Susan R. Peck, PhD

A common theme running through recent advances for metastatic cancers has been the increasing role of molecular or genomic information to identify tumors that are most likely to respond to a specific drug and to develop drugs that target specific cellular pathways.

For example, identification of the BCR-ABL mutation in chronic myeloid leukemia led to the development of effective drugs that turned a highly fatal cancer into one with survival times of 20 years and more. In colorectal cancer, the mutation status of the KRAS gene is being used to identify patients who are candidates for EGFR-targeted antibodies, while EGFR mutations may be used to select therapies in lung cancer. Overexpression of the estrogen receptor and HER2 can be used to determine treatments for patients with breast cancer. More recently, new agents have been developed for lung cancers with a rearrangement of the ALK gene and for melanomas that contain a BRAF mutation.

We use the information to assign the patients to the treatments, but we also use the tissue and material to potentially discover new things that could benefit future patients with lung cancer.

Molecular information is also beginning to drive the design of clinical trials to develop new therapies. One such trial is the BATTLE-2 lung cancer trial, a study “designed to understand how tissue biomarkers predict who will respond to targeted therapy or targeted therapy combinations,” according to Yale School of Medicine’s Roy Herbst, MD, PhD, one of the lead investigators. Patients entering the trial undergo a biopsy, the genetic status of their tumor is determined, and they are assigned to one of four different drugs or combinations. As the trial goes on and researchers learn about the predictive power of different biomarkers, this information will be used to help select the treatment that patients receive.

“We use the information to assign the patients to the treatments, but we also use the tissue and material to potentially discover new things that could benefit future patients with lung cancer,” says another lead investigator, Ignacio Wistuba, MD, of M.D. Anderson Cancer Center in Houston.

As researchers continue to mine the molecular make-up of cancers cells, patients can look forward to more effective treatments tailored specifically for them—and that’s a revolution to believe in.

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Molecular and genomic information can identify tumors most likely to respond to a specific drug.

The Molecular Revolution

Not too many years ago, when a patient received a diagnosis of cancer that had spread beyond the primary site, doctors had little to offer. Now, they have an increasing number of therapies, emotional and financial support and an improved quality of life. Years of research are yielding dividends in the form of more active drugs and more effective treatments to deal with metastatic disease. Many metastatic cancers are moving toward becoming manageable chronic diseases, and for a few types of cancer, cures are even possible.

At age 30 and having never smoked, Anne Marie Cerato received a diagnosis of stage 3 lung cancer in April 2009. The Toronto resident underwent chemotherapy and radiation together, followed by surgery, but the cancer came back in May 2011. Cancer cells had also spread to her other lung. Radiation and surgery were no longer options—doctors told her to wait until she was symptomatic, at which point they would treat her with chemotherapy.

But for Cerato, “going home and sitting and waiting and watching was not good enough,” she says. She began investigating her options and found a clinical trial for an investigational drug, now known as Xalkori (crizotinib). She spoke with her oncologist, who referred her to a nearby center participating in the trial. Analysis of her tumor cells revealed that they carried an uncommon mutation in the ALK gene, which produces a protein leading to growth and spreading of cancer cells that is blocked by Xalkori. She enrolled in a phase 3 trial where she received the experimental treatment. Cerato has been taking the drug for a year. “My scans are clear, everything is stable, and so far there is no evidence of disease in my lungs, which is great,” she says.

Cerato says that while receiving a diagnosis of metastatic (stage 4) disease was devastating, in some ways it was also liberating.

“It gave me permission to realize that my life would never really be normal,” Cerato says, “and allowed me to choose to live my life for myself and not for anyone else.”

One action she found therapeutic was getting tattoos, which was “a way of exerting control over my own body,” she says. While Cerato says she knows Xalkori isn’t a cure, “It has given me a completely clean slate and lots and lots of hope because I’m responding so positively and others are too.”

[My diagnosis] gave me permission to realize that my life would never really be normal and allowed me to choose to live my life for myself and not for anyone else.

The goal of treatment for late-stage cancer varies, depending on the type of cancer. In some cases, a cure may be possible with current therapies, even when the cancer has spread beyond the primary site. In other cases, although a cure may not be attainable, newer and better therapies are extending the time patients can live with their disease while maintaining a good quality of life. A few cancers are even becoming chronic diseases that can be stabilized and managed with a succession of different treatments.

Testicular cancer is a model of success, with one of the highest cure rates of any solid tumor. Over the past four decades, the cure rate has risen from 25 percent to about 80 percent for patients with metastatic disease. This dramatic improvement was the result of discovering that testicular cancers were particularly sensitive to the chemotherapy drug cisplatin, and regimens containing this drug have become a mainstay of treatment. For patients who relapse, a cure may still be possible with other therapies.

