Ovarian Cancer (July 2017): Molecular Oncology Tumor Boards

ASCO University
Jul 12, 2017 7:10 AM

Participant Instructions: Welcome to the Molecular Oncology Tumor Board Series! This educational initiative is a collaboration between the American Society of Clinical Oncology (ASCO), College of American Pathologists (CAP), and Association for Molecular Pathology (AMP).

A new case will be presented each month with discussions led by an expert pathologist and medical oncologist. This month’s topic is led by Drs. Carolina Reyes (Pathologist from the University of Pennsylvania) and Douglas A. Levine (Gynecologic Oncologist from NYU Perlmutter Cancer Center).

This discussion is built upon a hypothetical, ovarian cancer patient case that was suggested by a Molecular Oncology Tumor Board participant. Do you have an interesting case in mind? Submit your hypothetical patient cases for consideration in an upcoming Molecular Oncology Tumor Board discussion forum.

Participants are encouraged to leave comments and post questions about the case in order to generate a wide discussion among the cancer care community. You can also receive email notifications when new comments are posted by clicking the “Follow this Conversation” option located at the bottom of this page.

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Comments

14771

ASCO University
Re: Ovarian Cancer (July 2017): Molecular Oncology Tumor Boards
Jul 12, 2017 7:13 AM

Patient Case

Patient History: A 62-year-old woman with frequent abdominal bloating and urination for 3 months, now with pelvic pain is referred by a gynecologist for evaluation.  Ultrasound shows an 8.5cm complex right ovarian mass with a moderate amount of free fluid in the pelvis. There is no abnormal vaginal bleeding.  Baseline labs are significant for thrombocytosis with platelets of 650 K/uL, CA125 of 394 U/mL, and CEA of 1.6 ng/mL.  Family history is unremarkable. Abdominal exam is normal, pelvic exam demonstrates a mobile right adnexal mass.

Radiology: Diagnostic CT of the Chest, Abdomen and Pelvis with IV contrast showed a heterogeneous right ovarian mass, infiltration of the omentum, nodular carcinomatosis over terminal ileum and cecum, consistent with metastatic ovarian cancer.  There were no enlarged retroperitoneal lymph nodes or other disease noted in the upper abdomen.

Surgery: The patient underwent primary cytoreductive surgery and was found to have widespread disease that was completely resected through a total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, ileocecal resection with re-anastomosis, right diaphragm peritonectomy, and splenectomy for disease involvement and the splenic hilum. She tolerated the procedure well and was discharged home on POD#5.  

Pathology: Gross examination revealed bilateral ovarian masses measuring 10 cm and 14 cm and a mass attached to and in continuation with right fallopian tube. In addition, omentectomy specimen showed various tumor nodules measuring 3 cm in greatest dimension.

Histopathology revealed a high grade adenocarcinoma consisting of hyperchromatic nuclei with marked variation in nuclear size and prominent mitotic figures, involving bilateral ovaries, omentum and peritoneum .It showed various architectural patterns including papillary areas with slit-like spaces (Picture 1), solid patterns consisting of sheets of malignant cells without gland formation (Picture 2) and glandular areas with well formed glandular spaces lined by cells high grade nuclear features (Picture 3). In addition, the right fallopian tube revealed a characteristic mucosal lesion (tubal intraepithelial carcinoma), were the fallopian tube was lined by carcinoma cells similar to those found elsewhere with in the tumor (Pictures 4 and 5).

Morphology is most consistent with a high-grade serous carcinoma involving right fallopian tube, bilateral ovaries, omentum and peritoneum.  Also, serous tubal intraepithelial carcinoma (STIC) involving the right fallopian tube.

14776

ASCO University
Re: Ovarian Cancer (July 2017): Molecular Oncology Tumor Boards
Jul 12, 2017 7:14 AM

Discussion Questions

1.    Should this patient, without a known family history, undergo genetic counseling and testing?  
2.    What type of genetic testing should be performed, germline or somatic testing?
3.    How many genes should be tested for and what is the significance of testing for genes other than BRCA1 and BRCA2?
4.    Will the results of these tests influence the decision of the initial treatment regimen?
5.    Will the results of genetic testing influence the prognosis of this patient?

14786

Anis Toumeh, MD
Re: Ovarian Cancer (July 2017): Molecular Oncology Tumor Boards
Jul 12, 2017 10:52 AM

1- I would definitely refer this patient for pre-test genetic counseling as approximately 1 in 5 patients with epithelial ovarian carcinoma have a predisposing genetic mutation ( in BRCA 1/2 as well as other genes, e.g. RAD51, BARD1,PALB2).

