in 2004 to 1200 this year.

	There are about 1500 laboratories doing HER2 testing in the United States, Wolff said.

	The joint guidelines panel recommended tissue-handling guidelines for HER2 testing in 2007, with a key factor being a gap between gathering of a specimen at a hospital and testing the sample in a laboratory (

	It’s not an issue of which is the right test to do—IHC or FISH&mdash; but whether you’re doing the test right. ”

	Although clinicians and administrators at each point were following protocols, more coordination was necessary, Wolff said. “We are all responsible,” he said. “The enemy ultimately was us.”

	The stakes for an accurate determination of HER2 status have grown increasingly higher, Wolff noted. “We’re not talking about palliation any more,” he said. “We’re talking about literally life and death for women with curable disease in the adjuvant setting.”

	In 2010, the joint panel revisited the HER2 guidelines and also reviewed procedures for ER and progesterone receptor (PgR) testing. In January, ASCO issued a Clinical Notice summarizing recommendations of both the 2007 and 2010 panels.

	“Because the same tissue coming out of the same patient will be used both for ER and for HER2 testing, we felt that it was important to reconcile and to harmonize some of the original recommendations made for HER2,” Wolff said in an interview.

	Reports indicate that while HER2 testing has improved, there’s a long way to go in ER and PgR testing. As many as 20% of ER and PgR test results performed through IHC methods worldwide may yield either false positives or false negatives, chiefl y because of variations in preanalytic factors, thresholds for positivity, and interpretation criteria, the panel said (

	In the United States, there has been no standardized proficiency testing of IHC procedures for ER and PgR markers, although IHC became the predominant ER testng method in the 1990s.

					IHC 3 (uniform intense membrane staining in >30% of invasive tumor cells)

					IHC 2 (patients with uniform intense membrane staining in >10% and <30% of cells eligible for adjuvant trastuzumab trials)

					Count additional cells for FISH, retest, or test with HER2 IHC

		*Patients with HER2/CEP17 ratio ≥2.0 eligible for adjuvant trastuzumab trials.

		FISH indicates fluorescence in situ hybridization; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry.

		1. Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. 

		2. Wolff AC, Hammond ME, Schwartz JN, Hayes DF. On behalf of the ASCO/CAP Panel on HER-2 Testing in Breast Cancer [correspondence]. 

. 2007;25(25):4021-4023. doi: 10.1200/JCO.2007.11.4363.

	Studies in other countries, notably a quality assurance program in the United Kingdom, suggest significant variations and inaccurate results. An inquiry in the Canadian province of Newfoundland indicated that approximately one-third of 1023 ER tests conducted between 1997 and 2005 were scored falsely negative when compared with retested results from a central laboratory.

	One key point to emerge from both panels is the optimal method for clinicians to use for collecting samples.

	For HER2, the guidelines recommend that resection samples be preferentially used rather than core needle biopsies “because of the likelihood of artifacts that might confound interpretation.”

	For ER and PgR testing, core needle biopsies are recommended “because of higher likelihood that the samples will be quickly fixed.”

	Although the 2007 panel’s intention was to focus on improving testing accuracy, debate soon erupted over the appropriate algorithms for defining HER2- positive disease, and thus whether a patient would be a candidate for trastuzumab therapy.

	Wolff said the panel was seeking simply to recommend that results be validated with IHC or FISH methodology if they fell into an equivocal category the first time the samples were tested.

	In April, Wolff helped author a Clinical Notice letter that sought to clarify the issue. One figure already had been revised “to state that patients with a HER2-positive equivocal IHC test who had tumors with uniform intense membrane staining in more than 10% and less than 30% of cells were also eligible for the trastuzumab trials,” according to the notice. (published online ahead of print April 18, 2011. 

	“The panel did not recommend withholding anti- HER2 treatment in those patients with an equivocal HER2 test (or tests) whose results fell within ranges that would have allowed them to be treated in the first generation of adjuvant HER2-targeted trials,” the document said.

	In addition, Wolff is not recommending one test over the other. “It’s not an issue of which is the right test to do—IHC or FISH&mdash;but whether you’re doing the test right because both tests can be equally good in identifying patients who will benefit from therapy,” he said.

