Ovarian Cancer (June 2015): Molecular Oncology Tumor Board

ASCO University
Jun 10, 2015 9:50 AM

User Instructions: Welcome to the Molecular Oncology Tumor Board Series! This educational initiative is a collaboration of 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. Russell Broaddus (MD Anderson) and Mike Birrer (Massachusetts General Hospital). 

Users 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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Please click here for supplemental resources related to the case.

Comments

10701

ASCO University
Re: Ovarian Cancer (June 2015): Molecular Oncology Tumor Board
Jun 10, 2015 9:51 AM

Patient Case

A 52 year old woman with no previous medical or surgical history recently complained of new-onset abdominal bloating.  Physical examination and imaging revealed a pelvic mass. Serum CA-125 was elevated at 1,200.  A total abdominal hysterectomy, bilateral salpingectomy and omentectomy were performed with no post-operative complications.  The tumor was suboptimally debulked, with more than 1 cm of grossly residual tumor.  

Pathologic examination demonstrated that the pelvic mass was an ovarian high grade serous carcinoma with spread to the omentum. Following surgery, she received carboplatin (AUC6) and paclitaxel (175mg/mm Q 3 weekly) chemotherapy.  Six months following completion of this chemotherapy regimen, she suffers a tumor recurrence in the abdomen.

ASCO University
Re: Ovarian Cancer (June 2015): Molecular Oncology Tumor Board
Jun 10, 2015 9:52 AM

Discussion Questions

  1. What are the most important prognostic features for this type of ovarian cancer at diagnosis?
  2. How would you classify this patient: sensitive or resistant to platinum-based chemotherapy?  Provide your definition of platinum resistance.
  3. What would be your recommended treatment following this first recurrence?

10711

Anis Toumeh, MD
Re: Ovarian Cancer (June 2015): Molecular Oncology Tumor Board
Jun 10, 2015 1:41 PM

1- The most important prognostic features in this case would be the stage and the macroscopic residual disease after debulking surgery (> 1 cm)

2- Patients with a platinum free interval (PFI) of six months or longer are considered to have "platinum-sensitive" disease

3- This patient is likely to have a platinum sensitive disease so a platinum-doublet systemic therapy would be an appropriate standard of care. Options include Carboplatin/Paclitaxel (ICON4), Carboplatin/Gemcitabine (AGO OVAR 2.5) and (Carboplatin/PLD (CALYPSO). Although not approved in this setting, the addition of Bev could be considered in selected patients as it has been shown to improve PFS (OCEANS). Also, GOG 262 suggested that if no Bev is added, the administration of weekly Paclitaxel with q3 weekly Carboplatin may provide better PFS and OS compared to q3 weekly Paclitaxel and q3 weekly Carboplatin.

10716

Ernesto B. Sander
Re: Ovarian Cancer (June 2015): Molecular Oncology Tumor Board
Jun 10, 2015 9:43 PM

It is interesting case , like to enter a discussion on the role of Bevasizumab monoclonal antibody in ovarian cancer and the use of surrogate markers to follow up patients on treatment once it is an anti angiogenic drug like to see comments about angiogenic markers.

Michael J. Birrer, MD, PhD
Re: Ovarian Cancer (June 2015): Molecular Oncology Tumor Board
Jun 11, 2015 3:16 PM

Course Faculty Response
Ernesto - Currently bevacizumab is approved for use in combination with chemotherapy for platinum resistant recurrent ovarian cancer in the US. However, the use of bevacizumab in platinum sensitive recurrent disease is frequently covered due to the results from the OCEANS trial and now GOG213. There are no predictive biomarkers approved for identifying or following patients who would benefit from bevacizumab but at the recent 2015 ASCO Annual meeting, tumor associated CD31 and VEGFA levels were demonstrated to correlate with bev benefit in the upfront treatment of newly diagnosed ovarian cancer.

10731

Federico A. Monzon, MD
Re: Ovarian Cancer (June 2015): Molecular Oncology Tumor Board
Jun 12, 2015 10:33 AM

According to NCCN Guidelines, patients with invasive ovarian cancer should be recommended for genetic risk assessment (Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 1-2015). Also, genetic testing might have implications regarding therapy with PARP inhibitors. Could you comment on the appropriateness of germline genetic testing in this case?

Michael J. Birrer, MD, PhD
Re: Ovarian Cancer (June 2015): Molecular Oncology Tumor Board
Jun 12, 2015 11:01 AM

Course Faculty Response

Federico - Dr. Broaddus and I agree that given the recent data on the frequency of BRCA1 and 2 germ line mutation (14-17%), including women without a family history (8%), it is reasonable to have all newly diagnosed cases undergo genetic testing. This has prognostic implications (mutation carriers have a better prognosis) and certainly would be candidates for treatment with PARP inhibitors later in the natural history of the disease.

10746

Mayer Gorbaty, MD
Re: Ovarian Cancer (June 2015): Molecular Oncology Tumor Board
Jun 13, 2015 7:51 AM

Can you comment on the use of bevacizumab as part of upfront, first line treatment of ovarian cancer?  Specifically though not FDA approved do you feel it is a standard of care?  In what situations?  If used -for how long?