2- Would recommend both germline and somatic testing as this patient will probably be a candidate for treatement with one of the PARP inhibitors that showed efficacy in both germ-line and somatic BRCA mutations. This will influence treatment decisions as well as give prognostic information as patients with BRCA 1/2 mutations have a better prognosis at least partly because of sensitivity to platinums and PARP inhibitors 

A question I have is that, is there any data to suggest that patients who are carriers of non-BRCA mutations have better prognosis or more sensitive to platinums?

 

 

14791

Douglas A. Levine, MD
Re: Ovarian Cancer (July 2017): Molecular Oncology Tumor Boards
Jul 13, 2017 7:39 AM

Course Faculty Response

We agree with the participant that pre-test genetic counseling is very helpful, when those services are available, which may not be in all parts of the Unites States and the rest of the world.

Regarding the second comment:
1.    The prognostic information regarding a BRCA mutation is not likely to affect initial therapy at this time based on FDA-approved indications.  Prognostic information is useful, but may not outweigh the cost of a somatic molecular profile on its own.
2.    Regarding the utility of somatic mutation testing at diagnosis, one reason to delay somatic testing until a later date is that some patients may develop resistance mutations after initial treatment and if a future specimen becomes available (secondary cytoreduction, biopsy, etc) this could be used to identify resistance mutations. Additionally, somatic testing is often sent as part of a multigene panel and sending a post treatment specimen, if available, would more accurately reflect the post-treatment profile of the patient at the time of subsequent therapy.
3.    In regard to the question about non-BRCA mutations and platinum sensitivity, there are several reports showing that non-BRCA mutations are directly or indirectly associated with improved survival and/or better treatment response. (Pennington, 2014) (Kondrashova, 2017).

14796

Carolina Reyes
Re: Ovarian Cancer (July 2017): Molecular Oncology Tumor Boards
Jul 17, 2017 9:39 AM

Course Faculty Response

1. Yes this patient has high-grade serous carcinoma involving fallopian tube and bilateral ovaries. According to NCCN Guidelines, any individual with an epithelial ovarian, fallopian tube or peritoneal cancer should receive genetic counseling and be offered genetic testing, even in the absence of family history or young age.

2. Regarding somatic versus germline BRCA testing, generally, germline testing from a blood sample will be performed using single gene tests or multiple gene panels that can detect other mutations besides BRCA1/2. By performing a multiple gene panel and identifying other mutations different from BRCA1/2, it will give the clinician additional treatment options. Even if the patient is negative for BRCA1/2, the tumor may harbor other non-BRCA mutations involved in DNA repair, and therefore the patient could still receive poly adenosine diphosphate-ribose polymerase (PARP) inhibitors.
Because somatic mutations or methylation can also occur in BRCA1 or BRCA2 and other members of the BRCA1/2 homologous recombination pathway (RAD51, cHK1, cHK2, ATM, ATR and FANCF) some institutions will also perform somatic mutation.

3. Testing for other genes other than BRCA1/2 is recommended, because certain genetic alterations will stratify patients in prognostic categories. For instance, patients whose tumors harbor p53 mutations are associated with longer progression free and overall survival.  Some studies have shown that association of high-grade serous carcinomas with PTEN mutations is associated with outcome.

4-5. Studies have shown that BRCA1 and BRCA2 mutated ovarian cancers tend to be more sensitive to platinum agents and possibly PARP inhibitors than wild-type ovarian cancers. In addition, patients with BRCA2 mutation have better survival when compared with BRCA1 patients. BRCA2 mutation status may be a genetic marker for predicting prognosis and chemotherapy response, since they have been reported to be associated with longer platinum-free survival durations when compared with BRCA1 and BRCA wild-cases.

14801

Douglas A. Levine, MD
Re: Ovarian Cancer (July 2017): Molecular Oncology Tumor Boards
Jul 17, 2017 9:40 AM

Course Faculty Response

1.    All patients with ovarian cancer should have germline genetic counseling and testing. For women with ovarian cancer who are found to carry a germline mutation in an ovarian cancer risk gene that she is encouraged to inform all first-degree relatives recommend that they have genetic testing for the identified mutation.  This process is called cascade testing and due to highly effective methods of ovarian cancer prevention in high-risk individuals, cascade testing can play a major role in reducing the burden of ovarian cancer in the population at-large.

