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(Notes: FT = Fallopian Tube, HGSOC= High Grade Serous Ovarian Cancer, STIC serous tubal intraepithelial carcinoma, RRSOs = Risk-reducing salpingo-oophorectomy = high risk but not cancer yet removal of ovaries and fallopian tubes)
Here are Dr. Drapkin's responses to our questions:
T1. What makes HGSOC different from other sub-types in terms of the tumor itself, how it spreads, how it is treated, and its prognosis?
Point 1 (1/2):HGSOC is the most common subtype of ovarian cancer. Unfortunately, it tends to spread before detection. Once it is diagnosed, most patients get treated with surgery and chemotherapy.
Point 2 (2/2):Initially, the majority of patients will have a positive response to the treatment. Unfortunately, most will have their tumors come back.
T2. When did research start pointing to the fallopian tubes as the origin site of HGSOC?
Point 1 (1/4):After the BRCA genes were cloned in the mid-1990s, we began offering women at risk prophylactic surgery. That included mastectomy for breast cancer and removal of the ovaries (and fallopian tubes) for ovarian cancer.
Point 2 (2/4):The removal of the FTs along with the ovaries was surgically convenient and most of the attention was placed on the ovary. As early as 2000, reports began to emerge that some of these prophylactic specimens had abnormal looking cells in the FT.
Point 3 (3/4):Around 2005-2006, Dr. Chris Crum (my clinical mentor during residency) @BrighamWomens developed the SEE-FIM (Sectioning and Extensively Examining the FIMbriated end of the fallopian tube) protocol to get a better understanding of what was happening there.
Point 4 (4/4):That is when we realized that most of these tumors were arising from the tube rather than the ovary. Subsequent use of SEE-FIM confirmed this in publications around the world.
This is what the SEE-FIM protocol looks like (after a pathologist processes the FT) #gyncsm pic.twitter.com/8kvPXBwQeC— Ronny Drapkin MD PhD (@ronny_drapkin) April 11, 2019
T3: What characteristics did you study when you examined fallopian tube lesions versus lesions of the ovary? How are BRCA mutations involved?
Point 1 (1/6): Much of that data is based on histological studies. We wanted to see if we could definitively show that these tumors arise from precursor lesions in the FTs by using next generation sequencing and advanced bioinformatic tools.
Point 2 (2/6): We identified cases of HGSOC that had precursors identified in the FT by pathologists. We then used laser-capture microdissection to carefully isolate those cells and applied whole-exome sequencing to characterize the mutations and copy number changes.
Point 3 (3/6): These efforts revealed that mutations in p53 are among the earliest defects detectable. We also found that copy number alterations (amplifications or deletions in certain genes or chromosomal regions) are also frequent, early, and involve the BRCA genes.
Point 4 (4/6): As lesions become more complex they retain the early defects (p53 mutations and copy number changes) and acquire additional ones.
Point 5 (5/6): Using computational tools we were able to develop a molecular clock. This approach showed that there are 6-7 years between the development of a precursor lesion (called a STIC) and clinically evident 'ovarian' cancer.
Point 6 (6/6): However, once the tumor cells get to the ovary, there are only 1.9 years before they spread to the rest of the abdominal cavity. Hence, the window of opportunity to intervene is the 6-7 years before the cells get to the ovary.
This is what the FT precursors look like #gyncsm pic.twitter.com/6YNO16pYx7— Ronny Drapkin MD PhD (@ronny_drapkin) April 11, 2019
T4a: Are HGSOC cancer cells found in the fallopian tube different than those found in/on the ovary? How do they differ from Fallopian Tube Cancer cells?
While there have been many efforts to find early cancer cells in/on the ovary, no one has been able to reproducibly identify them. Since SEE-FIM, a number of systematic attempts have tried to find early precursors in the ovary but have failed.
T5: As we look to the future: How will knowledge of where a majority of ovarian cancers originate impact women at increased risk? How might this research help in the development of an early detection test? What is the impact for women diagnosed with ovarian cancer?
(1/4): Tremendous potential here! The most obvious areas will be in prevention and early detection.
(2/4): The significant morbidity associated with removal of the FTs and ovaries (surgical menopause) has led up to 30-40% of BRCA carriers to delay or refuse risk-reducing surgery.
(3/4): For these women, there are ongoing studies looking at the effect of removing the FTs first (interval salpingectomy) and later removing the ovaries (delayed oophorectomy). One example is the WISP study by @KarenLuMD
(4/4): For average risk women there is ‘opportunistic salpingectomy’ - for example, if you are having a hysterectomy for any reason, the rec is to remove the FTs
@temkins A5: For patients it's important to know that ovarian, fallopian tube and primary peritoneal high grade serous cancers are considered the same disease for the purpose of treatment
T6:How will knowledge of where a majority of ovca originate impact women at increased risk? How might this research help in the development of an early detection test? What is the impact for women diagnosed w/ ovca?
This is the most exciting part. How does the FT matter!?! Lots of activity in this area. We are actively working with a company (nVision Medical) that has developed a modified hysteroscope that can sample the cells in the FT. It is like a pap smear of the FT. We have a phase II clinical trial open at UPenn (and other place) looking at the utility of this device.
T6: the goal of such a device/method is to detect early FT cancers before they get to the ovary. We are currently testing it in women with pelvic masses but we are already planning to test it in BRCA mutation carriers.
T6: Another approach relates to the concept of 'tissue proximal sampling'. This means that if we can get closer to the source of the cancer, perhaps we can detect it earlier. Efforts from @HopkinsMedicine are resulting in exciting results with a PapSeek test. PapSeek uses a regular endocervical pap brush to collect cells and determine if they harbor molecular defects of ovarian cancer.
Save the Date! Join us on Wednesday, May 8th at 9pmET for our discussion on Supplements/Vitamins - Are they helpful?
See you next month,
Dee
#gyncsm Co-founder
RESOURCES
Sectioning and extensively examining the fimbriated end (SEE-FIM) of the fallopian tube in routine practices, is it worth the effort? https://www.ncbi.nlm.nih.gov/pubmed/30506766
Microscopic and Early-Stage Ovarian Cancers in BRCA1/2 Mutation Carriers: Building a Model for Early BRCA-Associated Tumorigenesis http://cancerpreventionresearch.aacrjournals.org/content/4/3/463
WISP - Women Choosing Surgical Prevention https://wisp.mdanderson.org/WISP_Mobile/index.html
Women’s cancers: how the discovery of BRCA genes is driving current concepts of cancer biology and therapeutics https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6411414/
High grade serous ovarian carcinomas originate in the fallopian tube Nature magazine https://www.nature.com/articles/s41467-017-00962-1