	Discussions over HER2 guidelines are far from settled. Wolff said the panel will be re-established and that an updated guideline likely would be released next year.

	He also noted that the focus on testing would be far-reaching.

	“The attention to detail will go a long way toward improving the performance of these tests,” he said. “These issues do transcend beyond breast cancer. As we have more and more targeted therapies for various diseases, we need to have assays that are as good as the treatment that we give.”

Improving the accuracy and value of tumor marker testing in patients with breast cancer has resulted in a dramatic upswing in accredited laboratories and the clarification of guideline definitions.

Efforts to Improve HER2 Testing Continue ASCO Panelist Sees Progress

Nita Maihle, PhD, is a professor of Obstetrics, Gynecology and Reproductive Sciences, and director of a clinically oriented cancer research laboratory at Yale University, New Haven, Connecticut. She is listed as an inventor on 10 US patents in the fields of cancer therapeutics and diagnostics, is a cofounder of a biotechnology company, and serves on the National Cancer Institute’s Board of Scientific Counselors. Her main interest is in improving healthcare through the emergence of more precise diagnostic tests and the development of rationally designed, biologically targeted therapeutics.

	What role does EGFR signaling play in normal cells?

	The roles of EGFR [epidermal growth factor receptor] in normal cells are diverse and “primitive.” From the earliest multicellular organisms, one finds expression of EGF and its cognate receptors playing a fundamental role in such processes as cell division, survival, and differentiation. In humans, these roles have evolved to the regulation of complex interactions between cells.

	How important is it in cancer development?

	EGFR, in the form of a retroviral oncogene called v-ERBB, was one of the earliest human oncogenes to be identified. Through studies of this viral homolog we learned that mutant forms of the EGFR could induce cancer in diverse tissues.

 (via binding to soluble and/or membrane-bound growth factors, such as EGF, TGF-α [transforming growth factor], and amphiregulin, among others) and 

 mechanisms of EGFR signaling, the latter being particularly important in cell survival signaling, where EGFR’s interaction with integrin, another cell surface protein, is responsible for regulating alternative signal transduction pathways.

		Overexpression of EGFR ligand transforming growth factor (TGF)-α can set off events that result in resistance to EGFR antibodies. Ub denotes ubiquitylation; CBL, E3 ubiquitin-protein ligase; SFK, Src family kinase; E2F1, transcription factor; P, phosphorylation; PCNA, proliferating cell nuclear antigen; PTEN, phosphatase and tensin homolog; STAT3, signal transducer and activator of transcription.

		The mechanisms of resistance to EGFR TKIs can start with a mutant form of the receptor called EGFR variant III. T790M denotes threonine 790 mutation; IGF, insulin-like growth factor; AXL, tyrosineprotein kinase receptor UFO (AXL oncogene); IGFBP, insulin-like growth factor-binding protein.

		Both graphics adapted from Wheeler DL, Dunn EF, Harari PM. Understanding resistance to EGFR inhibitors—impact on future treatment strategies. 

	What EGFR-targeted treatments are currently available?

	In brief, so far, there are basically two broad categories of drugs targeting this receptor. The most notable to date are small-molecule tyrosine kinase inhibitors [TKIs] such as Tarceva and Iressa. The second are several monoclonal antibodies, including cetuximab and panitumumab, among others.

	Many others are in the pipeline at major pharmaceutical and biotechnology companies. So far, these drugs have been approved by the FDA for the treatment of lung cancer, colorectal cancer, head and neck cancer, pancreatic cancer, and breast cancer, but further latestage clinical trials will see this list continue to expand.

	What has been the key discovery relating to EGFR signaling in cancer in recent years?

	A major discovery has been the utility of small-molecule EGFR/TKIs for the successful treatment of non—small cell lung carcinoma, based on the identification of specific EGFR mutations/ genotypes in tumor specimens from cancer patients.

	This discovery has provided proof of concept for the importance of personalized medicine. That is, based on knowledge of the expression pattern, as well as the sequence of key oncogenes in human tumors, we can now use this information to direct molecularly targeted, highly effective new therapies in a side effect—sparing manner in cancer patients.

	What is the main unanswered question with regard to EGFR signaling in cancer research or EGFR-targeted treatments?