Some forms of lymphoma may be curable at advanced stages, too. Overall, Hodgkin lymphoma has an 80 percent cure rate, while approximately two-thirds of patients with diffuse large B-cell lymphoma can currently be cured. For patients with lymphoma whose disease returns after a remission, one potential option is more aggressive treatment with highdose chemotherapy followed by a stem cell transplantation to replenish essential blood cells that are wiped out during the treatment. However, it has risks of its own and is only appropriate for patients in good overall health, but may be curative for relapsed lymphoma, as well as certain other blood cancers. New drugs are also being investigated for resistant lymphomas, and the FDA recently approved the anti-CD30 antibody drug conjugate Adcetris (brentuximab vedotin) for relapsed Hodgkin lymphoma.

Follicular lymphoma (FL) is a good example of a cancer that cannot be cured with current drugs, but because of its slow disease course and the effectiveness of available treatments, such as chemotherapy plus the anti-CD20 antibody Rituxan (rituximab), it can be managed for long periods of time. In fact, the median survival time is 14 years, with some patients living even longer. Since many patients are older and will likely die of other causes before succumbing to their cancer, the primary goal of treatment in many cases has shifted to maintaining quality of life and managing symptoms while living with FL.

Prostate cancer is similar in some ways to FL. Often, advanced disease can be controlled for years with currently available hormone therapies. The primary concern is managing disease symptoms as well as side effects of therapy. For patients whose disease has developed resistance after treatment with either hormone therapies or standard chemotherapy, a number of drugs have recently been shown to further extend survival, including Provenge (sipuleucel-T), an active cellular vaccine that takes immune cells from the patient and teaches them to recognize and destroy the cancer cells; Zytiga (abiraterone), a drug that blocks the production of androgens, the hormones that fuel prostate cancer cells; and Jevtana (cabazitaxel), a new taxane chemotherapy. Finally, another new drug that inhibits androgen receptor signaling in the cancer cells, Xtandi (enzalutamide), improved survival in men with castration-resistant prostate cancer and was approved by the FDA in late August.

Stage 4 breast cancer is another increasingly manageable cancer (see sidebar, page 19). For patients with estrogen receptor-positive cancer, there are a variety of hormone therapies that can be used, and patients often cycle through several of these before starting more toxic chemotherapy regimens. New targeted agents continue to be tested in combination with hormone therapies to to be tested in combination with hormone therapies to overcome tumor resistance. This approach has recently proven successful. Adding Afinitor (everolimus), a drug that inhibits mTOR (a protein that helps regulate cell growth) to exemestane (an aromatase inhibitor) more than doubled the time until their disease progressed. This combination was approved by the FDA in July.

For women whose breast cancers overexpress the HER2 receptor or exhibit HER2 gene amplification, the introduction of Herceptin (trastuzumab) marked a turning point in treatment and led to an explosion of research into additional HER2-targeted therapies. Perjeta (pertuzumab), an antibody that targets the HER2 receptor in a slightly different way than Herceptin, was recently added to the arsenal for metastatic HER2- positive breast cancer. Another new therapy, T-DM1, uses the Herceptin antibody to deliver a potent chemotherapy drug (emtansine) directly to tumor cells. This drug also extends the progression-free survival, as well as overall survival, and is currently being reviewed by the FDA.

Although colorectal cancer has traditionally had a poor outlook, advances in surgical techniques and systemic therapies have actually made it possible to cure some patients with metastatic disease, particularly if it has only spread to the liver. The use of chemotherapy before surgery may be able to shrink some tumors and make them operable, further expanding the subset of patients who can be treated with curative intent. For patients with more widespread metastases, the outlook has also improved significantly in the last decade. The introduction of targeted agents, such as Avastin (bevacizumab), Erbitux (cetuximab) and Vectibix (panitumumab), as well as refinements in standard chemotherapy regimens, led to an increase in median survival, from eight months to more than two years. More new therapies are poised to enter the clinic, including two new drugs that, like Avastin, block the formation of blood vessels in tumors. Zaltrap (ziv-aflibercept) was approved by the FDA in August, while Stivarga (regorafenib) was approved in September.

Years of patience and basic research is finally beginning to pay off even for those cancers that have traditionally been associated with a very poor prognosis and lack of treatment options. For example, the discovery that lung cancers with mutations in the epidermal growth factor receptor were more sensitive to drugs targeting this receptor triggered the start of individualized, molecularly targeted therapy for non-small cell lung cancer. More recently, about 2 to 7 percent of lung cancers were found to contain a rearrangement of the ALK (anaplastic lymphoma kinase) gene, leading to the rapid testing and approval of Xalkori (crizotinib), an ALKtargeted drug, as mentioned above in Cerato’s story.

