By Su Luo and Hensin Tsao, MD, PhD
Since breast cancer is the most frequently diagnosed noncutaneous (non-skin) cancer among women in the United States,1 it is not surprising that many individuals with breast cancer will develop melanoma (the deadliest form of skin cancer) and vice versa. However, recent studies exploring how often individual patients develop both cancers suggest that it has to do with more than just coincidence: A recent study by Murphy, et al, for example, found that patients with either breast cancer or melanoma were almost four times more likely to develop the other malignancy than probability would lead researchers to expect.2 Specific causes linking the diseases may be in play, and genetic or environmental factors may also contribute. On the other hand, the association may at least partly result from more rigorous detection – in other words, a detection bias. This occurs when health care providers who carefully monitor cancer patients detect a second cancer that might otherwise have been missed.
Whatever clues we can gather about an association between breast cancer and melanoma may help lead to patient interventions that could reduce the risk of a second cancer. Just what do we know so far about the links between these two cancers?
Population-based data provide the most statistically significant estimates of cancer incidence.3 When exploring the frequency of two primary cancers occurring together, epidemiologic studies often focus on a population-based registry of one cancer, then evaluate data for the development of the second. The findings are presented as a standardized incidence ratio (SIR), a ratio of observed to expected number of cases.
Melanoma After Breast Cancer
Recent registry-based studies offer SIRs ranging from 1.16 to 2.74 for melanoma development after breast cancer, meaning that 1.16 to 2.74 times the number of expected melanoma cases occurred after a breast cancer occurred.4-6 (The range may reflect differences in methodology or variations in the composition of the examined population.) An accurate estimate may be a 29 percent excess risk for melanoma in breast cancer patients, as found in the largest group study of over 500,000 breast cancer patients.7 Higher-risk still were breast cancer patients age 50 or younger, who in a study by Goggins, et al, had a 46 percent higher risk of melanoma after breast cancer.4
Breast cancer patients who receive external radiation therapy (XRT) also have an especially heightened melanoma risk 4,6 — Goggins, et al found a 42 percent higher risk of melanoma4 — even at non- irradiated sites.8
However, patients who undergo XRT for breast cancer may be examined more frequently, reflecting a detection bias that could lead to more melanomas being found.
Breast Cancer after Melanoma
Studies of melanoma patients have not generally shown statistically significant higher risks of a subsequent breast cancer.9, 10 However, using the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) data from 1973-1999, Goggins, et al did detect modest but significant increases in breast cancer risk after melanoma and vice versa.4 The risks of breast cancer among female melanoma survivors and melanoma among breast cancer survivors were elevated by 11 percent and 16 percent, respectively. This mutual association, especially among breast cancer patients age 50 or younger, suggests genetics may play a role.4
Investigators looking for a possible genetic link have zoomed in on several genes that are known risk factors for either melanoma (such as the CDKN2A gene) or breast cancer (such as the BRCA2 gene). A small number of melanoma cases are familial (occurring in people who have one or more close relatives with melanoma). Of these, about 20-40 percent have mutations in the CDKN2A gene. A study of familial melanoma cases with CDKN2A mutations showed these families not only had multiple cases of melanoma, but also an increased risk of breast cancer.11 However, the association between the two cancers was still quite weak. To date, genetic testing for mutations in high-risk genes for melanoma such as CDKN2A among breast cancer patients is not warranted.12
However, people who have high-risk genes for breast cancer may be predisposed to melanoma. The Breast Cancer Linkage Consortium found that BRCA2 mutation carriers have 2.58 times greater risk than non-carriers of developing melanoma.13,14
The Xeroderma Pigmentosum group D gene (XPD) has also been recently implicated in both melanoma and breast cancer. This gene is associated with xeroderma pigmentosum, an inherited skin condition in which sufferers are dangerously vulnerable to ultraviolet light (UV) exposure, and often suffer multiple skin cancers, including melanoma. Certain variations in the XPD gene are modestly associated with heightened breast cancer risk, while others are modestly associated with melanoma in patients over age 50.15
Detection bias can increase the apparent risk of a second malignancy. The SEER analysis found a higher than expected number of localized (but not thicker, later-stage) breast cancers diagnosed after melanoma, suggesting some role for detection bias; increased scrutiny may have led to earlier detection of the breast cancers.4 Indeed, patients as well as their physicians may be more vigilant with their skin examinations. However, this possible detection bias has not shown up with melanomas discovered after breast cancers; studies have demonstrated that the increased melanoma risk among breast cancer patients has fluctuated very little over time. A detection bias would have shown a gradual decline in risk, as intense scrutiny eased.7
Environmental and Hormonal Influences
Socioeconomic factors could also contribute to the association of breast cancer with melanoma.3 For instance, behaviors such as tobacco, alcohol and sunscreen use or lack there of could all be related behaviors in certain economic strata. The role of female hormones (such as estrogen receptors3), already known to play a role in breast cancer, have also been a concern with regard to stimulating melanoma growth, especially in light of associations between melanoma and pregnancy.16 (While pregnancy does not increase the risk of melanoma, melanomas diagnosed during pregnancy tend to be thicker, and more dangerous, than those in non-pregnant patients.)
While epidemiologic studies have long noted an association between breast cancer and melanoma, the exact nature of this relationship is far from understood. It could be that DNA damage and genetic changes hindering DNA repair may affect the risk of many different types of cancers.
For patients who have had breast cancer, an annual total-body skin check by a trained professional makes sense, and more frequent exams may be needed for those who have gone through radiation therapy. Likewise, post-melanoma surveillance typically should involve evaluation of the lymph nodes near the breast. Teaching patients to examine this area routinely could lead to earlier detection of breast cancer metastases.
Su Luo is a medical student at the University of Miami Miller School of Medicine. She is conducting research in mutation analysis of pigmented lesions at the Wellman Center for Photomedicine, Massachusetts General Hospital. She will receive her MD in 2011.
Dr. Tsao is the Director of the Melanoma and Pigmented Lesion Center and the Melanoma Genetics Program at Massachusetts General Hospital, and Associate Professor of Dermatology at Harvard Medical School. He leads a cancer genetics laboratory at the Wellman Center for Photomedicine at MGH. Dr. Tsao is widely published and has lectured internationally about melanoma, genetics, and skin disease.
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