Download The Association Between Melanoma and Breast Cancer and

Melanoma and Breast Cancer Links
The Association Between
Melanoma and
Breast Cancer and
Implications for Care
By Jonathan Wolfe, MD
T
he association between cutaneous malignancy
and the development of subsequent cancers is
well established. Patients with a history of nonmelanoma skin cancer (NMSC) are recognized
generally to be at increased risk of developing
subsequent NMSCs1 or other cancers.2,3 Similarly, individuals
diagnosed with melanoma are at increased risk for developing subsequent melanomas and other cancers.4-6 Given
these known risks, clinical vigilance is indicated for any
patient diagnosed with melanoma or NMSC. The manner
and degree of patient monitoring depends on the specific
presentation, as well as the individual’s personal and family
history of disease and the managing physicians’ expertise.
Presenting a possible management dilemma for dermatologists is a recognized but poorly understood and possibly
underappreciated association between breast cancer in
women and malignant melanoma, which is likely based on
genetic and hormonal factors.7-9 After years of speculation,
the accumulating evidence suggests that there is indeed a
correlation between cutaneous melanoma and breast cancer and that the relationship may be bi-directional.9 This
finding may have clinical implications for the dermatologist
managing a woman with a diagnosis of melanoma or one
with a history of breast cancer.
Historical Associations
One of the earliest available publications linking
breast cancer and melanoma appeared in the mid-1970s.
It documented a series of five cases in which melanoma
and breast cancer were diagnosed in the same patient. In
four of the five cases, melanoma developed after breast
carcinoma.10 A later analysis of a Connecticut cancer reg-
10
CUTANEOUS ONCOLOGY TODAY . OCTOBER 2011
Key Points
Patients with a history of skin cancer are recognized generally
to be at increased risk of developing subsequent skin cancers
or other cancers. There is a recognized but poorly understood
and possibly underappreciated association between breast
cancer in women and malignant melanoma.
Studies have suggested an increased risk for breast cancer in
patients diagnosed with melanoma and vice versa, though a lack
of consensus regarding the degree and nature of the association
persists. Some studies have failed to show any clear association
between the two. A number of potential hormonal and/or genetic factors are being explored as possibly contributing to the association between breast cancer and malignant melanoma.
For all melanoma patients, clinicians should obtain a thorough
history of any cancer. All dermatology patients with a history of
breast cancer should receive thorough skin exams and be
encouraged to undertake regular and careful skin self-examinations. These individuals should present to the office for skin
exams annually or more frequently. All female melanoma
patients, especially those with a personal or family history of
breast cancer, may be referred to a breast clinic for evaluation.
Such patients should be encouraged, at a minimum, to comply
with the American Cancer Society’s recommendation for annual mammography and undergo routine breast examinations,
provided at regular intervals by a trained physician as well as at
home by the patient.
istry found that the rate of diagnosis in the same patient
of both breast cancer and melanoma of the skin or eye
was more than 60 percent higher than the rate that would
be predicted for sporadic disease in the general population.11 A total of 18,010 women primarily diagnosed with
Melanoma and Breast Cancer Links
breast cancer and 835 women primarily diagnosed with
cutaneous or ocular melanoma were followed up in the
Connecticut Tumor Registry. Of these, 23 had both types
of tumors diagnosed at least one month apart, compared to the 14 or fewer predicted.
An increase in melanomas among patients initially
diagnosed with breast carcinoma was also reported in a
Danish cohort.12 This analysis involved a large sample of
55,000 women diagnosed with breast cancer in Denmark
between 1943 and 1980. Findings suggest that women
with breast cancer are at increased risk for developing
any subsequent cancer, given a higher than predicted
incidence of multiple primary tumors in the group. While
cancers of the lung, bone, and connective tissue were
common and potentially linked to breast cancer treatments, researchers also found an excess in incidence of
malignant melanoma in this population.
Based on an analysis of data for patients in one registry, Levi, et al. calculated a standardized incidence
ratio (SIR) of 1.4 for malignant melanoma in women who
had been diagnosed with breast cancer.13 The sample of
9,729 breast cancer patients were registered by the
Swiss Cancer Registries of Vaud and Neuchâtel and followed up from 1974 to 1998. The largest excess risk was
found for soft tissue sarcomas (STS) with an SIR of 3.2.
Other cancers with an SIR similar to melanoma included
endometrium (1.5), ovary (1.3), colorectum (1.1), gallbladder (1.4), kidney (1.4), lymphomas (1.4), and
leukemias (1.2).