	Given the importance of this receptor family in the development of cancer, and the emerging pipeline of EGFR-targeted therapeutics, it has been paradoxical that most/all EGFR-based diagnostic tests for directing EGFR-targeted therapy—with the exception of sequencing for specific EGFR mutations&mdash;fail to predict responsiveness to the diverse drugs available targeting EGFR.

	We have recently proposed that one reason for this failure is the existence of a number of different EGFR isoforms. As we learn more about these receptor isoforms, we will be able to develop isoform-specific tests that will allow us to better direct therapy using EGFR-targeted agents in cancer treatment.

Nita Maihle, PhD, is a professor of Obstetrics, Gynecology and Reproductive Sciences, and director of a clinically oriented cancer research laboratory at Yale University, New Haven, Connecticut.

5 Questions for Nita Maihle, PhD

When Roy S. Herbst, MD, PhD, looks back on his college days, he does not linger over memories of late-night parties or fraternity pranks.

It is thoughts of the labs where he worked, of mice studies and gene detection, that prompt the oncologist to reminisce.

Those years at Yale University allowed Herbst to explore his curiosity about research and medicine, discover what inspired him, and start defining the path his career would take. Twenty-seven years after completing a combined undergraduate and master’s program there, graduating Phi Beta Kappa and summa cum laude, Herbst has brought the fruits of that experience back to his alma mater.

The physician and translational researcher, whose work in developing novel, personalized therapies for lung cancer has helped drive significant changes in the way the disease is treated, has returned to his old stomping grounds to lead the section of medical oncology at Yale Cancer Center and Smilow Cancer Hospital at Yale-New Haven, Connecticut. His mission there is to build a clinical trial infrastructure that will allow Yale to delve further into the study of early drugs and the mechanisms of cancer.

In March, Herbst left a post at the University of Texas MD Anderson Cancer Center in Houston to return to Yale, where he also has been named a professor at the School of Medicine.

“I was enamored by the possibility of taking what I knew—translational cancer research, combination therapies, biomarker and surrogate assays, and understanding how to make the clinical trial a scientific endeavor&mdash;and doing it at a place that has a tradition of scientific discovery, yet not in the realm of clinical trials,” said Herbst, 48.

“I’m intrigued to be leading not just lung cancer research, but the entire solid tumor area. And it’s cool to be a professor at the residential college where I was an undergrad, to work with students and inspire them as my professors did me. I love the academic environment at Yale, and I will be an undergraduate advisor this fall,” he said.

When he isn’t working, likes to work out and travel

Is the son of 2 first-generation Americans

Was shy as a teenager and only later, after working with some of his role models, became comfortable interacting with scientists and patients

The Emperor of All Maladies: A Biography of Cancer

 by Siddhartha Mukherjee, as his favorite book (

Interview With Siddhartha Mukherjee, Author of 

In thinking about the fight against cancer, often reflects on a quote from Winston Churchill: “Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning.”

Is a consultant to companies including Bayer, Eli Lilly and Company, Pfizer Inc, and AstraZeneca

Volunteers on committees and forums for the Institute of Medicine and the American Association for Cancer Research, whose Tobacco Task Force he chairs. Through smoking cessation efforts, Herbst believes, “I can help more people than I can by treating patients with advanced lung cancer.”

Has done charitable work for his synagogue and for Aishel House, a Texas nonprofit that provides patients and their families with transportation, meals, accommodations, childcare, and counseling when they are away from home for medical care.

Has authored more than 200 peer-reviewed papers

Received awards for excellence at every level of his education, including an award for Distinction in Molecular Biophysics and Biochemistry from Yale University and the Dean’s Research Prize from Cornell Medical College. More recent awards have included the David Ben-Gurion Leadership Award and the Irwin H. Krakoff Award for Excellence in Clinical Research, given by MD Anderson

Believes that philanthropic funding of cancer research is more important than ever in the face of government budget constraints, and hopes that funders will not overlook hypothesis-based clinical trial research, which can be difficult to quantitate but can lead to the discovery of new molecules or targets

Herbst is uniquely prepared for the challenges and opportunities he is taking on as Yale Cancer Center’s chief of medical oncology and associate director for translational research. For the past 14 years, he served as a lab head, clinical researcher, professor, and physician at MD Anderson, making his mark in the area of translational research aimed at finding new and better treatments for metastatic disease—particularly non-small cell lung cancer (NSCLC).