David Gandara, MD, director of the thoracic oncology program at the University of California—Davis Comprehensive Cancer Center in Sacramento, Calif., says the biggest change has been the recognition that lung cancer is not just one disease, but multiple subtypes that originated in the lung. “To a certain extent, each patient represents their own subset,” Gandara says, “and we know that because we can distinguish the molecular biology of that cancer—it’s like a fingerprint, and that molecular fingerprint is almost different for every single patient. That’s what has changed therapy, thinking of the patients as individuals.

“I think what patients can look forward to in the future is coming into their oncologist’s office with their own genetic resume—here’s my molecular fingerprint&mdash; and working with their physician as a partner to decide what forks down the road they should take,” Gandara says.

There are collaborative efforts under way to study the genome of the two most common subtypes of lung cancer (adenocarcinoma and squamous cell carcinoma).

Some cancers, such as ovarian, are just beginning to enter the era of molecularly targeted therapy. There has been little progress in improving survival outcomes for patients with stage 4 ovarian cancer since the introduction of platinum-based therapy more than 30 years ago, but research efforts are now focusing on targeting therapies toward selected subsets of cancers. For example, inhibitors of PARP (poly [ADP-ribose] polymerase), an enzyme involved in DNA damage repair, are being investigated for patients with ovarian, breast and other cancers that are driven by inherited mutations in the BRCA1 or BRCA2 DNA repair genes. In a randomized phase 2, the PARP inhibitor olaparib extended the remission of ovarian cancer after platinum-based chemotherapy.

Niki Quasney of Munster, Ind., received a diagnosis of stage 4 ovarian cancer when she was 33 years old. The diagnosis didn’t come as a shock—when an older sister developed breast cancer at a young age, Quasney was tested for the BRCA mutations. After she had discovered she was positive for a mutation that increases the risk for breast and ovarian cancers she underwent a prophylactic mastectomy but delayed having her ovaries removed. She had always been told by her doctors that she could wait until she was 35 to 40 years old to remove her ovaries, and she thought she had time. But then a biannual blood test indicated increased levels of CA-125, a biomarker that is elevated in ovarian cancer as well as other conditions. Additional tests revealed ovarian cancer that had spread throughout her abdomen. The hardest part of the diagnosis was telling her family, particularly because her father was in the last stages of pancreatic cancer.

Quasney underwent surgery and intensive chemotherapy, and her cancer went into remission for two years before she experienced a relapse. After surgery and another round of chemotherapy put her cancer back into remission, Quasney enrolled in a clinical trial designed to test whether another investigational PARP inhibitor, veliparib, could help to maintain her remission. So far, it appears to be working, although there are not enough data on this drug yet to know whether it will extend her remission.

Despite the uncertainty, Quasney is putting this remission to good use and living life to the fullest—raising her daughter with her partner, biking and participating in sprint triathlons, fundraising for ovarian cancer research and pursuing social justice issues about which she is passionate. She gets a CA-125 test every three weeks to monitor for signs of the cancer’s return. Quasney compares getting good results to American Idol, “I feel like I’m safe for another three weeks. I haven’t been voted off yet.” If the cancer does return, Quasney says, “I don’t know what the next step is, but I know there are a lot of other drugs out there.”

It's very encouraging to know that these people [researchers] are devoting their jobs and their lives to finding cures for ovarian cancer and new drugs.”

Another cancer that has been traditionally hard to treat is pancreatic cancer, but even there, new treatments are finally beginning to show promising results. A new combination of chemotherapy drugs, FOLFIRINOX (5-FU [fluorouracil], leucovorin, irinotecan and oxaliplatin), was recently shown to improve overall survival in a phase 3 trial.

“Median survival is now over 10 months, close to a year, which is very encouraging, and we’re starting to see patients survive for two years, which we never saw before,” says Ramesh Ramanathan, MD, clinical professor at the Translational Genomics Research Institute and medical director of the clinical trials program at the Virginia G. Piper Cancer Center in Scottsdale, Ariz. Researchers are also investigating targeted agents, searching for biomarkers to identify patients who can benefit most from the already-approved Tarceva (erlotinib), a drug that targets EGFR (epidermal growth factor receptor), and evaluating new therapies that target overexpressed or mutated genes, such as the PI3 kinase inhibitors, c-Met inhibitors, IGF-1R inhibitors and agents targeting the stroma, the supporting nonmalignant tissue that tumor cells op-opt (or recruit) to help support them.

