By Julie Corliss

38-year-old Christopher Foley was working as a private investigator in Florida, just miles from the Gulf of Mexico, when disaster struck. Crippled by headaches so intense they left him “curled up in a little ball,” he was eventually diagnosed with glioblastoma multiforme—the deadliest of all brain tumors. Surgeons couldn’t completely remove the golf ball-sized tumor from his right frontal lobe, and his prognosis was bleak. They told his family that Foley—the youngest of seven siblings—had only one or two years to live.

Incredibly, that devastating forecast is now far brighter thanks to a family connection, a team of brain tumor specialists, and a molecular diagnostic technique known as FISH, or fluorescent in situ hybridization.

Molecular Techniques: FISH…

FISH is just one of several molecular diagnostic techniques used to unmask the genetic profiles of cancer cells. Findings from FISH and related molecular assays—including gene micro-arrays, PCR (polymerase chain reaction) and protein microarrays—can help doctors diagnose cancer with better precision, allowing them to tailor and time treatments to maximize effectiveness and minimize side effects.

These techniques also hold promise for detecting cancer and cancer recurrences early, when a cure is more feasible, as well as giving patients a better sense of their future. Combining molecular tests with other recently adopted techniques—namely, sentinel lymph node biopsy and PET/CT scans (a combination of positron emission tomography and computed tomography)—will enable doctors to fine-tune the way they treat and monitor a patient’s progress.

Foley had the good fortune to have a sister working at Boston’s Massachusetts General Hospital with John Henson, MD, a Harvard neuro-oncologist and neuro-
radiologist who specializes in brain tumors. After relocating to his hometown of South Boston, Foley saw Dr. Henson, who first double-checked the tumor’s pathology.

“We discovered that his tumor was an anaplastic oligodendroglioma,” says Dr. Henson. Furthermore, the FISH analysis revealed that the tumor cells were missing part of the short arm of chromosome 1. Tumors with this particular genetic signature, called a 1p deletion, typically respond well to chemotherapy. With this information, Dr. Henson told Foley and his family that his prognosis was much better, since the median survival for people whose tumors have this finding is closer to 10 years as opposed to just a few.

“I tell you, when he told me, I wanted to jump up and hug him,” says Foley. “My mother smiled for the first time in months, and I could see the weight lifted from her shoulders.”

Foley still faces many months of chemotherapy, but so far, he’s tolerating the daily Temodar® (temozolomide) pills well and has only minimal residual effects from the tumor, including slight weakness in his left leg and some loss of his left peripheral vision.

… And Chips

Optimizing chemotherapy is one goal behind another genetic diagnostic tool known as gene chips, or microarrays. With a sample of a patient’s tumor cells, these tests can determine the expression of thousands of genes simultaneously. The results can help determine which drugs will work best and whether the cancer is likely to recur. Currently, there are several different gene chips in use for women with breast cancer, including Oncotype DX™, MammaPrint® and Ipsogen’s ProfileChip™.

At the Translational Genomics Research Institute in Phoenix, researchers are using gene chips in a variety of research studies, including one that analyzes tumor samples from patients with either end-stage pancreatic cancer or melanoma. These patients have failed all the conventional treatments for their disease, says TGen’s scientific director Jeffrey Trent, PhD. “By identifying the genetic signatures of their cancer cells, we can potentially match them with chemotherapeutic agents known to have a possible benefit against that particular signature,” he says. In addition to the 30 or so currently available drugs, other experimental drugs still in the initial phases of testing also may be offered to these patients with end-stage disease. The future potential for this targeted treatment approach in all types of cancer patients is vast, says Dr. Trent, noting that of the 25,000 to 30,000 genes in the entire human genome, only about 1,000 are known regulators of cancer.

