Massachusetts General Hospital Cancer Center: At the Forefront of Personalized Care

Massachusetts General Hospital Cancer Center

Recognized as one of the nation’s leading cancer care providers, the Massachusetts General Hospital (MGH) Cancer Center comprises 23 fully integrated, multidisciplinary clinical programs, as well as an extensive array of support and educational services. With a network of affiliations that extend throughout New England and the southeastern United States, the MGH Cancer Center is consistently ranked as one of the nation’s top 10 cancer centers by US News & World Report.

The Center’s commitment to advancing oncology care by tailoring treatment options to the individual patient is apparent from the laboratory to the bedside. Physician investigators conduct nearly 400 clinical trials annually, and the Center is a founding member of a 7-member Harvard Medical School consortium designated by the National Cancer Institute as a comprehensive cancer center, forming what is the largest cancer research collaboration in the country and revolutionizing the future of cancer medicine with the novel treatments developed through this partnership. Furthermore, MGH nurses were the first in Massachusetts to achieve Magnet status from the American Nurses Credentialing Center in recognition of the hospital’s exceptional nursing care.

Two examples of the Center’s powerful synergy between laboratory scientists, bedside physicians, and nursing staff are its ground-breaking work with the CTC-chip and the genetic profiling initiative of the Molecular Pathology Translational Research Lab.

The CTC-Chip: A New Era of Cancer Research

It was 2008 when MGH Cancer Center scientists published 2 papers describing promising results for a new nanotechnology device that enables capture of circulating tumor cells (CTCs). Known as the CTCchip, the technology at long last provided the means to analyze these exceedingly rare, living solid-tumor cells in real time, and to unlock critical information with the potential to revolutionize the way cancers are detected, treated, and monitored.

Lecia V. Sequist, MD, MPH

“With the rapid emergence of highly personalized cancer care comes a pressing need for a thorough understanding of the genetic makeup of malignant tumors, and an equally clear understanding of what happens in those tumors over time,” said Lecia V. Sequist, MD, MPH, medical oncologist and co-lead author of The New England Journal of Medicine article that first described the CTC-chip. “The CTC-chip is proving integral to achieving this understanding and applying what we learn to clinical practice,” Sequist said.

In its first incarnation the CTC-chip, developed by MGH Cancer Center researchers and BioMicroElectroMechanical Systems (BioMEMS) Resource Center scientists, was a business-card-size silicon chamber containing thousands of microfluidic antibody-coated posts designed to attract and enable capture of CTCs from small blood samples. A pilot study demonstrated its ability to not only detect CTCs, but also to reveal the genetic signature of lung tumors in patients with nonsmall cell lung cancer, identify candidates for targeted therapy, define prognostic and predictive measures, and measure treatment response.

These findings notwithstanding, the post-based chip proved impractical to manufacture for largescale clinical trials, prompting the development of a next-generation herringbone CTC-chip, explains Shannon L. Stott, PhD, research fellow and coinventor of the new chip. “In this herringbone version, which is now transparent, the posts have been replaced with grooves that create chaotic flow of blood as it travels through the device, allowing more interaction between the CTCs and the chip’s antibodycoated surface, and making large-scale manufacturing more practical and cost effective,” Stott said.

Shannon L. Stott, PhD

To date, the herringbone chip has been used in clinical studies designed to identify CTCs from patients with metastatic prostate, lung, pancreatic, colon, and breast cancers, and is enabling identification of mutations that help to indicate which patients are likely to benefit from targeted therapies.

The Future Is Now: The “Dream Team” Meets the Challenge

Accelerating the translation of this technology from bench to bedside is a landmark grant from the Stand Up To Cancer (SU2C) initiative “to move groundbreaking cancer research out of the lab and into the clinic.” In keeping with SU2C’s research model requiring applicants to create unparalleled collaborations by reaching across disciplines and institutions, Cancer Center director Daniel Haber, MD, PhD, and BioMEMS director Mehmet Toner, PhD, created a “dream team” that more than fulfills those requirements. Within MGH, that team brings together the bioengineers, molecular biologists, and clinicians who worked together to make the CTC-chip a reality. Furthermore, MIT bioengineers work with MGH engineers to enhance the sensitivity of the CTC-chip technology, while clinical researchers from Memorial Sloan-Kettering Cancer Center, Dana-Farber Cancer Institute, and MD Anderson Cancer Center collaborate with MGH researchers to define applications.

