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SRI Magazine 2016

SRI Magazine 2016

Individualizing breast cancer therapy

New technologies can deliver highly specific information about a therapy’s effectiveness in days, not months; and help women with DCIS decide on the best course of action

Illustration: Lisa Henderling

About 25,000 Canadian women are diagnosed with breast cancer annually. If you’re one of them or know someone who is, there is hope: about 88% of women are alive five years after a diagnosis; furthermore, deaths from breast cancer have decreased by 44% since 1986 due to earlier detection and better treatments.

Despite these promising trends, the disease strikes deep fear in women. This fear has consequences that extend far beyond the psychosocial. Researchers from Brigham and Women’s Hospital in Boston, U.S. have found thousands of women with breast cancer are removing a healthy breast as a preventive measure without evidence that doing so is beneficial.

For these women, watchful waiting isn’t good enough. Dr. Eileen Rakovitch, a scientist at Sunnybrook Research Institute (SRI) and radiation oncologist at Sunnybrook’s Odette Cancer Centre, is developing a treatment strategy that aims to mitigate uncertainty and empower women with information and choices for optimal care.

She’s looking at ductal carcinoma in situ (DCIS), where cancer is confined to the lining of the milk ducts, and the most common type of noninvasive breast cancer. The upside of DCIS is that, for most, treatment will be successful. The downside: DCIS raises the risk of developing an invasive breast cancer.

Dr. Eileen Rakovitch

Dr. Eileen Rakovitch validated the Oncotype DX DCIS Score, a test that indicates a woman’s risk of cancer recurrence. Shown behind her is a slide of a lumpectomy sample. Ductal carcinoma in situ cells are circled.

Doctors can only estimate this risk using factors including a patient’s age and tumour size—an approach that’s unreliable, according to Rakovitch, who is also the medical director of the Louise Temerty Breast Cancer Centre at Sunnybrook. “There’s been a lot of variability and even confusion in management of DCIS—overtreating some women, undertreating others,” she says. “We know we overtreat many women with DCIS; how do we improve that? By better identifying women at risk so they can get treated, and then [with] those at low risk, backing off—de-escalating therapy.”

She led research on the Oncotype DX DCIS Score, a test that measures the expression of 12 genes in breast tumours to indicate a woman’s recurrence risk; the higher the score, the greater the likelihood of a cancer’s return. She looked at women diagnosed with DCIS in Ontario from 1994 to 2003 who had a lumpectomy. Their tumour samples were sent to a lab for genetic testing and scoring. She compared the women’s risk scores with their outcomes. She found those with a low-risk score had a low probability of recurrence; those with a high-risk score had a higher risk of recurrence. “We’re moving beyond clinical factors and pathological features to molecular features. That’s what’s exciting. This is the first molecular-based assay in DCIS that’s associated with outcomes,” says Rakovitch.

Showing the test works could overhaul treatment of DCIS, which is diagnosed in about 13 out of 100,000 Canadian women annually. For instance, in addition to surgery, women with DCIS are offered radiotherapy and medication to stave off recurrence. Many opt for more therapy—enduring adverse effects—in the hopes of preempting disease, even if the benefits are uncertain. Knowing which women with DCIS are most likely to develop invasive breast cancer could change all that.

“It’s creating individualized medicine where women have their score on their own DCIS, and they can have better information about their own risk of recurrence, rather than some generic estimate, which is what we’ve been doing up until now,” says Rakovitch. “We’re hoping that lower-risk women will then choose not to have [additional] treatment and, conversely, we’re identifying higher-risk women who really do need the treatment.”

Her research shows that the genes on which the test is based could serve as biomarkers to identify women at greatest risk of recurrence. This knowledge could in turn improve care and optimize use of resources.

There are also policy implications. She is working with the Ontario Clinical Oncology Group (OCOG) to evaluate how the test, which costs about $4,000 and is not covered by provincial funding, might change treatment decision-making and women’s satisfaction with their decision. With OCOG, Rakovitch is doing a cost-effectiveness analysis to determine whether paying for the test makes sense owing to potential savings from lower-risk women not needing radiation treatment.

If Rakovitch is reducing uncertainty by identifying the odds of recurrence, then her colleague, Dr. Gregory Czarnota, is decreasing it in the realm of treatment response monitoring. Czarnota is director of the Odette Cancer Research Program at SRI and a radiation oncologist at Sunnybrook. He and Dr. Ali Sadeghi-Naini, an imaging scientist at SRI, have developed a technique that uses quantitative ultrasound (QUS) to indicate early on how well women with breast cancer are responding to chemotherapy.

Most of us associate ultrasound imaging with pictures of a developing fetus. These pictures, known as B-mode images, are made by sending sound waves into the body. As the sound waves bounce off internal structures, the echoes are collected and processed by a computer to make an image. Czarnota and Sadeghi-Naini’s technique takes the raw data collected (and discarded) by ultrasound machines, and uses it to depict dying cancer cells in response to therapy. “We get, if you like, a digital fingerprint or readout of what the structural states of various cells are,” says Czarnota.

