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.

Ever since Sidney Farber discovered that an antineoplastic agent could induce remissions in children with leukemia in 1947, chemotherapy has been part of the treatment paradigm for hematologic malignancies. It might have taken 70 years, but chemotherapy’s preeminent position in at least one area—chronic lymphocytic leukemia (CLL)&mdash;is rapidly giving way to newer agents.

The profound changes under way in the treatment of this malignancy were among the highlights captured in our coverage of the 

International Congress on Hematologic Malignancies:® Focus on Leukemias, Lymphomas, and Myeloma, held February 20-21 in Miami.

Chemotherapy for CLL Not Yet Obsolete But in Flux

,” details the emerging paradigm from the perspective of expert William G. Wierda, MD, PhD. Although chemotherapy remains the frontline treatment now, targeted agents are widely used in relapse settings and clinical trials to advance the new therapies forward in the timeline are in progress.

When we talk about the end of an era in oncology, of course, we do so without any nostalgia. There is much excitement for the newer, better treatments that flow from decades of clinical research.

This excitement is palpable at major conferences where new clinical trial data are announced and at Physicians’ Education Research (PER®) meetings (such as the hematologic congress where Wierda spoke) where the world’s top experts gather to dissect those findings.

Yet for as much admiration as we have for the fruits of those efforts, Maurie Markman, MD, 

’s editor-in-chief, reminds us not to accept the conclusions that research teams draw without examining the validity of both the initial premise and the eventual outcome— even if those reports are described in peer-reviewed literature.

 series, Markman discusses several studies that illustrate the necessity for clinicians to read the oncology literature with a spirit of inquiry before implementing changes in patient care suggested by such reports.

In some ways, the thoughts expressed in these articles form bookends for advancement in cancer care: remarkable new therapies developed and vetted in a spirit of sober inquiry.

We appreciate the opportunity to convey this information to the oncology specialists who are working to improve the lives of patients with cancer in communities throughout the nation. Please let us know what you would like to learn about in our publications, on our websites, and in our video presentations from experts. And, as always, thank you for reading.

Articles

The profound changes under way in the treatment of leukemia were among the highlights captured in our coverage of the 19th Annual International Congress on Hematologic
Malignancies:® Focus on Leukemias, Lymphomas, and Myeloma.

On the Brink of Change

Alok A. Khorana, MD, specializes in predictive factors in gastrointestinal oncology and in cancer-associated thrombosis at the Cleveland Clinic, which he joined in 2013. Khorana is the Sondra and Stephen Hardis Chair in Oncology Research and vice chair (Clinical Services) and director of the GI Malignancies Program at the Taussig Cancer Institute, as well as a professor at the Cleveland Clinic Lerner College of Medicine. Previously, he served as an associate professor of Medicine at the James P. Wilmot Cancer Center of the University of Rochester. He provided insight on gastric cancer research in an interview with 

 What are the most promising targeted therapies for the treatment of gastric cancer?

 Ramucirumab and trastuzumab are, of course, approved and are the only currently available targeted agents in this setting. Probably the most impressive recent data are for AMG 337 [a MET inhibitor] which, in early-phase studies, has shown excellent responses in MET-amplified patients. Note that these data represent only a subgroup of an early-phase study and further validation is necessary. An alternative MET inhibition approach using a monoclonal antibody failed in more advanced-phase trials.

In your opinion, why did ramucirumab succeed where bevacizumab failed and are there any other antiangiogenic therapies that hold promise in gastric cancer?

Although both drugs target similar pathways, they may interact differently with angiogenic receptors. In addition, the study populations were somewhat different. Indeed, in the bevacizumab study, if only the subgroup of North American patients was analyzed, bevacizumab did appear to provide benefit. So there may be subtle issues related to ethnicity and staging that differ by geographic location and are incompletely understood.

What are the reasons behind the failure of EGFR-targeting therapy?

It is unclear; EGFR-activated pathways may not be as important as we had previously thought. Or they may be redundant with other pathways.

What insights do recent molecular characterization studies offer about how best to treat gastric cancer?

We have been treating many cancers, including gastric, by categorizing patients (and treatments) based on anatomic location. This may, however, not turn out to be the best way to categorize.