Herbst oversaw some of the earliest phase I studies of agents designed to inhibit tumor metastasis using epidermal growth factor receptor inhibitors or antiangiogenesis agents. Those drugs are now part of the daily clinical armamentarium in oncology, including cetuximab (Erbitux), gefitinib (Iressa), erlotinib (Tarceva), and bevacizumab (Avastin). The doctor’s pioneering work using erlotinib in combination with bevacizumab was among the first to combine multiple molecular—targeted agents for NSCLC.

More recently, Herbst conducted groundbreaking work as co-principal investigator of the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination, or BATTLE, trial, which involved using biopsies of participants’ tumors to decide which of 4 treatments they would receive. A second phase of the trial, in which combinations of agents are being employed to fight drug resistance, is now underway at both MD Anderson and Yale.

“The BATTLE trial has changed our field in that no one would treat lung cancer now without a biopsy,” Herbst said. “We feel very proud of the fact that we’ve helped make discovery such an important part of lung cancer therapy.”

In fact, Herbst said, the practice of analyzing tumors to identify their markers, and then matching them with the medicines most likely to be effective, will be the protocol for treating all or most cancers.

“We’re beginning to approach an era when the type of tumor won’t matter—only its profile, the genes that drive it,” he said. “That could mean we’ll sometimes use one inhibitor for both prostate and lung cancer, for example.”

In front of the classroom, Weinberg likes to entertain his undergraduates by revealing that he got a “D” in introductory biology, a course he didn’t enjoy when he took it at MIT. And he passes on this wisdom: “Most of the young people in high school have the conviction that biology is all about memorizing facts, when, in fact, it’s a very logical science with a lot of interesting questions that remain unexplored. It’s a very intellectually challenging field.”

Herbst is still settling in at Yale and setting up his new lab, but he anticipates that he’ll spend about 20% of his time at the institution with patients—less than he did at MD Anderson&mdash;so that he can reserve time to consider the projects of colleagues, conduct administrative duties within the center, and work closely with its leadership team. Most of his remaining time, another 40%, will be dedicated to doing his own research and writing papers and grants.

Within his busy schedule, Herbst expects to find time to continue lecturing and conducting grand rounds at other institutions around the world. “It’s important that people hear about your work,” he said, “and you learn a lot, too, if you take the time.”

In the classroom, Herbst plans to pass on a handful of principles he considers essential for those in his field.

“I’ll impress on them how important it is to be sensitive to patients,” Herbst said. “We need to care for their physical and emotional needs, to be honest and compassionate at the same time. I also always encourage students to develop a love and excitement for what we’re doing, for the possibilities. I want them to be eager to do better. When you’re in a field where people don’t survive, you have to be constantly looking for new drugs, new targets.”

We’re beginning to approach an era when the type of tumor won’t matter—only its profile, the genes that drive it. ”

Herbst decided to make lung cancer the focus of his career at the suggestion of Emil Frei III, MD, of the Dana-Farber Cancer Institute, regarded as a pillar of modern oncology. Herbst was in his mid-30s and completing a fellowship at the Boston institute at the time. Frei had stepped in as his mentor.

“No one wanted to work in lung cancer because it’s a really tough disease,” Herbst recalled. “Half the patients already have cancer that’s spread.”

Rather than resisting Frei’s challenge, Herbst dove into his work and has risen to the forefront of the field as one of 20 or 30 doctors who have made the disease their primary focus.

Growing up in New Rochelle, New York, Herbst was always interested in becoming a doctor. He credits his mother with passing her scientific ability along to him.

Although she made her career as a school librarian and media specialist, Herbst said, “My mother went to Bronx High School of Science and was very interested in science. She always used to wish she had gone to medical school, but she grew up without the finances or the opportunity to do so.”

Luckily, that door was open to Herbst, whose interest in his field flourished during his time as an undergraduate.

