New research from Johns Hopkins Medicine aims to illuminate how ovarian cancer develops by examining the role of serous tubal intraepithelial carcinomas (STICs), lesions believed to be the main precursors of high-grade serous carcinoma (HGSC), the most common and lethal form of ovarian cancer.

Pathologist Ie-Ming Shih, the Richard W. TeLinde Distinguished Professor in the Department of Gynecology and Obstetrics and co-director of the Women’s Malignancy Program at the Johns Hopkins Kimmel Cancer Center, was among eight recipients of the prestigious Pershing Square Foundation Lotus Award, which will provide $750,000 in funding over three years for the work. Shih and his colleagues are pioneers in ovarian cancer research and treatment.

The study aims first to identify the molecular mechanisms by which these early lesions arise in the fallopian tubes. That knowledge could inform how gynecologists manage patients with BRCA1 or BRCA2 germline mutations who have undergone risk-reducing salpingo-oophorectomy and for whom STICs are found in the fallopian tissue. Would these patients benefit from chemotherapy, a poly (ADP-ribose) polymerase (PARP) inhibitor or liquid biopsy, or is monitoring sufficient?

The lifetime risk of ovarian cancer with a BRCA1 mutation is 39%–46% by age 70. With a BRCA2 mutation, the risk by age 70 is 10%–27%.

Within 10 years, up to a quarter of women who carry BRCA mutations and have precancerous lesions at the time of salpingo-oophorectomy will develop HGSC. One theory is that precancerous cells may already have spread to the peritoneum before the surgical removal of the fallopian tubes that harbor STICs.

The current standard of care does not allow pathologists to confidently diagnose STICs in the fallopian tubes after salpingo-oophorectomy because they only examine less than 1% of the tissue under the microscope, leaving the remaining 99% potentially containing STICs unexamined. With Lotus Award funding, Shih and his team will use 3D imaging to examine the entire fallopian tube to identify lesions throughout the tissue from women with BRCA1/2 mutations.

Based on this comprehensive survey of STICs throughout the fallopian tubes, the research team will investigate the prevalence and biological characteristics of the lesions. The researchers will also assess whether certain STICs are associated with a higher risk of dissemination of HGSC later in life. Previous research by Shih and team showed that the majority of STICs are benign, but the sample size of examined tissue was small.

“The main goal is to perform risk stratification of precursor lesions in every patient after salpingectomy,” Shih says. “It would be a breakthrough to distinguish low-risk from high-risk STICs. We want to reassure patients with low-risk STICs that they just need regular follow-ups with their gynecologist. For women with high-risk STICs, we can suggest more intensive follow-up or even effective interventions to prevent HGSC.”

Nearly two decades ago, Johns Hopkins Medicine was among the first institutions to validate that HGSC comes from STICs in the fallopian tubes — a major advance in gynecologic oncology.

“This paradigm shift transformed not only our conceptual view of how ovarian cancer develops but also provided a new road map for diagnosing and preventing ovarian cancer,” Shih says. “We want to intercept ovarian cancer at its precancerous stage before it becomes invasive and disseminates.”

The Lotus Award builds on his team’s research of more than two decades, including the molecular characterization of different types of ovarian cancer and the discovery of cancer-promoting genes that can be harnessed to treat ovarian cancer. 

In the past few years, Shih has mentored several graduate students and fellows who have published articles that have further advanced this research in finding that STICs are composed of various lesions with distinct clinicopathological and molecular features, pointing to the existence of high-risk STICs.

“Most people with ovarian cancer don’t have a genetic predisposition or family history,” Shih says. “So we’re trying to intercept ovarian cancer not only in those with BRCA1 and BRCA2 mutations but also in women without these germline mutations, so we can have more impact on preventing ovarian cancer mortality and morbidity.”

The Department of Gynecology and Obstetrics is also a national and international leader and advocate in opportunistic salpingectomy — efforts led by gynecologic oncologist and director of the Kelly Gynecologic Oncology Service Rebecca Stone. These efforts were bolstered in February by a Canadian study showing that opportunistic salpingectomy can reduce ovarian cancer risk by 80%.

This low-risk surgery can be performed when there is an opportunity for a post-reproductive intra-abdominal procedure, such as a hysterectomy, tubal ligation or cholecystectomy. Both Shih and Stone collaborate with investigators around the globe to research and advocate for opportunistic salpingectomy as a way to reduce ovarian cancer risk.

Learn more about the Richard W. TeLinde Gynecologic Pathology Research Program.