In gastric cancer, for instance, patients with lower esophageal cancer invading into the gastroesophageal junction may have quite different pathophysiology than patients with body tumors—the former are likely caused by reflux/ Barrett esophagus and the latter related to 

So really what we think of as “gastric cancer” is a conglomerate of several different cancers entirely, yet due to a lack of better knowledge we have been grouping these together and treating them similarly. The Cancer Genome Atlas project suggests just as much, dividing gastric cancer into four distinct subtypes. This molecular classification provides clues to pathophysiology (important for prevention in the future) as well as differing approaches to treatment based on which pathways are upregulated.

What are the most significant hurdles to the development of targeted therapy in gastric cancer?

The lack of appropriate biomarkers to identify patients who benefit from targeted agents is a major challenge. There are no biomarkers to predict therapeutic benefit from ramucirumab. Similarly, issues with MET amplification versus immunohistochemistry (competing assays)

 may have been one of the potential causes for the failure of the MET-directed antibody mentioned previously.

Note: Several studies have suggested that the negative findings observed in trials of MET-targeted therapies may be related to difficulties in testing for MET aberrations. A significant number of patients who test positive for MET expression on immunohistochemistry (IHC) do not have MET-amplified disease. IHC or 

 gene copy number may not be optimal for detecting patients potentially sensitive to MET-targeting strategies. 

Alok A. Khorana, MD, specializes in predictive factors in gastrointestinal oncology and in cancer-associated thrombosis at the Cleveland Clinic. He provided insight on gastric cancer research in an interview with OncLive.

GI Specialist Discusses Hurdles in Targeting Gastric Cancers

Although publication of clinical trial findings in a peer-reviewed journal is a vital step in disseminating emerging research developments, there is a critical need for all readers of oncology literature to approach these reports with a healthy degree of skepticism. Among the important questions that readers should ask are whether the conclusions are truly meaningful to patients and why the study was initiated in the first place.

This commentary offers examples of clinical trials where the interpretation of study results is worthy of considerable additional discussion or where justification for the actual conduct of the study can be called into question. In fact, it is not hard to find studies in the peer-reviewed oncology literature where an objective observer could lodge a serious challenge against the conclusions reached by the study investigators. The examples discussed here include a colorectal cancer study and, due to the research interests of this commentator, several studies focused on the gynecologic cancer area. However, it is virtually certain that similar arguments could be advanced in regard to multiple other areas within oncology.

Debatable Conclusions in Colorectal Study

The recent publication of the results of a phase III trial that compared two multiagent combination chemotherapy regimens (FOLFOXIRI vs FOLFIRI) plus bevacizumab as first-line treatment of metastatic colorectal cancer serves as the starting point for this commentary.

 The issue here is whether the statistically significant improvement in progression-free survival (PFS) of a median 2.4 months (

 = .003) and a 12% increase the objective response rate (65% vs 53%), but nonstatistically significant superior overall survival (OS) of a median 5.2 month difference (

 = .054) associated with the delivery of the FOLFOXIRI program justify its use when the regimen is also associated with a rather impressive increased risk of certain highly clinically relevant grade 3-4 toxicities (peripheral neuropathy [5.2% vs 0%]; diarrhea [18.8% vs 10.6%]; stomatitis [8.8% vs 4.3%]).

How should the study be interpreted? Should the statistically significant improvement in PFS and objective response rate in this difficult clinical setting trump the associated increased risk of distressing side effects and permit the study to be labeled as a “positive” trial? Or should the toxicity profile in the absence of a statistically significant impact on OS result in the conclusion that this regimen is not a favored alternative in this clinical setting? This is especially relevant when another approach might be the sequential delivery of agents rather than a single combination program, resulting in equivalent survival, less treatment-related toxicity, and an overall superior quality of life.

Unfortunately, and perhaps surprisingly considering the risk of serious side effects, a formal quality-of-life assessment was not performed as a component of this study. The authors of this trial appear to conclude the added toxicity is justified based on the previously stated clinical endpoints. But considering the modest documented improvements noted in the presence of a substantial increased risk of clinically relevant side effects, it would not be difficult to challenge the interpretation of these investigators.

Pegylated Liposomal Doxorubicin Versus Topotecan

This study compared single-agent pegylated liposomal doxorubicin with single-agent topotecan as a treatment for platinum-resistant or recurrent potentially platinum-sensitive ovarian cancer.