“My real desire to be a physician developed early in my time at Yale,” he said. “I got to work in a lab in the field of neuroscience. I was able to do some animal work, studies of the hypothalamus in mice, and I found it incredibly interesting, so I pursued a combined bachelor’s and master’s degree in molecular biophysics and biochemistry. I also worked in a second lab, one devoted to molecular biology and developing new techniques for gene detection. It was very similar to what I’m doing now as I work in personalized medicine.”

Herbst was already in medical school at Cornell University Medical College—through an elite, government-funded PhD/ MD program at the Rockefeller University, in New York City&mdash; when his mother was diagnosed with breast cancer. Shepherding her through her journey to health helped Herbst decide that he wanted to specialize in oncology.

“When a family member has cancer, as a medical student, you don’t have expertise, but you know how to find the right people,” Herbst said. “That’s what medicine is, being a quarterback for a patient. I talked to the different medical experts I knew, and I got my mother access to top pathologists in the field. I did feel that was interesting, and I could see how important oncologic care was and what a difference it could make in a patient’s life.”

, an oncogene active in 25 percent of lung cancer patients. No targeted therapy or chemotherapy works against it. We want to target 

 with combined drugs, and will do that in our BATTLE 2 program investigating personalized lung cancer treatment, which was recently funded and will be conducted at both Yale and MD Anderson. I’m very excited about it.

 outside the structure of the BATTLE 2 trial?

 in a number of ways, including looking for some new molecules that might work to inhibit 

, and screening them. We’re working on animal models, cell lines, and data to suggest that different 

 mutations have differing effects on signaling, and we’re making some very good headway in that direction.

Herbst moved from that idealistic beginning to the top of his field by excelling at some of the nation’s best institutions and working with a handful of its most recognized scientists—including mentor Judah Folkman, MD, who had discovered endostatin and angiostatin, agents that caused tumors to disappear in mice.

Herbst graduated from Rockefeller University in 1990 with a PhD in molecular cell biology and finished medical school a year later. During an internship and residency at Brigham and Women’s Hospital in Boston, a teaching affiliate of Harvard Medical School, he did so well that he was pulled out of the program in his junior year to fill in for a hematology fellow who was unable to work.

“I got experience with clotting disorders, hemophilia, and things you don’t normally see in malignant oncology,” Herbst recalled. “At Yale, which is a general hospital, I see similar things, and I’m glad I’ve had that training.”

Later, Herbst completed an oncology fellowship at Dana-Farber Cancer Institute before returning to Brigham and Women’s for a fellowship in medical hematology. Simultaneously, he completed the HST/Pfizer Clinical Investigator Training Program at Harvard Medical School, something he said helped him “tie together” his study experiences and figure out what to do next.

“I knew I wanted a career in clinical or translational research,” Herbst said. “I didn’t want to go into basic laboratory research, because then I’d have to stop seeing patients to avoid being distracted from my mission.”

Herbst fulfilled that vision at MD Anderson, where he was guided by another mentor, Waun Ki Hong, MD, one of the founders of chemoprevention and now head of cancer medicine at the institution. There Herbst’s research led to an “aha” moment.

“When I was doing the first studies with Iressa, we started to see patients whose metastatic lung cancer tumors melted away,” Herbst said. “I knew we were onto something pretty amazing when I realized we could biopsy tumors and understand their genetic profiles. That woke me up to the fact that this was a future therapy. There was no point going forward giving therapy to patients without matching the right ones with their tumor types.”

Today, that goal helps keep Herbst grounded in the face of the sickness he sees every day.

“I don’t see how I could work in oncology if I wasn’t trying to discover new things,” he said. “Some of the things we treat are so horrible that it’s nice to know we’re trying to offer the most effective new treatments.”

Beth Fand Incollingo is a New Jersey-based writer and editor, and owner of the communications firm Texterity, LLC.

Herbst, left, and Gandara share a lighter moment during the congress.

Key Issues, New Research Featured at Lung Conference

The 12th International Lung Cancer Congress, held in August in Carlsbad, California, offered a focused overview and discussion of state-of-the-art care.

Topics included updates on individualized therapies and biomarkers, innovations in radiation therapy, questions about surgical resection, and the debate about computed tomography screenings.

Roy S. Herbst, MD, PhD, and David R. Gandara, MD, director of the Thoracic Oncology Program and a professor of Medicine at the University of California Davis Cancer Center in Sacramento, served as program directors.

