CNS Tumor (June 2016): Molecular Oncology Tumor Boards

ASCO University
Jun 15, 2016 8:26 AM

User 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. Have an interesting case in mind? Submit your hypothetical patient cases for consideration in an upcoming Molecular Oncology Tumor Board discussion forum.

This month’s topic is led by Drs. Daniel Brat (Neuropathologist, Emory University) and Lisa DeAngelis (Neuro-oncologist, Memorial Sloan Kettering Cancer Center).

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 see attached for supplemental resources related to the case.

Comments

12756

ASCO University
Re: CNS Tumor (June 2016): Molecular Oncology Tumor Boards
Jun 15, 2016 8:34 AM

Patient Case

Age/Sex: 41-year-old right-handed woman

Medical History: In 2004, she developed new onset right focal seizures and aphasia. MRI revealed a non-enhancing left parietal mass that was followed after seizures were controlled with an anti-epileptic.

Type of Tumor: Asymptomatic progression was noted in 2007 and she had a partial resection.  The diagnosis established at that time was oligodendroglioma, WHO grade II.

Relevant Markers:  1p19q co-deleted

Images/Scans/Pathology:    Image 1        Image 2

12766

ASCO University
Re: CNS Tumor (June 2016): Molecular Oncology Tumor Boards
Jun 15, 2016 8:36 AM

Discussion Questions

1.    What is the significance of the patient having only a partial resection?
2.    What is the importance of the 1p19q co-deletion status of the tumor?

12771

Anis Toumeh, MD
Re: CNS Tumor (June 2016): Molecular Oncology Tumor Boards
Jun 15, 2016 5:09 PM

1- Do we know the reason why the patient had only a partial resection? (e.g. risk of serious neurological sequelae) - Some observational series support more extensive resection, however I am not aware of randomized clinical data in regards to that particular question. 

2- The presence of co-deletion is prognostic (improved outcomes) and predictive of benefit of adding chemotherapy to radiothereapy in anaplastic Oligodendroglioma

12786

Daniel Brat
Re: CNS Tumor (June 2016): Molecular Oncology Tumor Boards
Jun 20, 2016 9:02 AM

Course Faculty Response

From a diagnostic perspective, a complete resection is preferred because of the potential for undersampling of the lesion. The classification and grade are based on identification of features identified under the microscope from tissue that has been resected. If features of a higher grade tumor are not identified because they were not surgically sampled, there is potential for undergrading the tumor.

In the 2016 update of the WHO Brain Tumor Classification, the diagnosis of Oligodendroglioma incorporates the finding of 1p-19q co-deletion and IDH mutation as a part of the definition. That is, oligodendrogliomas are now considered to be diffuse gliomas with IDH mutations and 1p/19q co-deletions. Importantly, the co-deletion in oligodendroglioma is associated with whole arm losses of chromosomes 1p and 19q.

12791

Lisa Marie DeAngelis, MD
Re: CNS Tumor (June 2016): Molecular Oncology Tumor Boards
Jun 20, 2016 9:05 AM

Course Faculty Response

A partial resection is associated with a worse prognosis, especially if there is 4-6cm or more of residual tumor.  In addition, this patient is over the age of 40 which also carries a worse prognosis and the combination of these 2 factors would suggest she should have received treatment at this time.

Co-deletion of chromosomes 1p and 19q is strongly associated with a better prognosis in low grade gliomas.  Together with IDH mutation, this finding is now considered to be a fundamental molecular feature that characterizes oligodendroglioma.  Not only do such patients live longer, they respond better to all types of treatment.

12796

ASCO University
Re: CNS Tumor (June 2016): Molecular Oncology Tumor Boards
Jun 20, 2016 9:14 AM

Patient Case Update

She continued on observation until progression was noted in 2009 and she was started on single agent temozolomide.  She completed 12 cycles and was lost to follow-up.

In 2013 she developed increased seizure frequency and MRI showed slow progression of the non-enhancing left parietal mass and now a faint hint of enhancement could be seen.

Image 1          Image 2

How tissue was acquired/preserved: Tissue from the original specimen was derived from the partial surgical resection and was fixed in formalin and paraffin embedded.

Testing Platform/Molecular Profiling: Immunohistochemistry performed on her original specimen for mutant IDH1 (R132H) was negative. Molecular profiling by direct sequencing of other IDH1 and IDH2 genes performed on her original specimen revealed an IDH1 R132C mutation.