 There was no observed difference in outcome (response rate, PFS, or OS) between the drugs in the platinum-resistant patient population. However, in the potentially platinum-sensitive group, the administration of pegylated liposomal doxorubicin was associated with a very modest improvement in PFS (median 28.9 weeks vs 23.3 weeks; 

 = .037) but a substantially greater difference in OS (median 108 weeks vs 71.1 weeks; 

 Somehow, a median difference of less than 2 months in PFS was translated into a median 9.2 month improvement in OS.

The investigators concluded that the administration of pegylated liposomal doxorubicin improved OS in recurrent platinum-sensitive ovarian cancer. But is this the only—or even the most likely&mdash;explanation for these unexpected and realistically unexplained findings?

An alternative perspective on the study results begins by noting that patients in this specific subgroup of the trial where the favorable impact on survival was observed potentially had platinum-sensitive disease (recurrent >6 months following the last dose of a platinum agent) when they entered the investigative program. As a result, at the time of progression on either study drug, there is a high probability the treating oncologist would select a platinum agent (most likely carboplatin) as the next therapeutic regimen. However, due to the recognized major hematologic toxicity of topotecan (delivered at the FDA-approved dose of 1.5 mg/m

 for 5 days and repeated on a 21-day schedule), it is reasonable to suggest that patients previously managed with this regimen on the trial were considerably less likely to be able to subsequently successfully receive carboplatin compared with individuals treated with the far less marrow-toxic pegylated liposomal doxorubicin.

Therefore, it is appropriate to hypothesize that rather than revealing the superiority of pegylated liposomal doxorubicin in improving OS in women with recurrent ovarian cancer, this study provided evidence for the negative impact of topotecan in preventing the adequate second-line administration of the single most important class of drugs (platinum) in this malignancy.

Erlotinib Versus Placebo In Epithelial Ovarian Cancer

The results of a recently reported phase III trial explored the use of erlotinib, a small-molecule inhibitor of EGFR, as maintenance therapy for patients with epithelial ovarian cancer who had achieved a clinically defined complete response. Erlotinib failed to improve either PFS or OS com- pared with a placebo control.

The fundamental question to be asked here is why this study was conducted when rather substantial previously reported clinical data in lung cancer had revealed overexpression of EGFR (present in a substantial percentage of epithelial ovarian cancers) was not a clinically relevant target for this class of agents? Is it acceptable that these patients were entered as “research subjects” into a trial whose biological basis was so seriously flawed?

By contrast, one could make a highly valid argument that the presence of activating mutations in EGFR, which have been shown to be a critically important target for tyrosine kinase inhibitors of EGFR in non—small cell lung cancer, might be a rational investigative strategy in ovarian cancer. In fact, the single ovarian cancer patient with such a mutation in a phase II trial of gefitinib, another small-molecular inhibitor of EGFR, in previously treated individuals with this malignancy demonstrated an objective response, while no objective responses were observed in the remainder of the patients in this study in the absence this mutation.

A phase III trial conducted by the Gynecologic Oncology Group compared the combination of cisplatin, doxorubicin, and paclitaxel (TAP) with the previous standard of care (cisplatin and doxorubicin) in recurrent or metastatic endometrial cancer.

 The study revealed an improvement in OS, but at the cost of considerable additional toxicity (similar to the observation of the FOLFOXIRI plus bevacizumab regimen in colon cancer).

However, the fundamental basis for the conduct of this trial must be challenged. First, it was known at the time of this study that single-agent paclitaxel was quite active in this malignancy.

 Second, in the closely related malignancy, epithelial ovarian cancer, the simpler and less toxic doublet combination of a platinum agent plus paclitaxel had improved OS, and there was no evidence that adding a third cytotoxic drug to a platinum-doublet further improved outcome in this setting.

Therefore, while the statistically significant superior survival observed with the TAP regimen might conceivably have resulted from the more intensive and toxic three-drug program, it could simply have occurred due to the addition of pacli- taxel to the regimen.

In fact, a subsequently conducted trial by the Gynecologic Oncology Group in the same clinical setting that directly compared the three-drug TAP regimen with the two-drug program of carboplatin/paclitaxel (the standard of care at this time in epithelial ovarian cancer) revealed the widely anticipated equivalent survival outcome between the two programs with considerably less toxicity associated with the administration of the plati- num doublet.

Again, it must be asked: Was it acceptable that these patients were entered as research subjects into a trial that was conceptually so seriously flawed?

, is president of Medicine & Science at Cancer Treatment Centers of America, and clinical professor of Medicine, Drexel University College of Medicine. maurie.markman@ctca-hope.com.