Michael J. Birrer, MD, PhD
Re: Ovarian Cancer (June 2015): Molecular Oncology Tumor Board
Jun 13, 2015 11:32 AM

Course Faculty Response

Mayer - The FDA approval for bevacizumab is limited to platinum resistant recurrent ovarian cancer based upon the AURELIA study. However in the US there are states where insurance will cover the use of the drug in the platinum sensitive recurrence setting (OCEANS and GOG213) and the upfront treatment of the disease (GOG218 and ICON 7). Given the results of the latter two randomized PHASE III trial, I do consider the use of bevacizumab as a up front option. I would utilize the GOG218 dose and duration.

10756

Rashmi Ramasubbaiah, MD, MS
Re: Ovarian Cancer (June 2015): Molecular Oncology Tumor Board
Jun 13, 2015 1:49 PM

Can you comment on the use of the dose dense regimen (carbo 3weekly, taxol weekly) in the adjuvant setting, esp as this was suboptimally debulked and serous histology. Based on the JGOG3016 and GOG 262 trial, it seems that outcomes may be better with the dd regimen, esp if bev was not used.

Michael J. Birrer, MD, PhD
Re: Ovarian Cancer (June 2015): Molecular Oncology Tumor Board
Jun 13, 2015 4:25 PM

Course Faculty Response

Rashmi - As recommended by the ovarian cancer consensus conference  (Vancouver), the dose dense regimens is an acceptable alternative to the Q3 weekly regimen. I do not consider it superior despite the JGOG3016 trial due to JGOG3016 small size and the differences in patient populations. The GOG262 result is interesting in that it suggests adding bevacizumab substitutes for the potential advantage of dose dense. Unfortunately, it is difficult to interpret as the non bevacizumab treated group was very small (approximately 20%).

10771

Russell Broaddus
Re: Ovarian Cancer (June 2015): Molecular Oncology Tumor Board
Jun 15, 2015 10:54 AM

Course Faculty Response

In response to the first discussion question ("What are the most important prognostic features for this type of ovarian cancer at diagnosis?"), from a pathology perspective, significant prognostic factors for this patient include the grade and stage of her tumor. She has high grade and stage III serous cancer of the ovary; the involvement of the omentum establishes stage III disease. These clinical factors are associated with poor survival when compared with early stage and low-grade serous carcinomas.

10776

Michael J. Birrer, MD, PhD
Re: Ovarian Cancer (June 2015): Molecular Oncology Tumor Board
Jun 15, 2015 10:59 AM

Course Faculty Response

My responses to the initial set of discussion questions are as follows:

  1. Important indicators of worse survival include the following:
    • Presence of residual disease at the time of surgical debulking;
    • Resistance to platinum-based chemotherapy.
  2. Platinum resistance is traditionally defined as a tumor that recurs within 6 month after the last platinum-containing cycle. This includes any treatment regimen, including 2nd and 3rd recurrence. This patient presents a dilemma in that she has suffered a recurrence at the six months cutoff. Usually, in this circumstance one decides the platinum status based on what is best for the patient. Factors that can influence this decision would be the number of recurrences and previous lines of treatment as well as the volume of disease. An extensive number of previous treatments would suggest a more resistant tumor while large volume disease would favor re-trying a platinum-based therapy.
  3. I would declare the patient to be platinum-sensitive. There is level 1 evidence for the equal efficacy of three potential platinum doublets. Retreatment with carboplatin/paclitaxel has been shown to be more effective than single agent carboplatin for this patient population. Further, carboplatin/gemcitabine has been shown in a randomized phase III trial to provide a PFS advantage over single agent carboplatin. Finally, carboplatin/liposomal doxorubicin has been demonstrated to be equally effective compared to carboplatin/paclitaxel in prospective trial. Thus, any one of these platinum doublets would be acceptable and might be tailored to the patient needs. Women who do not wish to lose their hair would not want a paclitaxel-based regimen; poor bone marrow reserve would not favor a gemcitabine combination; and those requiring a more convenient regimen might want the 28 day schedule associated with the carboplatin/liposomal doxorubicin regimen (28 days).

10781

ASCO University
Re: Ovarian Cancer (June 2015): Molecular Oncology Tumor Board
Jun 15, 2015 11:02 AM

Case Update and Discussion Questions

  1. Despite no family history of breast or ovarian cancer, the patient requests to be tested for a BRCA mutation. Is this reasonable?  Germline testing for your patient reveals a BRCA1 mutation.  How does this finding affect your management of this patient?
  2. What value does molecular testing of the tumor provide?