12801

ASCO University
Re: CNS Tumor (June 2016): Molecular Oncology Tumor Boards
Jun 20, 2016 9:14 AM

Discussion Questions

1.    What is the significance of the IDH1 mutation?
2.    What is the best course of therapy at this point in time?

12806

Anis Toumeh, MD
Re: CNS Tumor (June 2016): Molecular Oncology Tumor Boards
Jun 20, 2016 10:35 AM

1- As mentioned earlier, IDH1 mutation is associated with better outcomes (prognositc) and likely to be associated with better treatment response (predictive). Analysis from RTOG 9802 (although exploratory) showed that patients with IDH1(R132H) did better reagardless of the treatment and maybe better with adding chemotherapy to XRT. Another analysis from RTOG 9402 showed that even in pateints with non co-deleted tumors, those with IDH mutation seemed to benefit from adding chemotherapy to XRT (in anaplastic tumors). 

2- I beleive it is safe to consider that this tumor is evolving into a more aggressive histology (especially with the development of enhancement). Combined approach with radiation therapy and chemotherapy seems to be a reasonable approach that I would consider. PCV is more toxic than Temozolomide, I am curious to know which chemotherapy other providers are choosing in this scenario. 

12816

Ashley Love Sumrall, MD
Re: CNS Tumor (June 2016): Molecular Oncology Tumor Boards
Jun 21, 2016 9:28 AM

Interesting discussion. Loved how you incorporated the new WHO classification. This is a great teaching tool for our fellows and ACPs. Thanks!

12781

Lisa Marie DeAngelis, MD
Re: CNS Tumor (June 2016): Molecular Oncology Tumor Boards
Jun 21, 2016 3:28 PM

Course Faculty Response

The patient had only a partial resection because the tumor extended deep into the dominant (left) posterior temporal lobe and complete resection would have left her with an unacceptable deficit.  Gross total resection is always the priority, but not at the expense of neurologic function.

12821

Ali K. Choucair, MD
Re: CNS Tumor (June 2016): Molecular Oncology Tumor Boards
Jun 23, 2016 5:27 PM

It is worth noting that with the current WHO molecular classifciation we do not know what to do with the preciously utilized high risk factors (age, size of tumor, degree of resection, etc....). Actually there is data in the literature already that shows in an  oligodednroglioma with co-deletion and IDH-mutation neither the grade (II versus III), neither the age (>=< 40) nor the Ki-67 have any additional prognostic value. To me if this patient was to present today in light of the excellent survival data for co-deleted/IDH-mut oligo II or III treated with Radiation-chemotherapy, delaying treatment could be consdiered a malpractice.

 

12826

Lisa Marie DeAngelis, MD
Re: CNS Tumor (June 2016): Molecular Oncology Tumor Boards
Jun 23, 2016 6:04 PM

Course Faculty Response

I can appreciate Dr. Choucair’s enthusiasm regarding the survival benefit of combined radiotherapy and chemotherapy compared to radiotherapy alone in lower grade gliomas that are IDH mutated.  The missing information in those studies is the risk of long term neurotoxicity from this treatment and whether there is a significant effect on quality of life that would support delaying therapy; no one has really answered that question.  Furthermore, I think it depends greatly where in the brain the tumor is located and whether a radiographic complete resection has been achieved.  There are some patients who can be followed safely (eg right frontal polar lesions), and if progression is identified, re-resection can be performed and chemoradiation administrated at that time.  We don’t know whether such an approach compromises long-term outcome.  Given that even the recent data in the NEJM paper were restricted to clinical “high risk” patients, I think the jury is still out on the “low risk” cohort.

12831

Ali K. Choucair, MD
Re: CNS Tumor (June 2016): Molecular Oncology Tumor Boards
Jun 23, 2016 10:04 PM

I agree with Dr. DeAngelis about the risk for toxicity, which we have to weigh against survival benefit
As we all know RTOG 9802 was a 3-arm study for Grade II glioma (centrally reviewed): one arm was for the low risk group (observation no treatment) and  2 arms for the high risk: RT alone versus RT followed by PCV.
I am attaching few slides from the RTOG 9802 for the low risk group. The study was published in 2008, same year the first paper from the same study's  High Risk group was published. To me the numbers argue against the "watch and wait".
Additionally, we know from an old German study when LGG recurs on the avearge one third stay LGG, one third recurs as grade III and one third recurs as grade IV (those later ones are probably what we today would label as the tripple negative LGG).
In my approach to patients with LGG I recommend maximum safe resection followed by treatment, hopefully on a clinical trial.