Interestingly, another study suggests that the SIR for
developing breast cancer after melanoma is 1.4.14
Specifically among patients diagnosed with melanoma in
situ, researchers found an increased risk for secondary
tumors, with a statistically significant increase in risk of
1.4 for breast cancer in women. This analysis of 3,766
Swedish patients with a diagnosis of cutaneous
melanoma in situ from 1958 to 1992 found that among
women, there was a non-significant increased risk of
other cancers, including non-Hodgkin's lymphoma (SIR =
1.9), multiple myeloma (3.2), colon cancer (1.6), and pancreas cancer (1.6).
Goggins, et al. identified a modest but statistically significant increase of cutaneous melanoma among breast
cancer survivors and vice versa.7 They followed female
breast cancer patients and female cutaneous melanoma
patients registered in the 1973-1999 SEER database for
development of second primary tumors. Young breast cancer patients (age ≤50), specifically, had a 46 percent
increase in the risk for developing cutaneous melanoma.
Women who underwent radiation therapy for breast cancer
had a 42 percent increase in risk for cutaneous melanoma
relative to those who did not. Overall, the risk of developing breast cancer for a melanoma patient was 11 percent,
and the risk of developing cutaneous melanoma in a
breast cancer patient was 16 percent.
Contradictory Data
Despite the good deal of data suggesting an association between breast cancer and malignant melanoma, a
lack of consensus regarding the degree and nature of
the association remains. Some studies have failed to
show any clear association between the two. In a cohort
of 20,354 patients in the Swedish Cancer Register from
1958-1988, patients previously diagnosed with malignant
melanoma had increased risk for a second primary
melanoma or non-melanoma skin cancer, neuroextodermal cancers, and cancers involving the immune system.
Despite elevated risk for endometrial cancers, no
increased risk for cancers of the breast, ovary, testis or
other endocrine glands was seen in this sample.15 The
same researchers had uncovered an elevated risk for
breast cancer in the smaller melanoma in situ population
cited above.14
Another analysis aimed at identifying any effect of
breast cancer treatment on risk of developing subsequent primary cancers found no increased risk for malignant melanoma in the cohort.16 The 16,705 breast cancer
patients included in the analysis had been treated with
chemotherapy (various regimens), radiotherapy (highenergy photons from a 60Co unit or linear accelerator)
and/or hormone therapy (two to five years of tamoxifen).
Recent Findings
In a 2009 publication, Murphy, et al. offered additional
support for an association between breast cancer and
malignant melanoma.9 In light of a series of patients diagnosed either with a primary melanoma and subsequent
breast cancer or primary breast cancer and subsequent
melanoma over a six month period in their clinic, the
researchers undertook a review of data from the National
Irish Cancer Registry. This is a national histology-based registry for all cancers diagnosed since 1994.
In the 10-year period from 1994 to 2004, they uncovered
a four-fold increase in the number of individuals with both
breast cancer and melanoma compared to the predicted
rate. The age standardized incidence of breast cancer was
0.7 per 105 for men and 75.6 per 105 for women. The age
standardized incidence of malignant melanoma was 10.6
per 105 for men and 16.1 per 105 for women. Based on
these numbers, approximately 30-35 individuals should
have presented with both cancers. The actual number of
patients with both cancers was 127.