10786

Anis Toumeh, MD
Re: Ovarian Cancer (June 2015): Molecular Oncology Tumor Board
Jun 15, 2015 12:50 PM

I think this is reasonable since 13 to 15 percent of women with invasive ovarian carcinoma have a germline BRCA mutation. The fact that the patient turned out to have a BRCA1 mutation supports the observation that women with BRCA1 gene mutations usually develop ovarian carcinoma at an earlier age with an average age at diagnosis of 50. The BRCA status makes the patient a candidate for PARP inhibition therapy approach 

10811

Russell Broaddus
Re: Ovarian Cancer (June 2015): Molecular Oncology Tumor Board
Jun 19, 2015 10:03 AM

Course Faculty Response

  1. BRCA1 and BRCA2 germline mutations are typically associated with high grade serous histology ovarian carcinoma.  Testing for these germline mutations is therefore reasonable.  If the histology of the ovarian cancer was clear cell carcinoma or endometrioid adenocarcinoma, it would make sense to also evaluate the patient for Lynch Syndrome, a hereditary defect in DNA mismatch repair genes such as MLH1, MSH2, MSH6, and PMS2.  Tissue testing (immunohistochemistry for these mismatch repair proteins and PCR-based microsatellite instability analysis) could be performed first as an initial screen.  If the tumor showed IHC loss of a mismatch repair protein and/or high levels of microsatellite instability, germline testing could be next pursued.  For BRCA1 and BRCA2, however, no such tissue testing assays currently exist.
     
  2. Molecular testing to identify potentially actionable targets for enrollment in a targeted therapy trial is a reasonable approach for many patients with advanced solid tumor malignancies.  Unfortunately, in our experience with ovarian high grade serous carcinoma, not many targets are typically identified.  Nearly all of these tumors have TP53 gene mutations.  For high grade serous carcinoma, mutations in members of the PI3K/AKT pathway (PIK3CA, PTEN) are very infrequent – less than 5% of patients.  Alternative histologies, such as clear cell carcinoma and endometrioid carcinoma, may potentially yield more actionable targets, but these histologies have not yet been studied broadly in clinical settings.  While bevacizumab therapy can benefit some ovarian cancer patients, we currently do not have good predictive assays for identifying the patients who would benefit most.

 

10816

Michael J. Birrer, MD, PhD
Re: Ovarian Cancer (June 2015): Molecular Oncology Tumor Board
Jun 19, 2015 10:10 AM

Course Faculty Response

  1. Recent data strongly suggest that all patients with ovarian cancer should undergo germ-line testing for BRCA1/2. Approximately 8% of patients with ovarian cancer will have a family history and will test positive for BRCA1 or 2 mutation. An additional 8% of women with ovarian cancer will not have a family history but a germ-line BRCA1 or 2 mutation. The finding of a germline mutation is important for two reasons; 1.) it has important prognostic information, in that these patients have an improved survival; 2.) these patients would be candidates for treatment with PARP inhibitors at some point in the natural history of the disease. (J Ledermann at al 2015; AM Oza et al 2015)
     
  2. The molecular features of ovarian cancer involve few actionable mutations but many amplifications and deletions of uncertain impact. Thus, the majority of the results usually do not alter clinical management. There are two potential important results: 1.) somatic mutations in BRCA1/2 in tumors which are assumed to ascribe the same clinical impact are a germ-line mutation; 2.) low frequency mutations and amplifications can be used for triage to clinical trials.

 

10826

Russell Broaddus
Re: Ovarian Cancer (June 2015): Molecular Oncology Tumor Board
Jun 24, 2015 11:38 AM

Course Faculty Summary

Thank you for participating in this course.  Below are my summary points from this challenging case:

  • While frontline therapy for patients with ovarian cancer is relatively standard, therapeutic approaches for recurrences, which inevitably will happen, are much more challenging.
  • Molecular testing of the tumor may be considered for possible enrollment into targeted therapy trials, but to date the percentage of ovarian carcinoma patients with potential targets has been low.
  • Determination of BRCA1/2 germline mutation status should be pursued for all ovarian cancer patients.  Identification of germline mutations is helpful in that it is prognostic, it identifies patients who may be treated with PARP inhibitors, and it provides important cancer risk information to family members.
  • Histology of the ovarian tumor provides key information.  The vast majority of women with BRCA1/2 germline mutations have ovarian carcinomas with high grade serous histology.  Endometrioid and clear cell histologies have a tighter link to a different hereditary cancer syndrome, Lynch Syndrome.  For serous carcinomas, the clinical course and treatment approaches are entirely different for high grade tumors compared to low grade tumors.

10831

Michael J. Birrer, MD, PhD
Re: Ovarian Cancer (June 2015): Molecular Oncology Tumor Board
Jun 24, 2015 11:40 AM

Course Faculty Summary

I would also like to thank everyone for their participation in this course. Below is a summary of my thoughts based off of the available information:

  • The most important prognostic factors at the initial diagnosis of ovarian cancer include stage, grade and residual disease after surgery
  • The time between completion of a platinum based therapy and  recurrence is critical for determining platinum sensitivity of the recurrent tumor.
  • The value of germ-line sequencing of BRCA1/2 is in establishing prognosis for the patient, genetic risk for family members and potential benefit from the treatment with PARP inhibitors.
  • Molecular testing of ovarian tumors remains experimental and the primary application is determining somatic BRCA1/2 and triaging patients for clinical trial.

10836

ASCO University
Re: Ovarian Cancer (June 2015): Molecular Oncology Tumor Board
Jun 24, 2015 11:46 AM

Thank you to Drs. Broaddus and Birrer 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 and users have the opportunity to claim credit on ASCO University.

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

 


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