ASCO and CTEP have identified survival as the top priority in oncology clinical trials followed by QOL (and we as Neuro-oncologists have for years argued for adding  NCF). Only a well informed patient (and that takes good quality data) can decide between survival versus QOL as a benfit. 

 

Attachment: 

https://connection.asco.org/sites/asco_connection/files/LRLGG_0.pptx
Attachment:

12836

Daniel Brat
Re: CNS Tumor (June 2016): Molecular Oncology Tumor Boards
Jun 24, 2016 9:06 AM

Course Faculty Response

The presence of IDH mutations in a diffuse glioma identifies a subtype that has a more prolonged clinical course than those that are IDH non-mutated (IDH wild type). Immunohistochemical testing and targeted gene sequencing now used to identify IDH mutations on all cases of diffuse gliomas because the prognostic significance of IDH mutation is so significant. With the recent incorporation of molecular findings into the WHO classification of brain tumors, diffuse gliomas that are IDH mutated and also have 1p/19q co-deletion are now considered to be oligodendrogliomas. This molecular class of disease is associated with enhanced response to therapy and longer survivals.

12841

Lisa Marie DeAngelis, MD
Re: CNS Tumor (June 2016): Molecular Oncology Tumor Boards
Jun 24, 2016 9:07 AM

Course Faculty Response

IDH mutations are recognized as one of the earliest changes in the development of a lower grade glioma.  The most common mutation is the IDH1 R132H which can be detected by a routine immunohistochemical stain.  This will detect most (~85%) of all IDH mutations in gliomas.  However, there are other IDH1 and rare IDH2 mutations which can also occur, such as the IDH1 R132C mutation seen in this patient.  These other mutations can only be identified currently by genomic profiling.  All IDH mutations appear to confer the same better prognosis.

The development of some enhancement within the tumor may be indicative of a transformation to a higher grade.  Only another surgical procedure could establish transformation but the patient declined another operation.  Regardless of whether the tumor remained at a grade II or had transformed to a higher grade, the patient required additional treatment.  The recommendation was radiotherapy combined with chemotherapy.  Recent data demonstrate that radiotherapy alone is suboptimal treatment compared to the combination of both modalities.  

The triple drug combination of procarbazine, lomustine and vincristine (PCV) was the chemotherapy regimen employed in the recently published randomized trial of radiotherapy alone vs radiotherapy plus PCV.  Based upon this study, many are electing to use PCV as the adjuvant chemotherapeutic regimen in patients with low grade glioma.  Alternatively, many (myself included) use standard temozolomide given concurrently with radiotherapy followed by a minimum of 6 adjuvant cycles post-RT.  The reason to use temozolomide is that it is better tolerated and less toxic.  In the reported trial the median number of PCV cycles was 3 out of a planned 6 whereas temozolomide can be continued for 12-24 cycles in most patients.

12846

Victor Manuel Villalobos, MD, PhD
Re: CNS Tumor (June 2016): Molecular Oncology Tumor Boards
Jun 24, 2016 12:29 PM

Is there any understanding yet regarding mechanisms of resistance in patients with IDH1 related tumors such as in this case with gliomas, but also in leukemias, cholangiocarcinomas and chondrosarcomas? 

 

12851

Ahmad Daher, MD, PhD
Re: CNS Tumor (June 2016): Molecular Oncology Tumor Boards
Jun 25, 2016 12:13 PM

Had the patient presented today, current data supports the use of radiation followed by chemotherapy for a partially resected low-grade glioma. As already mentioned PCV was the chemotherapeutic regimen used in RTOG and EORTC trials, but Temozolomide is increasingly being used instead of PCV due to its more favorable side effect profile. Having said that, chemotherapy alone or radiation alone is still occasionally used for residual low-grade gliomas if it was felt that clinically the patient may not be able to tolerate both, while saving the unused modality for potential future recurrence. Despite evidence-based medicine, we are constantly encouraged to apply it within the specific clinical context we are facing, especially given the scarcity of toxicity data in the trials we base our management on. Additionally, molecular stratification of gliomas has greatly advanced our knowledge of the behavior of these tumors beyond their grade and is influencing management decisions.