2.    This is becoming a more controversial area with the recent FDA approval of three PARP inhibitors for ovarian cancer treatment.  Some physicians recommend somatic mutation testing and then reflex to germline testing when a mutation is identified in an ovarian cancer risk gene. The issue with this approach is that most somatic mutation tests are not designed in a way to detect certain germline events in BRCA1 or BRCA2 such as large gene deletions and certain other structural variations so a small portion of germline events will be missed through somatic testing alone. Another concern is that through somatic testing alone, some physicians will not realize that the variants may be germline in nature and fail to refer to genetic counseling when appropriate. The other issue with initial somatic testing is that the results will rarely affect initial therapy, and when the results may affect treatment, the tumor will have been exposed to various agents potentially affecting the molecular profile and/or selecting for reversion mutations that can result in therapeutic resistance (Edwards, 2008) (Kondrashova, 2017).

3.    Nowadays there are panels of genes for ovarian cancer risk testing. Clearly, BRCA1 and BRCA2 are the two most commonly mutated genes in hereditary ovarian cancer.  However, other genes have been found to substantially increase the risk of ovarian cancer including RAD51C, RAD51D, BRIP1 and likely PALB2.  Nonetheless, there are genes in these panels that may have variants but are unproven to be associated with increased ovarian cancer risk.

4.    It is unlikely that the results of testing would influence initial choice of therapy at this point, however ongoing clinical trials are testing PARP inhibition and checkpoint blockade as part of primary therapy.  Future results could identify biomarkers of response that may affect initial treatment. There are no well-designed studies at present that implicate any biomarkers to impact the drug choice or route of administration.

5.    It is well established that women with BRCA1 and BRCA2 germline mutations have in improved outcome, with BRCA2 having a stronger effect than BRCA1 likely due to the collinearity of BRCA1 and younger age at diagnosis. Though BRCA2 has a stronger effect, well-designed studies with sufficient statistical power confirm that BRCA1 carriers also have a better outcome than non-carriers (Bolton, 2012).

14806

ASCO University
Re: Ovarian Cancer (July 2017): Molecular Oncology Tumor Boards
Jul 17, 2017 9:41 AM

Patient Case Update

The patient had a complete response to initial therapy and entered into remission. After 38 months, the CA125 started to rise and a CT scan showed multifocal recurrence with more than a dozen separate small lesions in the peritoneum. The patient underwent laparoscopy to assess for secondary cytoreduction and was found to have widespread miliary disease coating all small bowel surfaces and cytoreduction was aborted after representative biopsies were obtained.  She went on to receive pegylated liposomal doxorubicin and carboplatin for six cycles and entered a second complete clinical remission. 

14811

ASCO University
Re: Ovarian Cancer (July 2017): Molecular Oncology Tumor Boards
Jul 17, 2017 9:42 AM

Discussion Questions

1.    Would you give her maintenance therapy now that she is in her second complete clinical remission?
2.    Would you send NGS at this time to help in your decision-making?
3.    Would any results from the NGS affect whether or not you would treat with a targeted agent now (in remission) or at the time of subsequent recurrence?  

14816

Anis Toumeh, MD
Re: Ovarian Cancer (July 2017): Molecular Oncology Tumor Boards
Jul 17, 2017 9:58 PM

With the approval of Niraparib as maintenance therapy, how would one choose between this agent and bevacizumab as maintenance therapy? (assuming one decides to apply maintenance therapy in a given patient). 

14821

Douglas A. Levine, MD
Re: Ovarian Cancer (July 2017): Molecular Oncology Tumor Boards
Jul 19, 2017 8:08 AM

Course Faculty Response

Bevacizumab maintenance therapy has only been tested as a continuation of bevacizumab treatment as part of combination chemotherapy, whereas niraparib is used for maintenance therapy on its own, without prior niraparib treatment of active disease.  Therefore, Bev could be considered as continuation if included in a treatment regimen, whereas niraparib could be used if Bev was not part of the prior regimen. 

14836

Carolina Reyes
Re: Ovarian Cancer (July 2017): Molecular Oncology Tumor Boards
Jul 21, 2017 7:11 AM

Course Faculty Response

1.    I would defer this question to Dr Levine.

2.    Regarding NGS, I would send tumor tissue for NGS. Studies have shown that the molecular diagnostic method of next generation sequencing in therapy resistant ovarian carcinomas, identifies a high frequency of unexpected genomic alterations that could influence targeted therapy. For example, a recent study were NGS was performed in high grade serous carcinomas showed that in addition to p53 and PTEN alterations, abnormalities in NRAS, PIK3CA and MET were detected. These results could potentially offer novel targeted and personalized therapy.