OCTOBER 2011 . CUTANEOUS ONCOLOGY TODAY
11
TABLE 1. SUMMARY OF STUDIES
Melanoma and Breast Cancer Links
Cohort/Sample
Positive Association
BC=Breast cancer
CM=Cutaneous melanoma
MM=Malignant melanoma
No Association
Findings
Connecticut Tumor Registry
18,010 women with BC,
835 with cutaneous or ocular
melanoma
60 percent higher rate of
concomitant BC and MM
Danish Cohort
55,000 women with BC in Denmark, 1943-1980
Increased risk for developing
any subsequent cancer;
“excess of MM”
Swiss Cancer Registries of
Vaud and Neuchâtel
9,729 BC patients
SIR for MM=1.4
Swedish cohort
3,766 Swedish patients with
CM in situ, 1958-1992
SIR for BC=1.4
SEER
Female BC and CM patients,
1973-1999
Overall, risk of BC in a CM
patient=11%; risk of CM in a
BC patient=16%
National Irish Cancer Registry
Patients with CM and MM,
1994-2004
Four-fold increase in patients
with BC/CM
Swedish Cancer Register
20,354 MM patients,
1958-1988
No increased risk for cancers
of the breast, ovary, testis or
other endocrine glands
Curie Institute Cohort
16,705 BC survivors
No increased MM risk
Exploring Links
A number of potential hormonal and/or genetic factors
are being explored as possibly contributing to the association between breast cancer and malignant melanoma. In
their analysis, Goggins, et al. specifically considered evidence that carriers of mutations in the breast cancer predisposition gene, BRCA2, have an increased risk of melanoma
and that carriers of mutations in the melanoma susceptibility gene CDKN2A exhibit a higher than expected risk of
breast cancer.7 In a Swedish cohort, it was shown that
CDKN2A 113insArg mutation families with melanoma had
increased rates of breast cancer in females. Six of the
113insArg families had at least one member with multiple
primary melanomas and a total of eight breast cancers (versus the expected 2.1; P =.0014).17
MC1R has been linked to both breast cancer and
melanoma. MC1R variants were found to be associated with
an increased risk of melanoma in carriers, and were positively associated with melanoma risk in first degree relatives of
carriers. However, there was no association of MC1R variants
and breast cancer risk in the studied cohort.18
12
Sample Description
CUTANEOUS ONCOLOGY TODAY . OCTOBER 2011
XPD gene variants have also been suggested to influence the risk for melanoma and breast cancer. In a genotyping study, results of analyses of linkage disequilibrium
and haplotype frequency suggested that a combination
of at least two SNPs (Lys751Gln_CC/Gly156Gly_CC or
Lys751Gln_CC/Asp312Asn_AA) inherited as a haplotype
was associated with disease.19
Because matrix metalloproteinases (MMPs) are associated with both malignant melanoma and breast cancer, a
very recent study was undertaken to elucidate a possible
association of MMP1 and MMP8 gene variation with each
type of cancer. While the study showed that the MMP8
gene rs11225395 polymorphism was associated with the
risk of developing malignant melanoma (odds ratio: 1.69;
95% confidence interval: 1.02-2.80; P=0.040) for the A/A
genotype and 1.49 (95% confidence interval: 1.03-2.17;
P=0.035) for the A/G genotype, compared with the G/G
genotype, there was no association detected between
this variant and breast cancer susceptibility. Furthermore,
there was no strong association between MMP1 variation
and the risk of malignant melanoma or breast cancer.20
Melanoma and Breast Cancer Links
Two melanoma associated antigen gene transcripts
(MAGE-A3, MAGE-A4 mRNA) recently were shown to be
associated with breast cancer in women. Specifically, the
presence of MAGE-A3 was significantly associated with
nodal status (P = 0.009), tumor size (P = 0.009), and
American Joint Committee on Cancer stage (P = 0.009);
MAGE-A4 positivity was significantly associated with histological grade (P = 0.020).21
Supporting a potential role for hormones is evidence
that hormone replacement therapy is associated with a
slight but statistically significant increase in breast cancer
risk and a slight increase in melanoma risk.22 When
researchers analyzed the risk for developing skin cancer
in a cohort of women who had received hormone
replacement therapy, they found an increased incidence
of malignant melanoma, though the increase did not
reach statistical significance. In this same population,
there was a slightly increased, statistically significant risk
of breast cancer. Data were not available regarding concomitant cancers. Nonetheless, the role of estrogen in
malignant melanoma remains unclear.23
Implications for Care
Despite inconsistencies in the data, the accumulated
evidence to date suggests that there is, indeed, an association between breast cancer and malignant melanoma.
Thus, a woman diagnosed with one is at increased risk of
subsequently developing the other. Therefore, patient
education and long-term monitoring must address this
possible association.
For all melanoma patients, clinicians should obtain a
thorough history of any cancer, especially breast carcinoma. All dermatology patients with a history of breast cancer should receive thorough skin exams and be encouraged to undertake regular and careful skin self-examinations. These individuals should present to the office for
skin exams annually or more frequently, depending on
their risk level.
Female melanoma patients, especially those with a personal or family history of breast cancer, may be referred to
a breast clinic for evaluation. Such patients should be
encouraged, at a minimum, to comply with the American
Cancer Society’s recommendation for annual mammography. In addition to mammography, MRI may be appropriate for some. Female melanoma patients should be
encouraged to undergo routine breast examinations, provided at regular intervals by a trained physician as well as
at home by the patient. Monthly skin and breast selfexams may be encouraged by the dermatologist.
Dr. Wolfe has no conflicts of interest to disclose.