Going back to this patient, RT + adjuvant Temozolomide or RT + adjuvant PCV were reasonable, literature-supported, options to her both after initial partial resection and after first recurrence. Now that her tumor recurred a second time, and having not received RT before, RT is highly recommended and should be followed by chemotherapy (Temozolomide or PCV). Temozolomide after RT is an option given that the tumor recurred ~3 years after using it the first time. PCV after RT is also an option given that she has not received it before and generally is recommended more strongly for tumors that recur shortly after completing adjuvant temozolomide. The 1p/19q co-deleted status also supports use of PCV given that oligodendroglial IDH-mutated tumors were the subgroup that benefited the most from sequential treatment of RT + chemotherapy; it is argued at times that giving a different agent for those tumors would deprive the patient from a proven highly effective therapy. The faint area of enhancement is worrisome for dedifferentiation to a higher grade but RT + adjuvant chemotherapy is the management of choice for both grade II and grade III IDH-mutated gliomas. It is only if the tumor dedifferentiated to a grade IV that management would change to RT with concurrent temozolomide followed by adjuvant temozolomide. The small area of enhancement may not justify the risk of further resection to confirm grade and it is less likely that a chemotherapy-treated IDH-mutated Grade II oligodendroglioma would progress to GBM in 3 years.

12856

Lisa Marie DeAngelis, MD
Re: CNS Tumor (June 2016): Molecular Oncology Tumor Boards
Jun 28, 2016 5:50 PM

Course Faculty Response

In response to the question from Dr. Villalobos, currently we are not aware of the mechanisms of resistance in patients with IDH1 related tumors in leukemias, cholangiocarcinomas and chondrosarcomas.

12861

Daniel Brat
Re: CNS Tumor (June 2016): Molecular Oncology Tumor Boards
Jun 29, 2016 8:55 AM

Course Faculty Summary

For patients with diffuse gliomas, it is critical to perform testing for IDH mutations, since the findings are used for molecular classification and are highly prognostic. Testing for IDH1 R132H can be achieved with immunohistochemistry, while other mutations of IDH1 and IDH2 require gene sequencing.

The finding of co-deletion of chromosome 1p and 19q co-deletion in a diffuse glioma with IDH mutation is diagnostic of an oligodendroglioma. While many labs use FISH for detecting focal losses of 1p and 19q, the assessment of whole arm chromosomal losses is a more accurate way to determine co-deletion.

Progression of oligodendroglioma, WHO grade II to anaplastic oligodendroglioma, WHO grade III is associated with increased proliferation, vascular proliferation and necrosis. IDH mutation and 1p/19q co-deletion are maintained following progression, but other genetic alterations may also arise.

12866

Lisa Marie DeAngelis, MD
Re: CNS Tumor (June 2016): Molecular Oncology Tumor Boards
Jun 29, 2016 8:59 AM

Course Faculty Summary

The patient refused radiotherapy and temozolomide was restarted.  However, she could tolerate only 5 cycles.  

Within one year she had asymptomatic progression on her MRI (Image 1, Image 2) and she received radiotherapy with concurrent temozolomide; she refused further adjuvant treatment.  Her post-RT MRI was stable.  In September 2015 she developed worsening seizures and MRI showed new enhancement within her lesion. (Image 1, Image 2)
   
She consented to a protocol of a novel IDH1 inhibitor but she progressed further after 4 cycles.  She had a re-resection and pathology now revealed a higher grade tumor with mitotic activity, vascular proliferation and focal necrosis, warranting the diagnosis of anaplastic oligodendroglioma.  Pathology also confirmed the IDH1 R132C mutation, 1p19q co-deletion and her tumor now had an additional 64 mutations.  

She enrolled in a trial of pembrolizumab for the hypermutator phenotype.

12871

ASCO University
Re: CNS Tumor (June 2016): Molecular Oncology Tumor Boards
Jun 29, 2016 9:10 AM

Thank you to Drs. Brat and DeAngelis 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 and participants can claim CME credit and 1 ABIM MOC point through ASCO University.

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

Have an interesting case in mind? Submit your hypothetical patient cases for consideration in an upcoming Molecular Oncology Tumor Board discussion forum.


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