3.    I would defer this question to Dr. Levine.

14841

Douglas A. Levine, MD
Re: Ovarian Cancer (July 2017): Molecular Oncology Tumor Boards
Jul 21, 2017 7:12 AM

Course Faculty Response

1.    The recently published NOVA trial found that progression-free survival (PFS) was statistically prolonged when a niraparib was given as maintenance therapy to ovarian cancer patients who were responding to platinum-based therapy or had a complete response.  The study performed molecular characterization of tumors for germline BRCA1 and BRCA2 mutations, as well as tests for homologous recombination deficiency (HRD). There was statistically significant improvement in PFS for all subgroups, but it was greatest for those patients with germline BRCA1 or BRCA2 mutations.   Though FDA approved for this indication, there is some controversy when considering the side effects of niraparib and the modest 3 month improved PFS for patients without germline mutations or HRD (Mirza, 2016). This study and others demonstrated that response to PARP inhibition is similar for patients with germline or somatic mutations (Swisher, 2017).

2.    Sending NGS at the time of first recurrence, in this case, and considering that the patient was undergoing a surgical procedure with biopsy, can be useful. Here you can see what mutations may have been selected for during the process of recurrence and you can see if there appears to be any secondary mutations that may indicate resistance to PARP inhibition.  You may identify a target that could result in referral to a clinical trial, which is usually the preferred approach in this setting, since standard agents are always available and clinical trial enrollment is dependent on many factors.

3.    Knowing whether or not the patient had a somatic BRCA1 or BRCA2 mutation (assuming germline testing was negative at diagnosis) may help with the decision making process.  If there is no somatic mutation, then PARP inhibition is only indicated in this maintenance setting, which may be reasonable after a thorough discussion of the risks of treatment and the small benefit in PFS.  If a somatic mutation is detected, though the PFS at maintenance is much longer, PARP inhibition would also be indicated at the time of next recurrence. Though we do not have head-to-head data to determine the sequence, it is unclear if PARP treatment during the maintenance setting is preferred over PARP treatment at next recurrence; again considering the side effect profile and benefits of treatment.

14856

Carolina Reyes
Re: Ovarian Cancer (July 2017): Molecular Oncology Tumor Boards
Jul 26, 2017 8:42 AM

Course Faculty Summary

We present a case of a woman with advanced stage ovarian high-grade serous carcinoma with complete response to initial treatment. After 3 years, patient presented with recurrence.

-    Current NCCN guidelines recommend testing for BRCA1/2 mutations in all patients with a diagnosis of high-grade serous carcinoma, regardless of family history or young age.
-    The most common genetic test performed is germline BRCA1/2, although some centers will also request somatic testing, since some patients with somatic alterations still respond to PARP inhibitors.
-    NGS is a tool that can identify additional molecular alterations in therapy resistant high-grade serous carcinomas with potential options for targeted therapy.

14861

Douglas A. Levine, MD
Re: Ovarian Cancer (July 2017): Molecular Oncology Tumor Boards
Jul 26, 2017 8:43 AM

Course Faculty Summary

We present a case of a woman with advanced stage ovarian high-grade serous carcinoma with complete response to initial treatment. After 3 years, patient presented with recurrence.

-    All patients with ovarian cancer of any histologic subtype should be referred for genetic counseling and testing.
-    All first-degree relatives of women known to carry a germline mutation should be offered genetic counseling and testing.
-    Panel testing can detect less commonly mutated genes that may be associated with ovarian cancer risk, but variants in genes without known ovarian cancer risk must be interpreted appropriately.
-    The preferred approach for germline and somatic testing is not clear when considering the interests of both inherited risk and therapeutic decision-making.  Traditional germline testing at diagnosis and subsequent somatic testing when results would impact treatment is a reasonable approach.
-    Whether to use PARP inhibitors in the maintenance or treatment setting requires careful consideration of the side effect profile, known benefits and patient preference.

14866

ASCO University
Re: Ovarian Cancer (July 2017): Molecular Oncology Tumor Boards
Jul 26, 2017 8:43 AM

Thank you to Drs. Levine and Reyes for leading the discussion of this case and also to all of those who contributed to the conversation! The forum is now closed to further comments but users have the opportunity to claim credit on ASCO University by clicking here.

Please check back in mid-August for a new case in this series related to lung cancer.