“I think in pancreatic cancer we are moving from standard cytotoxics [chemotherapy] to looking at the molecular profiles of patients,” Ramanathan says. “I think that’s a big advance for pancreatic cancer.”

Ramanathan encourages patients to ask about new approaches and clinical trials related to their individual care.

Cerato says if her cancer stops responding to Xalkori, she is open to trying one of the many new treatments currently under investigation.

“It is interesting what is coming down the line, and it is an exciting time,” she says.

“Clinical trials are where they are going to find things that are going to make a difference,” Quasney says. “It’s very encouraging to know that these people [researchers] are devoting their jobs and their lives to finding cures for ovarian cancer and new drugs.”

Reasons for Hope: Options are available to keep disease at bay.

Treating and Managing Metastatic Disease

While today’s imaging tests provide anatomical information about a tumor’s size and location, tomorrow’s imaging technologies will look deeper, at the molecular make-up of cancer cells.

Some potential uses for these more advanced technologies include detecting and characterizing cancers without the need for biopsies or other invasive procedures, ensuring that drugs are reaching the tumor and promptly monitoring the effect of therapies so treatment can be changed if necessary.

Positron emission tomography (PET) is leading the way in the molecular imaging revolution. Currently, in oncology most PET imaging is performed with a radioactively-labeled form of glucose, a type of sugar, called 18F-fluorodeoxyglucose, or simply FDG. Cancer cells, particularly those from aggressive tumors, metabolize significantly larger amounts of glucose than surrounding normal tissue. FDG-PET imaging measures glucose uptake, revealing how active a cancer is and detecting whether the cancer has spread beyond its original location.

Glucose metabolism is not unique to cancer cells; however, and not all cancers exhibit high metabolic rates, so researchers are working on developing agents that are much more specific. For example, scientists are studying how to detect when cells are dividing quickly or when they are dying as a means of determining whether a cancer treatment is effective. Others are looking at ways to target proteins on the surface of cancer cells, such as the HER2 receptor, the epidermal growth factor receptor (EGFR) or the estrogen and androgen receptors. Finding out whether the expression of these receptors increase or decrease when a cancer spreads may eliminate the need for repeated biopsies and allow therapies to be tailored to the individual cancer at each stage.

New agents are also being developed to visualize angiogenesis, or growth of blood vessels within and around tumors. This research may be useful in monitoring whether antiangiogenic therapies are working, or identifying which patients might best benefit from such therapy.

According to David M. Schuster, MD, director of nuclear medicine and molecular imaging at Emory University Hospital, “all of these agents are just experimental right now and studies are being done, but I think these new agents, especially coupled with advanced devices, may hold promise in the future — maybe not for mass screening, but in problem-solving situations and in helping to individualize therapy.”

Also on the horizon: molecularly-targeted dyes and probes that can work with common optical imaging systems. Fluorescent dyes that attach to proteins found on cancer cells are being tested with specially modified microscopes for use in screening procedures, such as colonoscopy or endoscopy. These dyes may be able to determine more quickly if an abnormal growth is cancerous.

In one early test, a colon cancer-specific dye showed a high degree of sensitivity and specificity for detecting cancerous cells in the colon. Another promising light-based technique uses a light source to create a high resolution, cross-sectional or three-dimensional image that can “see” 1 to 2 millimeters below the surface. The technique, called optical coherence tomography (OCT), is being investigated for the identification and surveillance of Barrett’s esophagus. Imaging tests like these could also be used for other cancers that can be reached with endoscopes or catheters, such as esophageal or bladder cancers.

Ultrasound and magnetic resonance imaging (MRI) tests are also getting upgrades. Non-specific contrast agents are currently used in contrast-enhanced endoscopic ultrasound to increase the ability of ultrasound to visualize tumors with low blood flow, such as pancreatic cancers. Now, next-generation molecularly targeted “microbubbles” are being designed to visualize disease-specific molecules in blood vessels and could be used to monitor response to antiangiogenic therapies. Likewise, molecularly-targeted magnetic particles are being developed for use with MRI.

“I think the most exciting area, though, is hybrid technology, where we take anatomic imaging techniques, such as MRI, and bring them together with molecular techniques,” Schuster says. “For example, combine mammography, say tomosynthesis, with using radiotracers—and these are all other areas, which also have great promise.”

Other hybrid techniques that are being tested include PET-MRI, which was recently cleared for use in June by the Food and Drug Administration, single-photon emission computed tomography (SPECT)-CT and MRI combined with optical fluorescence technology.

