Is Breast Cancer Part of the Tumor Spectrum of Hereditary Nonpolyposis Colorectal Cancer?

To the Editor:

In the January issue of the Journal, Scott et al. (2001) reported the incidence of various types of cancer in 95 families with hereditary nonpolyposis colorectal cancer (HNPCC [MIM 120435 and 120436]). The patients in these families were categorized according to their mismatch-repair (MMR) profiles. Of these families, 12 were identified as having an hMSH2 mutation, 22 families had an hMLH1 mutation, and, in 61 families, no mutation was identified. To our surprise, a remarkably high incidence of breast cancer was found in the family members with HNPCC, particularly in the hMLH1 (standardized incidence rate [SIR] 14.77 [95% confidence interval {CI} 6.2–35]) and the mutation-negative (SIR 18.03 [95% CI 12.2–26.7]) groups. No increased incidence was found in the hMSH2 mutation carriers (SIR 2.02 [95% CI 0.3–12.7]). Previous studies reported much lower incidences of breast cancer in HNPCC. For instance, Watson and Lynch (1993) identified only 19 cases of breast cancer in 23 families with HNPCC, occurring at a median age of 51 years. The observed:expected (O:E) ratio in the Watson and Lynch (1993) study was 0.9. Another recent study of 183 MMR-mutation carriers by Aarnio et al. (1999) reported an incidence (SIR) of 1.4 (95% CI 0.4–3.7). These contradictory data prompted us to evaluate the risk of developing breast cancer in the families registered at the Dutch HNPCC registry.

Almost 200 families suspected of HNPCC are currently known at our registry. A total of 138 families either meet the “Amsterdam criteria” or harbor a germline mutation in one of the MMR genes. In 79 families, a germline mutation has been identified (34 hMLH1, 40 hMSH2, and 5 hMSH6). Only 4 of 187 proven or putative hMLH1 mutation carriers and 3 of 141 hMSH2 mutation carriers developed breast cancer. The O:E ratio of breast cancer in hMLH1 mutation carriers was 0.6 (95% CI 0.2–1.5); in hMSH2 mutation carriers, the O:E ratio was 0.6 (95% CI 0.2–1.7). The mean age at diagnosis was 46 years (range 32–59 years).

One of these patients, a 32-year-old hMSH2 mutation carrier, underwent periodic examination of the colon and rectum, endometrium, ovaries, and stomach at the Department of Gastroenterology and Gynaecology, Leiden University Medical Center. Recently, she presented with an enlarged lymph node (5 cm in diameter) in the right axilla. On further analysis, a very small tumor in the upper lateral quadrant of the right breast was discovered. Fine-needle aspiration of the axillary tumor revealed an adenocarcinoma. The patient subsequently underwent a modified radical mastectomy. Histological examination of the surgical specimen demonstrated poorly differentiated adenocarcinoma in the breast and a metastasis in the axilla. Sixteen other lymph nodes were free of cancer. The estrogen and progesterone receptors were negative. The tumor exhibited widespread microsatellite instability (MSI).

In 1996, Risinger et al. performed molecular genetic studies in five patients with breast cancer from families with HNPCC. In three of the five tumors, MSI was observed. In one family with a known mutation, expression of only the mutant allele was identified in the breast cancer tissue. In 1999, Boyd et al. described a male patient, in a large family with HNPCC, affected by breast and colorectal cancer. This patient had an hMLH1 germline mutation, and the breast tumor exhibited MSI and reduction to homozygosity for the hMLH1 mutation.

Our study, like most studies reported in the literature, suggests that the relative risk of developing breast cancer is not increased in HNPCC. On the other hand, these studies show that breast tumors in families with HNPCC may present at an unusually early age, as illustrated by our patient. In addition, molecular genetic studies reveal MSI in breast tumors identified in families with HNPCC.

We propose a possible explanation for the contrasting observations of, on one hand, an unusually early age at diagnosis of breast cancer and, on the other hand, a normal (or even decreased) risk of developing breast cancer. It has generally been accepted that the development of breast cancer in the general population takes, on average, ∼20 years. This suggests that, like non–mutation carriers in the general population, a carrier of an MMR gene mutation may develop the first stages of a tumor at age 40 years. However, because of the defect in the MMR system, mutations may accumulate in genes involved in the progression of breast cancer. The accumulation of mutations may lead to acceleration of tumor development and to presentation of breast cancer at a much earlier age. The normal lifetime risk of developing breast cancer in HNPCC patients may indicate that the MMR defect is not involved in the initiation of breast cancer.

The answer to the question whether breast cancer is part of the tumor spectrum of HNPCC should be “no” if we consider the absence of an increased lifetime risk. Yet this question should be answered with “yes” if we take into account the possible role of the MMR defect in the progression of a breast tumor. Application of the latter criterion implies that a large variety of tumor types should in fact be regarded as part of the tumor spectrum of HNPCC. We believe that decisions as to whether surveillance should be advised for a specific type of cancer should be based on the age-specific cancer risk and the availability of sensitive and specific screening tools. Many cancers that are currently not included in the surveillance program may develop at an early age in patients with HNPCC. Therefore, we urge clinicians managing HNPCC to be especially alert when the patient presents with unusual symptoms.