Head and Neck (September 2017): Molecular Oncology Tumor Boards

ASCO University
Sep 13, 2017 9:47 AM

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. Anthony Snow and Roger Cohen.

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Comments

14981

ASCO University
Re: Head and Neck (September 2017): Molecular Oncology Tumor Boards
Sep 13, 2017 9:53 AM

Patient Case #1

Age/Sex:  71 year old man

Medical History:

The patient has a history of T1N0M0 glottic laryngeal cancer diagnosed in 2005 and treated with radiation.  He did well until 2010 when he developed a T2 supraglottic laryngeal cancer, thought to represent a 2nd primary tumor, and underwent laryngectomy with neck dissection and tracheostomy with four positive lymph nodes and no ECE. No adjuvant therapy was recommended.

In 2015, he developed a T1 p16 negative squamous cell carcinoma of the right tongue base that was treated with robotic resection with achievement of negative surgical margins.  Surveillance scans one year later (2016) showed at least 6 pulmonary nodules, the 2 largest measuring 8 x 11 mm in the LUL and 11 x 11 in the RLL, respectively. VATS wedge resection of the LUL lesion showed a poorly differentiated p16 negative squamous cell carcinoma with visceral pleura involvement and lymphatic invasion, pathologically favoring metastatic carcinoma.

The patient then began chemotherapy with carboplatin, 5FU and cetuximab.  He completed 4 cycles uneventfully with a minor radiographic response by RECIST, and then began maintenance cetuximab.

After 4 months of weekly maintenance cetuximab a restaging CT scan of the chest demonstrated progression of disease by RECIST with increasing size of the lung nodules.

Type of Tumor:

1.    Larynx 2005- well-differentiated squamous cell carcinoma
2.    Laryngectomy 2010- moderately differentiated squamous cell carcinoma
3.    Base of tongue 2015- poorly differentiated squamous cell carcinoma
4.    Wedge resection RUL 2016- poorly differentiated squamous cell carcinoma

Relevant Markers: p16 negative (all specimens)

Prior Treatment History/Response:
2005: T1N0M0 larynx SCCa: Radiation therapy, complete response
2010: T2N0M0 supraglottic laryngeal SCCa, laryngectomy, complete response

2015: T1N0Mo base of tongue SCCa, robotic resection, negative margins

2016: Recurrent/metastatic (R/M)  disease:carboplatin, 5FU, cetuximab, minor response

2017: maintenance cetuximab, progression of disease in the chest (enlarging lung nodules)

Co-morbidities:  

He is currently retired but maintains a very active lifestyle.   ECOG PS 0

There is a 30-year history of tobacco use (quit 5 years ago) and regular past social alcohol use.  He does not have any personal history of cardiac, liver or kidney disease, hepatitis, or diabetes.

 

14986

ASCO University
Re: Head and Neck (September 2017): Molecular Oncology Tumor Boards
Sep 13, 2017 9:58 AM

14991

ASCO University
Re: Head and Neck (September 2017): Molecular Oncology Tumor Boards
Sep 13, 2017 10:00 AM

Discussion Questions

1.    What is a next step in the treatment of this patient?
2.    What, if any, additional tests should be ordered at this time?

14996

Anis Toumeh, MD
Re: Head and Neck (September 2017): Molecular Oncology Tumor Boards
Sep 13, 2017 5:30 PM

I would offer this patient second line immunotherapy with Nivolumab, which showed superiority over systemic chemotherapy in regards to overall survival as well as other secondary end points

15001

Roger B. Cohen, MD
Re: Head and Neck (September 2017): Molecular Oncology Tumor Boards
Sep 18, 2017 9:35 AM

This patient had a minor response to a platin-based regimen and it did not last very long.  In addition, the patient progressed while receiving cetuximab.  Therefore, he is formally cetuximab-refractory and platin-resistant. The response rate in this setting to other cytotoxic agents such as methotrexate is very low.  

Anti-PD-1 monoclonal antibodies can now be used in this setting. Pembrolizumab or nivolumab are FDA-approved and others, including PDL-1 antibodies, are in development.