Facilitating this collaborative effort is a centralized website, created by MGH’s engineering team, where all participating centers can report their data, access the data of other centers, and view actual CTC images, Stott explained. “This centralized venue helps to guide all involved in their decisions about data interpretation, protocol development, and clinical trial design,” she said.

Sequist, whose primary area of research is new drug development for lung cancer, noted that the possibilities for the technology are nearly endless, as researchers with varied interests and priorities share their findings and perspectives. Citing prostate cancer as just one example, she noted that researchers have shown changes in CTC numbers over time in patients treated surgically. In lung cancer, the herringbone chip is being studied as a means to not only detect and analyze genetic abnormalities in those with the disease, but also as a tool for analyzing blood samples of those never diagnosed with cancer, potentially bringing primary care physicians to the forefront of early detection.

“This is not your ‘grandfather’s biopsy,’” said Sequist, noting that the CTC-chip is, in many cases, providing tumor-specific information not provided by conventional imaging studies, and may ultimately reduce the need for repeated conventional biopsies. Acknowledging that the technology is still in its infancy, she cited screening and diagnosis, guiding treatment decisions, monitoring for recurrence after treatment or during remission, and even predicting drug sensitivity patterns in patients with a wide range of cancers as among the myriad of potential applications. “We’re also hoping that this technology will usher in a new understanding of the biology of cancer that will enhance our knowledge and detection of blood-borne metastasis, enabling more rapid and targeted treatment,” Sequist said.

Noting that the CTC-chip’s full clinical potential will be realized only when the technology can be widely adopted by industry, Sequist sees great promise in the agreement signed with Johnson & Johnson to develop future CTC technologies, and predicts that the chip will become widely available within 5 years or less. Thanks to the SU2C grant, large-scale manufacturing is underway, as is dissemination to centers across the country.

Massachusetts General Hospital Cancer Center Timeline

1976

2001

2002

2009

The MGH Cancer Center is opened.

The Proton Beam Therapy Center opens.

The Yawkey Center for Outpatient Care opens its doors.

Leading the way in a new era of cancer care, MGH opens its new Molecular Pathology Translational Research Lab.

1929

1989

2008

2009

Massachusetts General Hospital (MGH) founds the first of its kind tumor clinic and tumor bank.

Department of Pathology research fellow J. Michael Bishop, MD, receives the Nobel Prize in Physiology for his discovery that normal cells contain genes capable of becoming cancer genes.

A team of MGH researchers, led by

Mehmet Toner, PhD, and Daniel Haber, MD, PhD, takes the oncology research world by storm with the publication of 2 articles describing promising findings for the CTC-chip.

The Cancer Center is awarded $15 million to fund the CTC-Chip Dream Team by a blue ribbon scientific advisory committee commissioned by Stand Up To Cancer’s scientific partner, the American Association of Cancer Research.

Genetic Profiling: The MGH Cancer Center Translational Research Laboratory

In another endeavor aimed at speeding novel therapies into clinical use, knowledge gained at the molecular genetic level takes center stage at the MGH Cancer Center Translational Research Lab, where the goal is to minimize generalizations made in treatment decisions by providing “rapid personalized genomic testing as an important component of routine care.” To this end, the lab, jointly developed by the Cancer Center and Pathology Department and opened in 2009, guides personalized medicine to the forefront of patient care through the collaborative efforts of oncologists, pathologists, and basic scientists.

Genotyping: Unlocking the Door to Personalized Care

The flagship of the lab’s endeavors is its tumor genotyping initiative, which, by analyzing the genetic codes and identifying gene mutations from a large proportion of MGH’s cancer patients, is providing specific information about tumor properties that lead to highly personalized targeted therapy.

Leif William Ellisen, MD, PhD

Tumor genotyping involves interrogating the more than 12 major molecular pathways that, when activated or dysregulated, can turn normal cells into tumor cells. Currently, scientists test for approximately 130 tumorigenic genetic mutations, many of which are involved in several different types of cancers. “While cancers are currently classified by the organs from which they arise, many different types of tumors share the same genetic mutations, offering the potential for treatment with the same therapeutic agent that targets that abnormality,” said oncologist Leif William Ellisen, MD, PhD, who serves as the lab’s co-executive director, and as clinical director of Breast and Ovarian Cancer Genetics.