			Loupakis F, Cremolini C, Masi G, et al. Initial therapy with FOLFOX- IRI and bevacizumab for metastatic colorectal cancer. 

			Gordon AN, Fleagle JT, Guthrie D, et al. Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylat- ed liposomal doxorubicin versus topotecan. 

			Vergote IB, Jimeno A, Joly F, et al. Randomized phase III study of erlotinib versus observation in patients with no evidence of disease progression after first-line platin-based chemotherapy for ovarian carcinoma: a European Organization for Research and Treatment of Cancer-Gynaecological Cancer Group, and Gynecologic Cancer Intergroup study [published online December 23, 2013]. 

			Schilder RJ, Sill MW, Chen X, et al. Phase II study of gefitinib in patients with relapsed or persistent ovarian or primary peritoneal carcinoma and evaluation of epidermal growth factor receptor mutations and immunohistochemical expression: a Gynecologic Oncology Group study. Clin Cancer Res. 2005;11(15):5539-5548. Fleming GF, Brunetto VL, Cella D, et al. Phase III trial of doxoru- bicin plus cisplatin with or without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology Group study. 

			Ball HG, Blessing JA, Lentz SS, Mutch DG. A phase II trial of paclitaxel in patients with advanced or recurrent adenocarcinoma of the endometrium: a Gynecologic Oncology Group study. 

			Lincoln S, Blessing JA, Lee RB, Rocereto TF. Activity of paclitaxel as second-line chemotherapy in endometrial carcinoma: a Gyneco- logic Oncology study. Gynecol Oncol. 2003;88(3):277-281. McGuire WP, Hoskins WJ, Brady MF, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and IV ovarian cancer. N Engl J Med. 1996;334(1):1-6.,/li> McGuire WP, Hoskins WJ, Brady MF, et al. Assessment of dose-intensive therapy in suboptimally debulked ovarian cancer: a Gynecologic Oncology Group study. 

			Gore M, Mainwaring P, A’Hern R, et al. Randomized trial of dose-in- tensity with single-agent carboplatin in patients with epithelial ovarian cancer: London Gynaecological Oncology Group. 

			Miller D, Filiaci V, Fleming G, et al. Late-breaking abstract 1: randomized phase III noninferiority trial of first line chemotherapy for metastatic or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. 

Maurie Markman, MD, offers examples of clinical trials where the interpretation of study results is worthy of considerable additional discussion or where justification for the actual conduct of the study can be called into question. 

Controversies in Clinical Care: Questioning Research

	Assistant Professor, Division of Hematology and Medical Oncology

Lymphomas are a heterogeneous and complex group of malignancies, with more than 67 distinct subtypes. The American Cancer Society estimates that lymphoma will account for nearly 72,000 new cases of cancer this year and, even more alarming, 20,000 deaths in 2015 alone. Fortunately, recent developments in research activity have unveiled new findings on the biology of lymphomas, and the complex relationship between the lymphoma cell and the cells that surround it. These biologic insights point to distinct mechanisms that will aid in better stratifying patients for individualized therapies, and provide increased options for patients with advanced disease, where treatments remain limited.

Research and development are proliferating at such an accelerated pace that the promise of biomarker-driven targeted therapies is moving closer toward reality. It is bound to proceed at an even more accelerated pace with an infusion of dollars from the new Precision Medicine Initiative, announced by President Obama in his State of the Union address in January. It is aimed at delivering the right treatment at the right time to the right individual. This will definitely bolster our work in lymphoma, and enhance research and development into drug resistance, genomic heterogeneity of tumors, the monitoring of responses and tumor recurrence, and the use of drug combinations.

Our lymphoma research group at the Laura and Isaac Perlmutter Cancer Center at NYU Langone Medical Center is actively involved in drug development and biomarker research, focusing primarily on patients with advanced disease who are no longer responding to standard treatments. We have a stellar group of researchers in the fields of clinical research, immunotherapy, radioimmunotherapy, radiation therapy, and small-molecule drug development.