The safety profile of the PD-1 antibodies is generally favorable although one must watch for and be prepared to manage a variety of autoimmune side effects such as  colitis and pneumonitis.

Nivolumab, which is given every 2 weeks, was approved based on a survival advantage in patients whose tumors had grown despite platin-based therapy when compared to standard cytotoxic agents such as methotrexate and docetaxel.  

Pembrolizumab, which is given every 3 weeks, received an accelerated approval based on a tumor response rate of ~15% in patients whose tumors had grown despite platin-based therapy.  Most of the observed responses were also long-lasting.  Unlike nivolumab, however, pembrolizumab has not shown a survival advantage when compared to chemotherapy in the treatment of R/M HNSCC.

With both drugs responses were seen in patients with HPV-positive and  HPV-negative tumors.  Responses were seen in patients whose tumors were PD-L1 positive as well as PD-L1 negative. 

15006

Anthony N. Snow
Re: Head and Neck (September 2017): Molecular Oncology Tumor Boards
Sep 18, 2017 9:36 AM

No further testing is mandatory from the perspective of the pathologist.  At the discretion of the clinical team, in the setting of neoplasms that have progressed after application of standard-of-care therapies, molecular tumor characterization may be considered to look for therapeutically targetable lesions or lesions that would allow enrollment in a clinical trial. This analysis is typically done using massively parallel DNA sequencing (also known as next generation sequencing or NGS) panels to assess multiple genes. This coverage may include selected exonic coverage of tumor suppressor genes and “hot-spots” or common regions of activating mutations of oncogenes. NGS testing is offered in a wide variety of gene and coverage combinations ranging from tens to hundreds of genes. In this case, a 50-gene hot-spot panel with selective exonic coverage was selected. The method used in this instance requires a very small amount of input DNA (10ng). This amount can be extracted from as few as ~1600 cells or a microscopic section of tumor tissue 1 to 2 mm in diameter in a formalin fixed paraffin embedded block. A cellular Diff-Quick or Papanicolaou stained cytology smear can be used as well. Results are discussed in subsequent sections.

As Dr. Cohen noted, anti-PD-1 monoclonal antibodies can be used in this setting. Prescribing guidelines  do not require assessment of PD-L1 status in the clinical setting of R/M HNSCC. This is distinct from other clinical contexts such as non-small cell carcinoma of the lung in which PD-L1 assessment using immunohistochemistry on tumor tissue is usually performed.

Note: At the time of diagnosis of oropharyngeal lesions, assessment for HPV as a potential etiologic factor should routinely be performed.

Immunohistochemistry for p16 is helpful in this setting when using appropriate criteria (≥75% of tumor cells showing strong positivity, 2+ to 3+, in the nucleus with or without cytoplasmic positivity)  

In the oropharynx, p16 status has been established as an independent prognostic factor.

In non-oropharyngeal head and neck cancer sites, p16 IHC should be interpreted with caution as HPV infection is not the only mechanism for overexpression. Additional methods are now available to add specificity to assessment of high risk HPV association. For example, RNA in situ hybridization may be performed for the E6 and E7 genes, which are implicated in oncogenesis when high risk HPV is an etiologic factor. This test can be performed on formalin fixed paraffin embedded tissue and is becoming more widely available.

IHC for p16 was negative in the oropharyngeal tumor in this case.

15011

ASCO University
Re: Head and Neck (September 2017): Molecular Oncology Tumor Boards
Sep 18, 2017 9:42 AM

See related reports linked below for an Update to Patient Case 1

Based on the FDA approval in late 2016 of two PD-1 antibodies (nivolumab and pembrolizumab) the patient began therapy with pembrolizumab and had a partial response by RECIST, which is ongoing.  He is tolerating pembrolizumab uneventfully except for mild fatigue.

In addition, the lung wedge specimen was subjected to next generation sequencing.


•    Results from NGS of the lung wedge biopsy: Attachment A

•    Guide for Molecular Pathology Reporting for Multigene Panels:  Attachment  B

 

15016

ASCO University
Re: Head and Neck (September 2017): Molecular Oncology Tumor Boards
Sep 18, 2017 9:43 AM

Discussion Questions

  1. What is the role of NGS (molecular profiling) in the management of patients with R/M HNSCC?
  2. Knowing the mutational profile in this patient what is the role for molecularly targeted therapy now or in the future?
  3. How long should the patient continue on pembrolizumab?
  4. What are the next steps if and when the patient progresses on pembrolizumab?