Surgical Advances: Sparing Tissue and Avoiding Side Effects

In some cases, tumor profiling and chemotherapy is done before cancer surgery, says Mehra Golshan, MD, a breast cancer surgeon at Brigham and Women’s Hospital. A recent study in the Journal of Clinical Oncology illustrates the promise of this neoadjuvant (before surgery) approach. Researchers from M.D. Anderson Cancer Center in Houston studied chemotherapy in women with early-stage HER2-positive breast cancer. Women with these cancers produce too much HER2 protein, and their tumors tend to grow back faster and are more likely to recur than HER2-negative cancers. Prior to surgery, study participants received chemotherapy alone or with Herceptin® (trastuzumab), which slows or stops the growth of HER2-positive cancers. Researchers stopped the study early because the results were so much better in the combined therapy group: 66.7 percent had a pathological complete response (meaning all traces of cancer in the breast were gone) compared with 25 percent in the chemotherapy-alone group.

One advantage of chemotherapy prior to surgery is that the drugs may shrink the tumor, possibly allowing a breast-conserving lumpectomy instead of a mastectomy, says Dr. Golshan. Thirty to 40 percent of breast cancer patients who initially require a mastectomy may be offered lumpectomy and radiation if chemotherapy before surgery is effective, he adds.

Another relatively new technique now commonly done in women prior to breast cancer surgery is sentinel lymph node biopsy (SLNB). First validated in melanoma and currently recommended for certain breast cancers, the procedure is also being studied in cervical, colon, and other cancers. Lymph nodes—small, bean-shaped structures—filter bacteria, cancer cells and other unwanted substances through a nearly clear fluid called lymph. When cancer cells spread beyond the primary tumor, they usually appear first in one or several nearby lymph nodes, known as the sentinel nodes.

To locate them, a doctor injects a radioactive substance, a blue dye or both near the tumor, then uses a scanner to detect the radioactive or dye-stained lymph node. The surgeon removes the node (or nodes) through a small incision, after which a pathologist tests the node for cancer cells. If the sentinel node is negative (cancer-free), there’s no need to remove additional lymph nodes.

In the past, surgeons took out the majority of nearby lymph nodes (between 10 and 30) under the armpit (known as axillary lymph node dissection, or ALND) during breast cancer surgery, which increases the risk of uncomfortable swelling caused by excess fluid build-up, or lymphedema. Lymphedema is far less common in women who receive SLNB instead of ALND. In one study of nearly 500 women, the risks were 3 percent versus 17 percent, respectively.

Kathleen Bunnell of Harvard, Massachusetts, had an SLNB prior to a lumpectomy in 2005. Although the dye injection was uncomfortable, the results were good: None of the three nodes the surgeon removed showed any evidence of cancer. The only side effect was a bruise-colored mark (known as “tattooing”) left by the dye, says 56-year-old Bunnell. Still, losing even a few lymph nodes means taking extra care to avoid infections, especially in that area of the body. Bunnell took antibiotics when her cat scratched her chest, and she avoids mosquito bites and wears gloves when gardening.

When analyzing lymph node tissue, pathologists traditionally use special staining techniques that highlight cancerous cells among the normal tissue. But a new application of a widely used laboratory technique called reverse transcriptase polymerase chain reaction, or RT-PCR, is now being tested as a potentially more sensitive means of hunting down a single cancerous cell trapped within a lymph node or traveling in the bloodstream.

Like gene chips, this molecular diagnostic technique relies on known, cancer-specific genetic abnormalities to find these wayward cells. But so far, its role in improving the treatment or survival of cancer patients remains unclear. The same goes for using RT-PCR to detect cancer cells in blood samples, although researchers have identified an array of potential genetic markers for a host of different cancers.

Proteins Versus Genes

Some researchers assert that while considerable attention has focused on pharmacogenomics (the use of genomic signatures to guide and direct cancer therapy), an equally and perhaps even more relevant focus is pharmacoproteomics.

Proteomics refers to the large-scale study of the actual products (proteins) that are encoded and expressed by genes. Research shows that only 2 percent of cancers result from a single genetic mutation, which means multiple genes and their proteins cause most tumors. The complexity of the proteomics field can be illustrated with a simple numbers game: Scientists have identified the 25,000 to 30,000 genes present in the human body, but they estimate there may be up to 10 million proteins.

