Summary Doctors are now able to identify whether patients with early-stage lung adenocarcinoma have an aggressive form called solid predominant subtype. Following surgery, this type of lung adenocarcinoma often returns within two years in multiple locations, even when tumors are small. These patients may require closer follow-up and adjuvant treatments in addition to surgery in order to reduce risk of recurrence. Highlights Patients with early-stage lung adenocarcinoma traditionally had surgery alone.

An aggressive subtype often returns after surgery even when tumors are small.

Surgeons and oncologists are now able to identify this subtype.

This form of lung adenocarcinoma is called solid predominant subtype.

These patients may require closer follow-up and additional treatments.

Patients with early-stage lung adenocarcinoma, the most common form of lung cancer in the United States, typically have their tumors surgically removed without additional treatment. This has been the standard therapy for stage I patients whose tumors are small and have not spread to nearby lymph nodes.

Now research led by Memorial Sloan Kettering thoracic surgeon and scientist Prasad Adusumilli has identified a subset of these patients whose cancer is more likely to return soon after removal, often appearing in multiple locations and ultimately proving more lethal.

These patients have a form of lung adenocarcinoma called solid predominant subtype.

“Our study shows that tumor size alone is not sufficient in predicting how the cancer will behave,” says Dr. Adusumilli. “We can now identify aggressive tumors among early-stage lung cancers, and these patients may require closer follow-up and additional adjuvant treatments, such as chemotherapy, or newer therapies which include drugs that target specific genetic mutations.”

We can now identify aggressive tumors among early-stage lung cancers. Prasad S. Adusumilli thoracic surgeon

Until now, surgery was thought to be sufficient for treating patients with tumors less than 5 centimeters in diameter. The new study, published in the Journal of Clinical Oncology, shows that some of these tiny tumors — even those smaller than 2 centimeters — come roaring back soon afterward.

This finding could change the course of treatment for a significant number of patients with lung adenocarcinoma, a form of non-small cell lung cancer. Although currently only about 20 percent of patients are diagnosed before the cancer has spread to other parts of the body, this portion is expected to increase as more people undergo low-dose CT scans to screen for the disease. Medicare recently approved coverage of these scans for people who are at high risk for lung cancer due to smoking.

Stark Differences among Subtypes

There has been a growing appreciation that the multiple subtypes of lung adenocarcinoma behave differently. As a result of tumor data from MSK and other cancer centers, the International Association for the Study of Lung Cancer (IASLC), the American Thoracic Society (ATS), and the European Respiratory Society (ERS) jointly issued a new tumor classification system in 2011 that characterizes lung adenocarcinomas as a mixture of five subtypes based on histology (how cancer cells look under a microscope).

To help determine prognosis, pathologists now report the proportions of the five subtypes within the tumor — including the predominant subtype, which makes up the highest proportion of tumor tissue — as well as tumor size.

A low-dose chest CT scan of a patient with solid predominant subtype of lung adenocarcinoma.

The new classification system has already begun to change the management of lung adenocarcinomas. In 2013, Dr. Adusumilli, working with MSK pathologist William Travis, showed that a subtype called micropapillary (MIP) morphology was more likely to recur after a limited operation known as wedge resection, in which the tumor and only a small amount of surrounding tissue are removed. This high rate of recurrence held true even for MIP tumors smaller than 2 centimeters.

However, the recurrence rate was lower if the patient had undergone a more extensive procedure called lobectomy, which removes the tumor along with up to a third of the lung. This discovery has helped guide doctors in deciding how much of the lung must be removed to adequately reduce risk of MIP recurrence.

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Rapid Recurrence at Multiple Sites

In the new study, Dr. Adusumilli and colleagues investigated how various subtypes were related to recurrence in a larger group of patients. They looked at more than 1,000 stage I lung adenocarcinoma patients who had their tumors removed at MSK and who were followed afterward with CT scans for an average of five years. They found that the solid predominant subtype, which made up one in seven stage I tumors, was especially aggressive.

Patients with this subtype had a 33 percent risk of recurrence over five years, compared with a risk of only 17 percent in the entire group. More importantly, solid predominant tumors usually recurred within two years, often at locations outside the chest area. The chance of recurrence was actually highest at the one-year mark. Patients with the solid predominant subtype were also more likely to die from their lung cancer more quickly after the cancer returned.

Solid predominant tumors usually recurred within two years, often at locations outside the chest area.

“With the risk of recurrence peaking at one year and the cancer coming back outside the chest at multiple sites, it shows this is a very aggressive subtype that has either already spread undetected or spreads quickly and has poor outcomes,” Dr. Adusumilli says. “If I operate on a patient now and see a solid predominant tumor, I know the chance of it coming back is high, so I need to closely follow up with more frequent CT scans and possibly add adjuvant therapy to help decrease that risk.”

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Identifying Aggressive Tumors before Surgery

Dr. Adusumilli emphasizes the urgent need to identify these aggressive tumors well before operating. His laboratory, along with others at MSK, is already working on identifying several markers that can serve as early detection indicators.

He also underscores the importance of surgeons working closely with pathologists to determine tumor subtype and choose the best course of treatment for the patient after the tumor is removed. “Even for these early-stage tumors, we need the kind of multidisciplinary approach that is possible at centers like ours that involves the highly developed expertise of our pathologists to help surgeons make the best treatment decisions,” he says.

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