My role includes serving as the national principal investigator of a phase I Eastern Cooperative Oncology Group study (NCT01896999), which is the first trial in Hodgkin lymphoma that combines immune stimulation with direct tumor targeting. Patients with relapsed or refractory Hodgkin lymphoma are eligible for enrollment. The trial combines direct tumor targeting with the anti-CD30 antibody—drug conjugate brentuximab vedotin, and the immune-activating agent ipilimumab, an anti-CTLA-4 agent. We hypothesize that in Hodgkin lymphoma, a tumor that is to a large extent dependent on its microenvironment, this combination strategy may result in increased tumor cell elimination by the immune system, and an increased clinical response. Recruitment for this trial at NYU Langone and its Perlmutter Cancer Center is now open.

I am also the lead principal investigator on a second phase I treatment study for patients with relapsed and refractory low-grade mantle cell and low-grade B-cell lymphoma (NCT01695941). This trial, sponsored by the National Cancer Institute’s Cancer Therapeutics Evaluation Program, is testing the combination of the novel aurora kinase inhibitor alisertib with the proteasome inhibitor bortezomib, and the anti-CD20 monoclonal antibody rituximab. It is founded on the hypothesis that these drugs may work better in combination than they work by themselves. We will investigate whether giving alisertib and bortezomib together with rituximab may be a better treatment for relapsed or refractory mantle cell lymphoma or B-cell low-grade non-Hodgkin lymphoma. Recruitment for the trial at NYU Langone is now open as well.

Another treatment trial under way is for patients with advanced mycosis fungoides. This trial, at NYU Langone and other sites, is designed to find out whether a novel treatment regimen, consisting of focal lesional radiation with or without a second immune stimulant, can induce a response to the therapy out of the radiation field in patients receiving histone deactylase inhibitor therapy (NCT02061449). The overall goal is to augment both immune activation and the response to that therapy.

What is abundantly clear in multiple relapsed lymphoma subtypes is that current management strategies need to improve, and we need to have more novel and biologically based therapies to offer our patients. In addition to the above-described studies, we also are participating in many clinical trials sponsored by industry that offer innovative and novel therapies for our patients with high risk or relapsed lymphoma.

Our group has also been actively pursuing research into developing better biomarkers to improve patient stratification, thus bolstering early recognition of relapses as well as pointing to more effective precision therapies. At NYU Langone and its Perlmutter Cancer Center, we are running a pilot study to evaluate biomarkers of treatment response in patients with Hodgkin lymphoma using systemic immune profiling. At the American Society of Hematology Annual Meeting in 2014, early results were presented, showing that systemic T cells from Hodgkin lymphoma patients displayed evidence of chronic activation and exhaustion (Blood. 2014;124(21):abstr 4400). This study is open at NYU Langone for all patients with Hodgkin lymphoma.

In yet another study, in collaboration with Martin J. Blaser, MD, the Muriel G. and George W. Singer Professor of Translational Medicine and director of the NYU Human Microbiome Program at the NYU Langone, we are investigating the intestinal micro- biome and systemic immune function in lymphoma patients. This study is due to begin soon, and is open to all patients with active lymphoma and patients whose lymphoma is in remission.

Prognostic Indices and Clinical Trial Planning

Part and parcel of working in oncology is deriving the best prognostic tools for our patients. Toward that end, I have been leading a group effort in reevaluating the International Prognostic Factors Project Score and in developing a new prognostic index for advanced Hodgkin lymphoma. In this study we reviewed clinical factors from 850 patients with advanced-stage Hodgkin lymphoma treated on the Intergroup trial E2496 comparing ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) with the combined modality Stanford V regimen. We have learned that in this patient population, a streamlined three-factor risk score consisting of age, stage, and hemoglobin may provide a more accurate framework for risk prediction.

It wasn’t that long ago that there were limited options we could offer our patients with relapsed or advanced lymphoma. However, with new drug approvals and a plethora of ongoing research, we have plenty to be excited about at NYU Langone and in the field of lymphoma research.

Research and development in lymphomas are proliferating at such an accelerated pace that the promise of biomarker-driven targeted therapies is moving closer toward reality.

Molecular Biology and Immunology Discoveries Drive Novel Strategies for Lymphoma

The idea that one kind of cancer may include several subtypes, each marked by unique mutations that can be targeted with tailor-made therapies, is taken for granted these days.

Much of today’s research is focused on identifying hallmarks of cancer subtypes and developing medications to target them, and more than 65 targeted therapies for various cancer types are on the market in the United States.

Follow that trend back to its beginning and you’ll find Dennis J. Slamon, MD, PhD, standing on the starting line.