MGH was the first center to conduct molecular profiling of positive biopsies and tumors from its patients as part of basic patient care. The lab began by genotyping lung cancer patients, and then gradually phased in the profiling of all patient tumors. While other centers have since jumped on the profiling bandwagon, Ellisen is quick to point out how MGH’s efforts differ. “Rather than developing a research assay or database, our interest was in developing a clinical assay that any physician could order and use to guide decision-making about each patient’s care,” he explained.

The assay was first offered to physicians treating patients with lung adenocarcinoma, and was gradually made available for use in a broader range of cancers. Now 3 years since its launch, MGH physicians order the assay just as they would any other test. The information gleaned from the assay then follows the patient; once used to select an appropriate clinical trial or approved agent, the information is stored in the patient’s chart and made available to all treating physicians.

“The point is to focus on the genetic mutations relevant to the care of individual patients,” Ellisen said. “Because the assay is intended for use in conjunction with approved treatments or in clinical trials, the genetic mutations we test for are those known to be cancer-causing (not inherited). We look for roughly 130 mutations known to cause cancer, the pathways for which the new targeted agents are being developed.”

A New Era: The Right Drug for the Right Patient

The MGH tumor genotyping initiative is also expected to dramatically shorten the time it takes to find the right drug for the right patient; while research results can take a decade or longer to be translated into clinical use, genotyping can bring new therapies to patients in just months. “If, for example, we identify a mutation in a case of lung cancer and know that a particular drug has been successful in treating colon cancer patients with the same mutation, we can then enroll such a patient in a smart clinical trial to see if the drug will work in the lung cancer patient as well,” Ellisen explained.

“For years we’ve been operating with an outdated paradigm, characterizing tumors solely by the organs from which they arise and basing treatment decisions on routine tumor staining and little else,” he said. “We now understand the essential role that information about each patient’s tumor plays in selecting the appropriate treatments.” Citing lung adenocarcinoma as an example, Ellisen noted that each of the 6 or more different mutation patterns identified in such patients will likely require a different form of therapy. “Lung cancer is not a single disease; different lung tumors have different genetic drivers that require different agents to shut them off.”

Increasingly, efforts in this area are focusing on maximizing the efficacy of novel therapies by basing their use on an underlying genetic fingerprint most likely to complement the drug’s actions, thereby accelerating the process of matching a drug to the patients most likely to benefit. “This approach will be repeated for every type of cancer,” said Ellisen, “and is already changing the way we develop, test, and bring novel therapies into clinical use.”

Implications for Nursing

Without a doubt, these initiatives are translating into hope. And with hope comes enthusiasm, optimism— and the unknown.

Theresa McDonnell,

RN, MSN, ACNP-BC

As a nurse practitioner involved in both direct patient care (GI oncology) and administration, MGH Cancer Center director of Nursing Theresa McDonnell, RN, MSN, ACNP-BC, has seen significant changes over the past several years. “Until 5 years ago, we had limited options to offer many of our patients,” she said. “Our relatively new understanding of tumor genetics, coupled with the advent of targeted therapies, is now allowing us to offer hope where, not long ago, there was none,” McDonnell said. According to McDonnell, this is especially apparent in patients who have exhausted all conventional treatment options. “We now have a new level of confidence in referring patients for phase I trials or when preparing them for treatment with already-approved targeted agents. And, in many cases, we’re able to reassure them that what they’ll experience is much more tolerable than what they’ve already endured with treatments such as chemotherapy. I have no doubt that our patients can sense that confidence in our explanations.”

Challenges Remain

Of course, with new treatments come new challenges. As an administrator, McDonnell is acutely aware of the reimbursement issues that come to the forefront as science pushes the envelope, and notes that this is an area that, in particular, calls upon the nursing staff to advocate for their patients. “Insurance companies tend to put all novel therapeutics into a bucket of ‘unknown biologics,’ forcing us to justify what has already been demonstrated in the lab,” McDonnell explained. “Our entire team works together to submit all necessary material upfront, such as data and letters of necessity, to avoid delays and denials, which are intensely frustrating for the patient. Despite our best efforts, we do see a few denials. But, as with all new processes, we need to trip and fall a few times before we learn to walk.”

Despite these challenges, McDonnell remains optimistic. “Every day we get closer to unlocking the keys to specific cancers,” she said, adding that the era of “off-the-shelf” cures is at long last coming to an end. “The ability to offer enhanced quality and, hopefully, duration of life makes these exciting times for patients and nurses alike.”