Although most of these techniques are still experimental, researchers are hopeful that advances in imaging detection systems will further improve the lives of patients with cancer through earlier detection, when the cancer is at a more curable stage, as well as better management and personalization of treatment for cancers at a more advanced stage.

Cancer Imaging Gets Sophisticated

In January, researchers, oncologists, and other physicians from around the world gathered in San Francisco for the 2009 American Society of Clinical Oncology Gastrointestinal Cancers Symposium. The research presented included a wide spectrum of diseases, including colorectal cancer, and covered a variety of topics, including prevention, treatment, and the management of side effects. Several notable studies stood out: 

Antibodies targeting the epidermal growth factor receptor, specifically Erbitux (cetuximab) and Vectibix (panitumumab), are frequently used in the treatment of metastatic colorectal cancer. These agents can significantly improve outcomes for patients with tumors that express the normal form (also called wild-type) of the KRAS gene. However, the most common side effects associated with these drugs are skin rash, which can be moderate to severe in some cases, and can affect quality of life, increase risk of infection, and may ultimately delay treatment.

Edith Mitchell, MD, of the Jefferson Kimmel Comprehensive Cancer Center in Philadelphia, presented results from the STEPP (Skin Toxicity Evaluation Protocol with Panitumumab) study, which compared skin treatment at the start of Vectibix as a preventive measure versus skin treatment after reactions occurred. The study found that a daily regimen consisting of steroids, sunscreen, skin moisturizers, and 100 mg of the antibiotic doxycycline twice daily was more effective when given at the start of Vectibix therapy, significantly reducing the incidence of skin rash, and interestingly, diarrhea. Importantly, this regimen did not appear to interfere with the effectiveness of the drug therapy.

Sandostatin LAR (octreotide long-acting release formulation) is commonly used to relieve symptoms such as diarrhea and flushing associated with the production of hormones by certain neuroendocrine tumors, which are somewhat rare cancers that involve the gastrointestinal tract and other areas. However, researchers did not know whether the suppression of the effects of these hormones might also have an anti-cancer impact.

Results from the randomized PROMID study were presented by Rudolph Arnold, MD, of Phillips University in Germany. The study compared the effect of Sandostatin LAR with placebo in 85 patients with relatively rare metastatic neuroendocrine tumors in the midgut. Sandostatin LAR dramatically delayed the time to tumor progression, from six months to 14.3 months. At six months, two-thirds of patients treated with Sandostatin LAR had stable disease, compared with 37 percent of patients who received placebo.

Outcomes were better in patients with smaller or less widespread tumors, emphasizing the importance of early detection and treatment, and in those who had undergone resection of their primary tumor. 

For patients with metastatic colorectal cancer that has spread only to the liver, surgical resection can potentially be curative. Sometimes, though, the metastases may be too large, or may be in a location that makes surgery difficult or impossible. In some of these cases, preoperative chemotherapy may shrink the metastases enough to allow a surgeon to operate successfully. However, the optimal length of treatment is not known, and the duration of preoperative therapy can vary depending on the tumor response.

In a study by Daria Zorzi, MD, and colleagues at M.D. Anderson Cancer Center in Houston, the connection between length of preoperative chemotherapy and outcome was investigated in 219 patients. They found that longer treatment (nine or more cycles) with FOLFOX-based combination chemotherapy did not improve response rates and increased the chance of developing postoperative complications, such as liver damage compared to shorter treatment (eight or fewer cycles).

In addition, patients who received Avastin (bevacizumab) with their chemotherapy had better response rates than those treated only with chemotherapy, regardless of length of treatment. These results suggest that compared with historical data, Avastin improves response rates compared with chemotherapy alone. 

A study presented by Gunnar Folprecht, MD, of the University Hospital Dresden in Germany, evaluated the addition of Erbitux to either FOLFOX or FOLFIRI regimens before surgery for treatment in patients with colorectal cancer who had inoperable liver metastases. They found that for patients with KRAS wild-type tumors, both combinations were highly effective, with a 70 percent response rate.

Importantly, surgeons were now able to operate in approximately 40 percent of cases, and were able to completely remove the liver metastases 34 percent of the time. The response rate was only 43 percent in patients with KRAS-mutant tumors, reinforcing the need to test for KRAS mutation status before using Erbitux in patients with colorectal cancer. Common side effects included rash, neutropenia, and diarrhea.

 from the Winter 2008 issue. And read about ASCO’s recent KRAS testing recommendation in 

Treatment updates from the 2009 ASCO Gastrointestinal Cancers Symposium.

Susan R. Peck, PhD

The Molecular Revolution

Treating and Managing Metastatic Disease

Cancer Imaging Gets Sophisticated

Treatment Updates

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