Gary P. Nolan, PhD, director of the Stanford University Proteomics Center in California, says the field is now moving toward learning how proteins interact with the entire cell and drive cell function. Proteomics is used for early detection by finding signs in the blood or other fluids that signal the presence of cancer cells, and a cancer found early enough is much easier to treat. Most of the currently used biomarkers for cancer detection, such as elevated prostate-specific antigen (PSA) and CA-125 (used to monitor ovarian cancer), are proteins. Likewise, FISH technology or HercepTest is used to detect the overexpression of the protein HER2 in breast cancer biopsy cells, which tells doctors whether the patient is likely to respond to Herceptin.

Dr. Nolan’s own experience with cancer gave him the understanding that knowing more about an individual person’s disease can help determine treatment and eliminate some of the uncertainty a patient experiences.

“If you’re told that 20 percent of patients respond to chemotherapy, you can imagine the thoughts that would go through your head, but if you know that you fall in that 20 percent, it can save a lot of psychological pain,” Dr. Nolan says. “With this information, you can make much more powerful choices—medically and psychologically.”

A new technology, reverse-phase protein microarrays, should reveal an even more nuanced portrait of cancer cells and their ill-fated functions. This information goes beyond genomic profiling, which can only predict who will respond to specific treatment and who won’t. Protein microarrays provide a map that can drive new drug discovery, experts say.

Imaging Update: The Best of Both Worlds

Once such new therapies are in hand, a novel imaging technique that combines two, well-known diagnostic techniques—PET and CT—into a single scan may help rapidly reveal how well a certain treatment works on a specific tumor. PET highlights the metabolic activity of cancer cells, while CT provides the exact location of the tumor. The resulting well-defined, three-dimensional images from PET/CT enable doctors to better identify, stage and monitor many types of cancer, including lymphoma, melanoma, colon, breast and other cancers.
The most promising application of PET/CT is in detecting the tumor’s stage and assessing a patient’s response to chemotherapy. Most PET scans for cancer entail injecting patients with a substance known as FDG, a radioactive glucose molecule that travels to every cell in the body. Compared to normal tissue, cancer cells are more “hungry” for this sugar to fuel their growth, and the PET image detects this high level of radioactive sugar in the tumor.

If a baseline PET/CT reveals tumor activity in a specific location that subsequently disappears in a scan following chemotherapy, you know the drug is working, explains Annick Van den Abbeele, MD, clinical director of radiology at Dana-Farber Cancer Institute. “Instead of waiting months to see if the tumor shrinks, you can evaluate the response right away.”

One of the most dramatic examples has been seen in patients with a rare form of sarcoma (soft-tissue cancer) called gastrointestinal stromal tumor (GIST). The discovery of a similar, underlying genetic mistake in both GIST and chronic myelogenous leukemia (CML) led researchers to test Gleevec® (imatinib)—the highly successful CML drug—on patients with GIST. The results were striking, with tumors shrinking in more than 75 percent of patients and by at least 50 percent in more than half the patients.

Now, Dr. Van den Abbeele and colleagues are testing new, improved forms of drugs based on Gleevec and other molecular target mechanisms on patients with GIST and other solid tumors, such as lung and metastatic breast cancer. In some cases, PET/CT scans showed that tumor activity shut down a mere 24 hours after the patient took the drug, according to Dr. Van den Abbeele.

Christopher Carley, 62, was the second person in the United States to receive Gleevec for GIST at Dana-Farber back in 1995. Although Carley, who is the founder of Fordham Co., a prominent Chicago real estate development company, has endured at least 30 PET, CT or MRI (magnetic resonance imaging) scans during the course of his treatment, he’s only had one PET/CT so far, because his remarkable response occurred before the technology existed.

When Carley awoke from his third surgery, the surgeon told him that he had 38 tumors ranging in size from a marble to a golf ball. “He said they just closed me back up because there was nothing they could do. But I remember him saying, ‘Chris, they’re always coming up with new treatments.’ ”

Five months later he began taking Gleevec. Within a month his tumors vanished, a response his physicians described as “jaw-dropping.” Now a 10-year survivor with eight grandchildren, Carley has since founded the Chicago chapter of the Lance Armstrong Foundation and the Carley Cancer Research Center.

Although recovery stories like Carley’s are admittedly rare, researchers and doctors alike are cautiously optimistic that such stories may become more common as these new diagnostic technologies evolve, ultimately paving the way to better cancer treatments.