Slamon, now director of Clinical/Translational Research at the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles (UCLA), conducted the laboratory work and testing that resulted in trastuzumab (Herceptin), the first molecularly targeted therapy for breast cancer. The monoclonal antibody made by Genentech helps counteract a mutation of the HER2 gene, which is found in about 25% of patients with breast cancer. It reduces recurrence rates by half in specific types of early HER2-positive breast cancer and by one-third in metastatic HER2-positive breast cancer, and increases survival rates by about 35% and 30% in early and metastatic disease, respectively, according to the researcher.

The intravenously administered medication was approved by the FDA in 1998, and within 10 years, it had been used to treat 420,000 women worldwide. Its approval also marks the moment that the area of targeted therapies for cancer really began to take off.

“That’s the area where things are moving the fastest—finding molecular heterogeneity and taking advantage of that to develop novel therapeutic approaches for subtypes, rather than one-size-fits-all approaches,” said Slamon. “That’s where a lot of effort is going on, not just by us, but in a number of labs around the world. Trastuzumab was one of the things that really broke that wide open.”

It’s an accomplishment that made Slamon the subject of both a Lifetime television movie, Living Proof, and a book by Robert Bazell, HER-2: The Making of Herceptin, a Revolutionary Treatment for Breast Cancer. His is a particularly intriguing story because the scientist had to fight for 12 years to get trastuzumab from development through approval, keeping the project alive despite a nearly crippling early lack of funding.

“We followed the data, and if it’s there and it says your approach is right, it doesn’t matter what anyone else’s preconceived notion is,” Slamon said. “We never gave up when people said we were wasting our time.”

Those achievements have been heralded worldwide, and they are certainly appreciated by OncLive. For bringing the world trastuzumab, helping to launch an important new path for cancer research, and developing additional promising anti-breast cancer drugs during a career that has spanned about 40 years, Slamon has been selected as one of OncLive’s Giants in Cancer Care for 2014, in the Breast Cancer category.

“I was honored, as I think were all the honorees, and I felt very good about being named among those peers,” Slamon said upon learning he would receive the award.

These days, Slamon is continuing his fight against cancer through his roles at UCLA. Serving as chief of its Division of Hematology-Oncology and also as a professor of Medicine, the doctor devotes about 30% of his hours to administrative duties, including raising money for research; another 20% to seeing cancer patients; and a small percentage to teaching and giving lectures.

He spends the remainder of his time—nearly half&mdash;reviewing data and considering where it might lead.

“The highlight of my day is to meet with mid- and junior-level investigators and see this new stuff,” he said. “With colleagues capable of pushing the agenda in a positive way, we can think about exciting ideas.”

One of the most promising recent developments to come out of Slamon’s lab has been palbociclib, an oral inhibitor of CDK 4/6 that was developed for the treatment of hematopoietic malignancies but was only mildly active in that cancer type. In February, the FDA granted accelerated approval to palbociclib, which Pfizer developed under the trade name Ibrance, in combination with letrozole as a first-line treatment for HER2-negative advanced or metastatic breast cancer in postmenopausal women.

Another project of Slamon’s lab has involved BMN 673, a PARP inhibitor being developed by BioMarin that targets BRCA1/2 mutations in patients with locally advanced or metastatic breast cancer, but that also may have promise for the treatment of triple-negative breast cancer, some breast cancers, and other malignancies, Slamon said. The drug is being tested in a phase III clinical trial.

Not surprisingly, Slamon and his colleagues are also continuing to work with trastuzumab.

In 2010, the drug was approved by the FDA for use in HER2-positive metastatic stomach cancer, in combination with chemotherapy. Now, Slamon’s group is considering potentially better ways to use the drug, such as in combination with other antibodies or other targeted agents.

“We’re looking at what other pathways you might be able to block in combination with HER2 to be more efficacious in any malignancy where the alteration is—breast and gastric, although some ovarian cancers, 8% to 10%, have the alteration, as well,” he said.

The son of a coal worker and a homemaker, Slamon knew from the age of 5 or 6 that he wanted to be a doctor, inspired by the physician who used to make house calls to treat his family.

“He was very caring, very gentle, and very effective,” Slamon recalled. “I thought it would be great to be able to help people like that and make a family feel so good.”

In high school in New Castle, Pennsylvania, a student teacher fueled Slamon’s interest by infusing his lessons about biology with enormous enthusiasm. Slamon moved on to Washington & Jefferson College, in his home state, excited to learn more.