There are other ways of imaging tumour cell death, including single photon emission computed tomography and positron emission tomography. These methods are costly and require injections of radioactive contrast agents. Quantitative ultrasound, on the other hand, does not use contrast agents.

Czarnota and Sadeghi-Naini were the first to show that QUS could detect tumour cell death in women with locally advanced breast cancer (LABC), an aggressive subtype characterized by large tumours. Typically, these patients receive chemotherapy to shrink tumours before having surgery to remove them. It can take up to six months before this change—if it happens—is visible on standard imaging scans. Czarnota and Sadeghi-Naini have shown QUS can identify which women with LABC will respond to therapy within one week of the start of treatment.

How can they tell so soon? A cancer cell’s death is heralded by the destruction of its nucleus, the storehouse of genetic information. When this happens there is increased echogenicity, or return of the ultrasound signal, says Sadeghi-Naini. “When cell death, or apoptosis, starts, the size of the cells changes, and their morphology alters. The nucleus starts to be more condensed and fragmented. These are the microstructures within tissue that scatter back the ultrasound signal,” he explains. “The intensity of the ultrasound signal that is detected increases by about 25 decibels—fivefold, so it’s very significant,” says Czarnota.

To validate the predictive value of QUS, Czarnota turned to Dr. Martin Yaffe, a senior scientist in Physical Sciences at SRI. The idea was to compare their findings against the gold standard in cancer diagnosis: pathology. “If you’re developing a new technique, you need to test it. The best way to test it is against truth, which is usually found in the tissue in pathology,” says Yaffe.

Dr. Martin Yaffe

Dr. Martin Yaffe developed a technique that aims to make pathology more accurate so doctors can determine the best way to treat patients. It uses whole slices of tumour tissue.

Yaffe’s method uses whole slices of tissue cut from tumours that are removed during surgery. The whole-mount technique gives pathologists an overview of tumour margins and lets them see where the margins are in relation to normal tissue. Lab-developed software digitizes the slides, making it easy to store, retrieve and work with images of the tissue slices. In addition to getting the “big picture” of a tumour, pathologists can zoom in on single cells, which are only a few thousandths of a millimetre in size. “We can go back and forth between those two scales simply using the computer mouse. It becomes an easy way of looking at an enormous amount of information,” says Yaffe.

Rather than waiting months to learn that a therapy isn’t working, doctors can determine this within weeks and switch patients to a treatment that might work.

The whole-mount technique is already making the job of pathologists easier. (“They love working with large slides,” notes Yaffe.) It provides contextual information that tells doctors where the disease ends and whether all of the cancer has been removed during surgery, for example. His goal is to make pathology more accurate and to provide greater insight into disease so doctors can determine how best to treat patients.

Yaffe notes a second application: validating new in-the-body imaging tools, including the QUS method developed by Czarnota and Sadeghi-Naini. The researchers published a study in Clinical Cancer Research that highlights this collaboration. In it, they verify that tumours of women classified as “responders” through QUS imaging had indeed disappeared or shrunk considerably, as confirmed by Yaffe’s whole-mount technique, which was done about six months after the start of chemotherapy. The implications are significant: rather than waiting months to learn that a therapy isn’t working, doctors can determine this within weeks and switch patients to a treatment that might work. On the flip side, patients who are responding to treatment can have peace of mind.

Having proved the technique in breast cancer patients at Sunnybrook, Czarnota and Sadeghi-Naini are evaluating it in a multicentre trial that, in addition to Sunnybrook, includes Princess Margaret Hospital, St. Michael’s Hospital and the University of Texas MD Anderson Cancer Center. Preliminary data are promising and consistent with previous findings.

Along with publishing research on QUS, Czarnota and Sadeghi-Naini are working to ensure that the technology has widespread impact through development and commercialization. They have engineered software that uses raw data from ultrasound imaging to generate and analyze QUS “maps” of cancerous tissue for computer-aided prognosis. They are working with GE Healthcare to adapt the software for use in its ultrasound devices.

Although their work has focused on breast cancer, they have shown that QUS also can differentiate between benign and malignant disease in prostate cancer. It has the potential to be used in multiple cancers, says Sadeghi-Naini. “[Tumour] cell death is the main goal of many anticancer therapeutics, so it can be adapted for various applications in different cancer sites.”

Research Funding

Czarnota: Canadian Institutes of Health Research (CIHR), Federal Economic Development Agency for Southern Ontario, Natural Sciences and Engineering Research Council of Canada (NSERC), Ontario Institute for Cancer Research (OICR) and Terry Fox Foundation. Rakovitch: Canadian Cancer Society Research Institute, Canadian Breast Cancer Foundation (CBCF) and OICR. She holds the LC Campbell Breast Cancer Research Chair. Sadeghi-Naini: CBCF, CIHR and NSERC. Yaffe: CBCF and OICR. He holds the Tory Family Chair in Cancer Research. Infrastructure support is provided by the Canada Foundation for Innovation, and Ontario Ministry of Research and Innovation.