The full agenda of virtual presentations and downloadable slides are available free of charge at the OncLive meeting page for the 12th International Lung Cancer Congress.

Watch for the next issue of the magazine for more coverage.

Roy S. Herbst, MD, PhD, is a physician and translational researcher, whose work in developing novel, personalized therapies for lung cancer has helped drive significant changes in the way the disease is treated.

Making a Mark in Lung Cancer: An Interview With Roy S. Herbst, MD, PhD

		EGF denotes epidermal growth factor; HB, heparin-binding; NRG, neuregulin; bFGF, basic fibroblast growth factor; P, phosphate; TGF, transforming growth factor.

		Adapted from Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. 

	The epidermal growth factor receptor (EGFR) is the prototypical receptor tyrosine kinase (RTK) and one of the most comprehensively studied molecular targets in clinical oncology. Therapeutic agents specifically targeting EGFR have shown highly promising activity in the clinic.

	However, resistance to these agents and the question of which patients are most likely to derive therapeutic benefit from them have posed significant challenges to their optimal use. A greater understanding of the molecular mechanisms underlying EGFR signaling is now beginning to stimulate the development of new diagnostic and therapeutic strategies to enhance the impact of EGFR-targeted therapies.

	EGFR was the first of the RTKs to be identified, following the Nobel Prize-winning discovery of its principal ligand EGF in the early 1960s. It is a member of the ERBB family of receptors and can be activated by numerous other ligands besides EGF, including transforming growth factor (TGF) α.

	As with other members of the ERBB family, ligand binding drives the formation of receptor pairs, either between 2 EGFR molecules or between EGFR and another member of the family (homo-/heterodimerization), which stimulates the intrinsic tyrosine kinase activity of the receptor. Among the key intracellular signal transduction cascades subsequently activated by the EGFR are the MAPK cascade and the phosphatidylinositol 3-kinase/ protein kinase B (PI3K/Akt) cascade.

	Under normal conditions, EGFR activation is tightly regulated by the availability of the ligand. Dysregulation of the EGFR pathway by overexpression or constitutive activation can promote 5 of the 6 hallmarks of cancer. Defects in the EGFR signaling pathway have now been implicated in a diverse range of cancers, including colorectal, head and neck, lung, breast, and pancreatic cancers.

		Epidermal growth factor receptor (EGFR) tyrosine kinase domain with 4-anilinoquinazoline inhibitor erlotinib (Tarceva). Surface (gray) of EGFR and kinase; Tarceva in ball-and-stick (carbon-green, oxygen-red, nitrogen-blue).

	EGFR-specific treatments that have been developed thus far fall into 2 distinct categories: (1) small-molecule tyrosine kinase inhibitors (TKIs) that block the adenosine triphosphate (ATP)-binding site and prevent tyrosine kinase activity; and (2) monoclonal antibodies that block extracellular ligand binding. Four of these agents are currently approved by the FDA.

	Gefitinib (Iressa, AstraZeneca) was the first EGFR-specific TKI to be introduced and was originally fast-tracked for FDA approval in 2003 for the treatment of patients with non-small cell lung cancer (NSCLC). Following its subsequent poor performance in the INTACT 1 and 2 phase III trials, which showed no improvement in overall survival (OS) or time to progression (TTP) in the first-line setting, the FDA limited the indication for gefitinib to patients who are currently or have previously benefited from gefitinib.

The epidermal growth factor receptor (EGFR) is the prototypical receptor tyrosine kinase (RTK) and one of the most comprehensively studied molecular targets in clinical oncology.

September 2011 | Oncology Live®

Resistance Strategies in Focus: Combinations Target Multiple Pathways

Expanding the Scope of Cystoscopy: Imaging Agent Illuminates More Lesions

Efforts to Improve HER2 Testing Continue ASCO Panelist Sees Progress

5 Questions for Nita Maihle, PhD

Making a Mark in Lung Cancer: An Interview With Roy S. Herbst, MD, PhD

Oncogenic Signaling of the EGFR: Familiar Target Faces New Questions

5 Abstracts Among SGO Highlights

Novel PET Strategy May Predict Utility of Clinical Options