Screening & Prevention: Controversies & Unresolved Issues

CHICAGO-Progress in understanding the causes of cancer has improved the ability to screen for various types of cancer and develop treatments aimed at prevention. Still, as Judy Garber, MD, Director of the Cancer Risk and Prevention Program at Dana-Farber Cancer Institute, explained at a Meet the Expert session for journalists at the ASCO Annual Meeting here, there are still many controversies and unresolved issues.

For example, newer screening tests as well as some older ones have some limitations, and more studies are needed to elucidate differences among aromatase inhibitors and selective estrogen receptor modulators (SERMS) as chemoprevention of breast cancer.

Although screening healthy individuals for cancer often does provide health benefits, there are, of course, also risks, she noted. In particular, false-positive results of screening tests lead to more tests and biopsies, which raise anxiety and discomfort for patients as well as increase the already-strained health care budget.

A study presented at this year's ASCO meeting showed that over a three-year period, 5% of men and 3% of women had false-positive results in screening tests for prostate, lung, colon, and ovarian cancers. (Abstract 1503: Jennifer H. Miller, MD: Cumulative false-positives in the prostate, lung, colorectal, ovarian [PLCO] cancer screening trial.)

In that study, 68,415 healthy men and women aged 55 to 74 were randomized to receive usual care or annual screening for those four cancers. Individuals having more positive screening tests over the course of the study had progressively higher risks of a false-positive test result.

For a healthy person who is compulsive about health care, these risks are not insubstantial, Dr. Garber said.

Figure. Judy Garber,...

Mammography also carries a risk of false-positives. Magnetic resonance imaging screening has emerged as a potential alternative to mammography, because of its greater sensitivity in detecting lesions in women at very high genetic risk. MRI is also more comfortable for patients, since it does not entail squeezing the breasts but does involve a contract injection.

At Dana-Farber, Dr. Garber noted, about 25% of very high-risk women screened with MRI have had false-positive results requiring at least additional focused ultrasound testing.

The American Cancer Society's 2007 guidelines suggest annual MRI screening for women with BRCA mutations and those with a 20% or greater risk of developing breast cancer. The recommendation is extended to women who have had chest radiation between age 10 and 30 and to women with rare hereditary syndromes that carry increased risk of breast cancer.

MRI screening is currently not recommended for other high-risk women, such as those with dense breasts on mammography or who have a personal history of breast cancer or ductal carcinoma in situ not detected on mammography. These grey areas remain controversial, Dr. Garber said.

Another study at the ASCO meeting (Abstract #1504; OT Special Edition Meeting Reporter Supplement to 8/10/07 issue) showed that MRI was superior to mammography at detecting high-risk lesions, including high-grade DCIS and HER-2 positive breast cancer, while mammography was able to detect low-grade, estrogen receptor-positive DCIS, all of which are lower risk.

Dr. Garber pointed out, though, that this study was done using high-resolution MRI, which is not widely available. MRI equipment in the United States is highly variable, as is the reading of MRI results, she said, adding that more studies are needed to determine the best use of MRI. Also, better MRI equipment and more standardized methods of evaluation are needed before screening MRI can be adopted on a widespread basis in the US, she said.

MRI finds more lesions, but also increases the need for unnecessary biopsies.

HPV Prevention

Young sexually active women can now be protected from human papilloma virus (HPV) with the quadrivalent HPV vaccine (for Types 6, 11, 16, and 18); in fact, some states in the US recommend or require vaccination of young women at the age of 12. The efficacy data are compelling, but Dr. Garber emphasized that this recommendation comes in the absence of long-term safety and efficacy data on the vaccine.

Despite enthusiasm for the quadrivalent HPV vaccine, this is not likely to be the only HPV vaccine, she said. Others are under development specifically for Types 16 and 18, which account for about 70% of cervical cancer, she said.

The HPV vaccine, at $360 for a course of three injections, is too costly for the developing world, presenting policy challenges that are also likely to face vaccines in development that will cover additional HPV subtypes as well.

We should celebrate the progress represented by this vaccine, which reduces cancer risk from an infectious disease, but we may be able to further optimize prevention through HPV, she said.

Chemoprevention

Regarding chemoprevention, she noted, This is a complicated time. Large, expensive trials have shown that chemoprevention is effective in breast cancer and prostate cancer. But there is no free lunch, she said. One study showed that celecoxib was effective in preventing colorectal cancer, but the risk of cardiac effects make it unlikely that celecoxib will be used for prevention outside of very high risk groups.

Tamoxifen reduces the risk of invasive breast cancer and DCIS by about 50%, and also has positive effects on bone, but is falling out of favor because of concerns about its side effects-specifically, an increased risk of endometrial thickening and thrombosis in older women.

Dr. Garber said she does not prescribe it for risk reduction in women over age 65. However, in women age 35 to 49, the benefits do outweigh the risks for most women.

A study presented at the most recent San Antonio Breast Cancer Symposium showed that the protective effects of tamoxifen at five years persist for at least another five years, and a risk reduction was observed in women who took tamoxifen even after 20 years.

Tamoxifen is a very effective drug in the right patient, Dr Garber said, but this drug has gotten a bad rap.

The Study of Tamoxifen and Raloxifene (STAR) showed that raloxifene, a selective estrogen receptor modulator (SERM), and tamoxifen were similarly effective in reducing the risk of breast cancer, but had different side-effect profiles. For now, women with a strong history of blood clots and endometrial atypia and those with an increased risk of stroke or are older should not take a SERM, Dr. Garber said.

Aromatase inhibitors are now being increasingly prescribed as an alternative to tamoxifen, and these drugs do not increase the risk of endometrial effects or pro-thrombotic effects; however, aromatase inhibitors have other side effects that include hot flashes, weight gain, decreased bone mineral density, bone and joint pain, and lipid elevations.

Several placebo-controlled trials have been conducted on aromatase inhibitors, but head-to-head comparisons are lacking, Dr. Garber noted, adding that it is now unlikely that such studies will ever be conducted.

She concluded by saying that many oncologists had been looking forward to the large NCI-funded Study to Evaluate Letrozole and Raloxifene (STELLAR) trial, which would compare the drugs in about 13,000 postmenopausal women and would have been conducted by the National Surgical Adjuvant Breast and Bowel Project.

This trial, though, has now been cancelled by the NIH, so it looks like we won't have definitive direct comparative data on aromatase inhibitors versus raloxifene any time soon, Dr. Garber said.