“I took all but one of the biology courses the school had to offer, because I couldn’t fit any more into my schedule,” he said. “I loved the topic, the diversity of it, and the more I learned, the more I thought about combining my interests in biology and medicine.”

Slamon did exactly that, simultaneously earning his medical degree and doctorate in cell biology in 1975 through a combined MD/PhD program at the Pritzker School of Medicine at the University of Chicago.

It was there that he began the research that paved the way for trastuzumab. In the lab of Winston A. Anderson, PhD, a cell biologist in the Anatomy Department, and under the tutelage of Werner Kirsten, MD, of the Pathology Department, Slamon participated in research on retroviruses that caused cancer in mice.

“They were incredibly potent, more than anything we’d seen—acutely transformative retroviruses that caused cancer 2 to 3 weeks after injection,” Slamon said. “We learned, ultimately, that they were carrying an oncogene,” a gene with cancer-causing potential.

Long Battle, Long Hours On Path To Trastuzumab

That work led to a breakthrough several years later as Slamon completed a fellowship at UCLA’s Division of Hematology-Oncology.

“We realized that what these acutely transformed viruses were carrying that made them so potent were genes stolen from normal cells,” Slamon said. Once stolen, the researcher found, those genes—known as proto-oncogenes&mdash;were altered, becoming abnormal and contributing to the growth of cancer.

Slamon built on that knowledge in 1986, when he was asked by a Genentech researcher to look for siblings to the epidermal growth factor receptor, also known as HER1, a protein that sits on the surface of a cell and can cause cancer if mutated. One of the six genes Slamon was asked to investigate was HER2, and the results intrigued him.

“In 25% of breast tumors, we saw an alteration of gene amplification, an overabundance of numbers of the HER2 gene,” Slamon recalled. “Then, we realized that women whose tumors contained the alteration had a much different outcome. They had a more aggressive tumor that recurred more rapidly, and they died more quickly.”

The chilling finding proved something that would help change the face of cancer treatment.

“It told us right away that we were not dealing with one disease in breast cancer,” Slamon said, “even though the dogma at the time was that each disease was a monolith, defined by the tissue where it arose and treated with a one-size-fits-all approach.”

To Slamon, HER2 looked like a perfect target for treatment with an antibody, but not everyone agreed.

“No one was interested in pursuing antibodies because so many had failed,” Slamon said. “I was trying to convince Genentech to stay with the program based on the data, and it took a couple of years of hard sell. The company wasn’t terribly enthused, but there was a core of people there who believed in the data and kept the project alive.”

Luckily for Slamon, there were also private funders who felt certain he was on the right track.

One was Lilly Tartikoff (now Lilly Tartikoff Karatz), whose husband, Brandon, then president of NBC’s Entertainment Division, had been treated for cancer by Slamon. The other was Tartikoff’s friend, Ronald O. Perelman, chairman of Revlon, whom Tartikoff approached for support.

Initially, Slamon recalled, Perelman donated $1.8 million to help with his research. In 1995, Perelman gave $7.5 million to establish the Revlon/ UCLA Women’s Cancer Research Program, which Slamon still directs.

Millions more have been raised for Slamon’s research, first through an annual Fire and Ice Ball founded by Tartikoff and Perelman, and now through the yearly Revlon Run/Walk. There’s one Run/Walk in Los Angeles and one in New York, which together largely fund the translation of work from Slamon’s lab into clinical trials, he said.

“Lilly told me what amazing work Denny was doing, and said that if he only had the funding, he could help many people,” recalled Perelman, who also is CEO and chairman of MacAndrews & Forbes Holdings. “After meeting him and seeing the potential in what he was working on, I immediately wanted to get involved. Denny is one of the most brilliant and dedicated researchers in medicine today, and his work has saved many women’s lives. I am so proud to have been able to help him accomplish that.”

A major supporter of Slamon’s preclinical work has been the US Department of Defense’s Breast Cancer Research Program, through its Innovator Award, the doctor added.

With funding still difficult to come by for many scientists, Slamon wants to see every grant and donation used as effectively as possible. That’s why the researcher spent 3 years as part of a Dream Team put together by Stand Up To Cancer, a project of the Entertainment Industry Foundation that utilizes the star power of celebrities to raise funds aimed at slowing the competition between labs and bringing them together to collaborate.

“The idea that one lab will make progress quickly is archaic,” he said. “Putting funds behind the effort to bring labs together is a good experiment.”

