Germline PTEN Mutations Raise Second-Cancer Risk

Janis C. Kelly

May 13, 2014

Individuals with germline PTEN mutations who have PTEN hamartoma tumor syndrome (PHTS) are known to be at increased risk for cancer, but a new study shows that the increased risk holds not only for first cancer, but for secondary malignancies as well.

In the study, almost half of cancer patients who had germline pathogenic mutations in PTEN developed second malignant neoplasms (mostly breast, thyroid, and endometrial cancers), and having the mutation raised the lifetime risk for breast cancer to 85%, report senior author Charis Eng, MD, PhD, FACP, director of the Center for Personalized Genetic Healthcare at the Cleveland Clinic, and colleagues.

"Prophylactic mastectomy should be considered on an individual basis given the significant risk of subsequent breast cancer," the authors conclude.

The results were published online April 28 in the Journal of Clinical Oncology.

In this study, we showed "that patients are at elevated risk, compared with the general population, for a second malignancy: 7-fold for all cancers and 9-fold for breast cancers. Because of the natural history of PHTS, patients are advised to have regular surveillance for the component cancers," Dr. Eng explained. "Our present data suggest that patients should be encouraged to continue with surveillance, likely for life, given the very real risk of second cancers."

"This is a very significant observation for patients with PTEN mutations. Like patients with BRCA1 or BRCA2 mutations, who have a lifetime risk of developing breast and ovarian cancers, patients with PTEN mutations should also be followed closely after treatment of their first malignancy for the development of subsequent cancer," said Constantine Stratakis, MD, in an accompanying podcast. Dr. Stratakis, who was not involved in the study, is senior investigator at the Eunice Kennedy Shriver National Institute of Child Health and Human Development in Bethesda, Maryland.

Second Cancers Becoming Important Health Concern

Second malignant neoplasms now account for 18% of incident cancers in the United States, which is more than first cancers of the breast, lung, and prostate, Dr. Eng and colleagues note. The occurrence of a second malignant neoplasm could prompt referral for genetic testing, leading to a diagnosis of PHTS. In this study, PHTS was diagnosed in 45 of 46 patients only after they presented with a second malignancy.

The researchers conducted a 7-year multicenter prospective study of 2912 patients with Cowden syndrome or Cowden syndrome–like disease. The syndrome is autosomal-dominant and is associated with the development of multiple hamartomas and with carcinomas of the thyroid, breast, endometrium, and kidney. Hamartomas are benign tumor-like malformations resulting from developmental errors and are characterized by abnormal mixtures of cells and tissues found in the area of origin.

All patients underwent comprehensive PTEN mutational analysis, which identified germline pathogenic PTEN mutations in 144 patients (5.6%). Of those patients, 46 (40%) developed a second malignant neoplasm at a median age of 50 years. Median time to the appearance of the second cancer was 5 years (range, <1 to 35 years).

Breast cancer risk in patients with PTEN mutations was dramatically elevated. Of the patients who presented with primary breast cancer, 51 had PTEN mutations. Of those, 11 (22%) had a subsequent new primary breast cancer, for a 10-year second breast cancer cumulative risk of 29%.

Compared with the general population, patients with PTEN mutations were nearly 8 times more likely to develop some type of second cancer. Second cancer risks were particularly high for breast cancer (standard incident ratio [SIR], 8.92), thyroid cancer (SIR, 5.92), and endometrial cancer (SIR, 14.08).

"We have anecdotally known the increased risk of a second breast cancer in our patients. Although the numbers were relatively small, we now formally show that 22% of patients had a second breast primary with a 10-year cumulative risk of a second breast primary, which is significant and will need to be followed up on," Dr. Eng said.

Implications for Prophylactic Mastectomy

The difficulty detecting early breast tumors in patient with PTEN mutations should be taken into account when prophylactic mastectomy is considered, she explained.

"We would like to have our data validated by a larger series and longer follow-up, but we do know from our clinical experience that patients with PHTS have high incidence of coexisting fibrocystic breast disease. This is distinct from other hereditary breast cancer syndromes," Dr. Eng reported. "This means that relying on mammographic or MRI surveillance alone to detect early breast cancers can be challenging. In these circumstances, a conversation discussing the relative pros and cons of prophylactic mastectomy may be useful to help patients make an informed decision," she said.

Thyroid Cancer Risk Especially High in Men

"We would advise that clinicians be vigilant when seeing patients with thyroid cancer. In addition to the 2 red flags we have described (i.e., male sex and [follicular thyroid cancer]), clinicians should look specifically for additional clinical clues suggestive of [Cowden syndrome], such as an enlarged head circumference or pediatric age of onset. Of the PTEN mutation-positive patients included in this study, 5 had pediatric onset cancers, all of which were thyroid (age range, 7 to 17 years). This is in keeping with our published work and our recommendation that patients with a germline PTEN mutation receive baseline thyroid imaging and examination at the time of PTEN mutation detection," the authors advise.

Patients with PTEN mutations and no known thyroid pathology should be screened with a clinical examination and potentially with imaging of the thyroid gland, according to Dr. Stratakis.

"Our study confirms what we have noticed all along. What we need to now do is identify why certain patients are at risk for certain cancers, and why some patients seem to have higher cancer burdens. Our work previously showed that PTEN interacts with SDHx genes, resulting in a higher risk of breast and thyroid cancers. It is likely that many more such interactions exist and are waiting to be discovered," Dr. Eng said.

"Although the overall prevalence of PTEN germline mutations among patients with thyroid cancer is less than 1%, the data from this study suggest that thyroid cancer patients who present with a second neoplasm, especially if they are male, should be considered candidates for PTEN gene testing," Dr. Stratakis noted.

PTEN Data Raise Questions About Cancer Biology and Genetics

This study "not only presents data on previously unsuspected associations, it is also significant for the new questions in cancer biology and genetics that it poses," Dr. Stratakis said.

For example, "What is it that makes these patients develop a second tumor? If late recurrence of the same tumor cells in the same organ occurs, what made these cells stay dormant for so many years? If the most likely scenario of a subsequent new primary tumor is the case, why does this not happen in every patient? Why do some patients develop a second and additional tumors and some do not? Why do some develop them early and others as late as decades after?" he asked.

Dr. Eng and Dr. Stratakis have disclosed no relevant financial relationships.

J Clin Oncol. Published online April 28, 2014. Abstract, Podcast


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