Jonathan Wolfe, MD
University of Pennsylvania, Philadelphia, PA;
Private practice, Plymouth Meeting, PA
1. Marcil I, Stern RS. Risk of developing a subsequent nonmelanoma skin cancer in patients with a history of nonmelanoma skin cancer: a critical review of
the literature and meta-analysis. Arch Dermatol, 2000; 136(12):1524-30.
2. Chen J, Ruczinski I, Jorgensen TJ, Yet al. Nonmelanoma skin cancer and risk
for subsequent malignancy. J Natl Cancer Inst, 2008; 100(17):1215-22.
3. Rosenberg CA, Greenland P, Khandekar J, et al. Association of nonmelanoma skin cancer with second malignancy. Cancer, 2004; 100(1):130-8.
4. Bradford PT, Freedman DM, Goldstein AM, Tucker MA. Increased risk of second primary cancers after a diagnosis of melanoma. Arch Dermatol, 2010;
146(3):265-72.
5. Spanogle JP, Clarke CA, Aroner S, Swetter SM. Risk of second primary
malignancies following cutaneous melanoma diagnosis: a population-based
study. J Am Acad Dermatol, 2010; 62(5):757-67.
6. Gutman M, Cnaan A, Inbar M, et al. Are malignant melanoma patients at
higher risk for a second cancer? Cancer, 1991; 68(3):660-5.
7. Goggins W, Gao W, Tsao H. Association between female breast cancer and
cutaneous melanoma. Int J Cancer, 2004; 111(5):792-4.
8. Hehir DJ, Dawson KJ, Parbhoo SP. Primary breast carcinoma in patients with
malignant melanoma. Eur J Surg Oncol, 1992; 18(1):77-9.
9. Murphy GM, Ho WL, Comber H, et al. Malignant melanoma and breast carcinoma: a bidirectional correlation. Irish Journal of Medical Science. Online
First, March 2009.
10. Lokich JJ. Malignant melanoma and carcinoma of the breast. J Surg
Oncol,1975; 7(3):199-204.
11. Schoenberg BS, Christine BW. Malignant melanoma associated with breast
cancer. South Med J, 1980; 73(11):1493-7.
12. Ewertz M, Mouridsen HT. Second cancer following cancer of the female
breast in Denmark, 1943-80. Natl Cancer Inst Monogr,1985; 68:325-9.
13. Levi F, Te VC, Randimbison L, La Vecchia C. Cancer risk in women with previous breast cancer. Ann Oncol, 2003; 14(1):71-3.
14. Wassberg C, Thörn M, Yuen J, et al. Cancer risk in patients with earlier
diagnosis of cutaneous melanoma in situ. Int J Cancer, 1999; 83(3):314-7.
15. Wassberg C, Thörn M, Yuen J, et al. Second primary cancers in patients
with cutaneous malignant melanoma: a population-based study in Sweden. Br
J Cancer, 1996; 73(2):255-9.
16. Kirova YM, De Rycke Y, Gambotti L, et al. Second malignancies after breast
cancer: the impact of different treatment modalities. Br J Cancer, 2008;
98(5):870-4.
17. Borg A, Sandberg T, Nilsson K, et al. High frequency of multiple
melanomas and breast and pancreas carcinomas in CDKN2A mutation-positive
melanoma families. J Natl Cancer Inst, 2000 ; 92(15):1260-6.
18. Debniak T, Scott R, Masojc B, et al. MC1R common variants, CDKN2A and
their association with melanoma and breast cancer risk. Int J Cancer, 2006;
119(11):2597-602.
19. Debniak T, Scott RJ, Huzarski T, et al. XPD common variants and their association with melanoma and breast cancer risk. Breast Cancer Res Treat, 2006;
98(2):209-15.
20. D´bniak T, Jakubowska A, Serrano-Fernández et al. Association of MMP8
gene variation with an increased risk of malignant melanoma. Melanoma Res,
2011; 21(5):464-8.
21. Hussein YM, Gharib AF, Etewa RL, et al. The melanoma-associated antigenA3, -A4 genes: relation to the risk and clinicopathological parameters in breast
cancer patients. Mol Cell Biochem, 2011; 351(1-2):261-8.
22. Adami HO, Persson I, Hoover R, et al. Risk of cancer in women receiving
hormone replacement therapy. Int J Cancer., 1989; 44(5):833-9.
23. Althuis MD, Brogan DR, Coates RJ, et al. Hormonal content and potency of
oral contraceptives and breast cancer risk among young women. Br J Cancer,
2003; 88(1):50-7.
OCTOBER 2011 . CUTANEOUS ONCOLOGY TODAY
13