While Slamon’s grant through Stand Up To Cancer has been completed, he remains convinced that collaboration between labs is essential.

“That’s still the ideal way to do research, although I’m not sure we’ve yet mastered it,” he said. “There are still improvements we can have on that model, but I think that kind of collaboration, team research, can be conducted and is the best way to approach problems on a given drug.”

Regardless of the format, Slamon is committed to continuing the work that was his childhood dream—and the embodiment of the values he absorbed during those years.

“My parents taught us that doing something productive that could help others was the pinnacle of what you might want to achieve,” he recalled. Accomplishing that through the development of trastuzumab was “enormously gratifying,” he added. “It’s what it’s all about.”

	Saluting the “Quintessential Mentor”

Co-Director, JCCC Signal Transduction and Therapeutics Program Area

“I have worked with Dr Slamon since I wandered into his laboratory as an undergraduate at UCLA. Dennis has been the quintessential mentor: inspiring, supportive, and constructive. Other than my parents, it’s hard to think of someone who has influenced me so much.

“His seminal observation in linking HER2 amplification to outcomes in breast cancer led to a paradigm shift in our approach to not only breast cancer but all of oncology. He then drove the approval of trastuzumab, the epitome of bench-to-bedside oncology.

“He brings a drive for basic scientific investigation that does not lose sight of the main objective: improving the outcomes of patients. It is no coincidence that his contributions have led to both the approval of not only trastuzumab, but also of palbociclib. I am fortunate to be able call him a friend and colleague.”

“There are few people in the oncology community who have had a greater impact on developing drugs for cancer than Dennis Slamon. The preclinical work and follow-on clinical trials that he has led have led to curative and life-prolonging therapy for breast cancer patients around the world.

“This research pedigree, which has now continued with the development of a new targeted therapy palbociclib, is the gold standard for a translational researcher who has had a direct impact on patients.”

Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study [published online December 16, 2014]. 

Perez EA, Press MF, Dueck AC, et al. Immunohistochemistry and fluorescence in situ hybridization assessment of HER2 in clinical trials of adjuvant therapy for breast cancer (NCCTG N9831, BCIRG 006, and BCIRG 005) [published online February 19, 2013]. 

Wainberg ZA, Anghel A, Rogers AM, et al. Inhibition of HSP90 with AUY922 induces synergy in HER2-amplified trastuzumab-resistant breast and gastric cancer [published online February 8, 2013]. 

Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. 

Valero V, Forbes J, Pegram MD, et al. Multicenter phase III randomized trial comparing docetaxel and trastuzumab with docetaxel, carboplatin, and trastuzumab as first-line chemotherapy for patients with HER2-gene-amplified metastatic breast cancer (BCIRG 007 study): two highly active therapeutic regimens [published online November 29, 2010]. 

Hurvitz SA, Allen HJ, Moroose RL, et al. A phase II trial of docetaxel with bevacizumab as first-line therapy for HER2-negative metastatic breast cancer (TORI B01). 

O'Brien NA, Browne BC, Chow L, et al. Activated phosphoinositide 3-kinase/AKT signaling confers resistance to trastuzumab but not lapatinib [published online May 25, 2010]. 

Slamon DJ, Press MF. Alterations in the TOP2A and HER2 genes: association with adjuvant anthracycline sensitivity in human breast cancers [April 28, 2009]. 

Jones LW, Haykowsky M, Peddle CJ, et al. Cardiovascular risk profile of patients with HER2/neu-positive breast cancer treated with anthracycline-taxane-containing adjuvant chemotherapy and/or trastuzumab. 

Mass RD, Press MF, Anderson S, et al. Evaluation of clinical outcomes according to HER2 detection by fluorescence in situ hybridization in women with metastatic breast cancer treated with trastuzumab. 

Tripathy D, Slamon DJ, Cobleigh M, et al. Safety of treatment of metastatic breast cancer with trastuzumab beyond disease progression. 

Vogel CL, Cobleigh MA, Tripathy D, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. 

Dennis J. Slamon, MD, PhD, has had an immeasurable impact on the treatment of women with breast cancer by developing trastuzumab (Herceptin) and helping to launch the era of targeted therapies. He was honored in the Breast Cancer category with a 2014 Giants of Cancer Careâ„¢ award, a program that the Intellisphere® Oncology Specialty Group launched to honor leaders in the field. 

March 2015 | Oncology Live®

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