15021

Anis Toumeh, MD
Re: Head and Neck (September 2017): Molecular Oncology Tumor Boards
Sep 18, 2017 10:27 AM

I personally believe NGS is an extermely helpful tool especially in cases progressing after all standard regimens, from a therapeutic standpoint when showing tier I variants, and from a research stand point when allowing patients to  participate in some clinical trials. Having said that, foreseen problems with reimbursments from insurance companies will be an obstacle in some cases and will be challenging. For example, imagine a case like this with NGS showing a tier I variant with FDA approved agent but for a different malignancy. Outside a clinical trial, it is going to be difficult to get reimbursment with more updated regulations and strict reimbursment criteria we are receiving, more frequenttly in recent months,  from different insurance companies. 

 

 

15026

Roger B. Cohen, MD
Re: Head and Neck (September 2017): Molecular Oncology Tumor Boards
Sep 22, 2017 7:52 AM

Course Faculty Response
I would continue pembrolizumab for up to 2 years as long as the patient is benefitting from the drug without excessive toxicity.  In the event of disease progression, effective options are unfortunately quite limited.
 
The patient already received cetuximab and was found to be resistant to it.  Afatinib, an oral EGFR/her2 inhibitor, has been extensively evaluated in the treatment of HNSCC but is not formally approved in this disease and I would not give it here.

It is reasonable to consider this patient for enrollment into a clinical trial based on the results of next generation sequencing.  The most common mutations detected in HPV-negative HNSCC include mutations in genes such as p53, PI3K and CDKN2A. Moreover, there are ongoing clinical trials exploring a variety of agents alone or in combination (with chemotherapy, for example) targeting these respective mutations.  Experience targeting PI3K in HNSCC is very limited to date and clinical benefits very modest so far.  Side effects of PI3K inhibitors in the clinic not surprisingly have included hyperglycemia.  

p53 is the most commonly mutated gene in HPV-negative HNSCC but targeting p53 in the clinic has not been successful to date.  Drug development in this area must still be considered in its infancy.

Another strategy is to consider the patient for one of the “post-PD-1” clinical trials that are ongoing, adding a variety of drugs or therapies such as radiation to a backbone therapy such as pembrolizumab or nivolumab in an attempt to obtain or restore an immune response to PD-1 (or PDL-1) inhibitors.  Experimental strategies being evaluated in this area include radiation therapy (SBRT) and drugs added to anti-PD-1 antibodies such as IFN-gamma or antibodies directed against targets such as CTLA4, TIGIT, GITR, LAG3 mAb and OX 40.

15031

Anthony N. Snow
Re: Head and Neck (September 2017): Molecular Oncology Tumor Boards
Sep 22, 2017 7:55 AM

Course Faculty Response

1. In this setting there are no tier I variants (variants of strong clinical significance) that one would expect to identify. There are some tier II variants (variants of potential significance) that may be identified, but a low probability of identifying definitive therapeutic options. If consulted by clinical colleagues I would not recommend extended NGS mutational profiling as a rule in this clinical context. If an open clinical trial were being considered, however, I would definitely approve testing for targets that are the focus of the clinical study. This decision point will vary depending on the clinical scenario and should be assessed by the entire clinical team and patient in the context of available data and any available local or outside clinical trials.

2. The most common mutations in HNSCC are in TP53 and PI3K.  PI3KCA is the 2nd most commonly mutated gene across human cancers.  The PI3K-AKT-PTEN pathway has been identified as the most frequently mutated or amplified oncogenic pathway in HNSCCs in the TCGA cohort. PI3K pathway alterations include somatic amplification, mutation, loss of heterozygosity, or changes in DNA methylation. PIK3CA is the most frequently mutated, potentially druggable oncogene in HNSCC;  PI3K pathway alterations occur in up to 2/3 of HNSCCs.  Mutations and/or amplifications of PIK3CA were seen in 36.9% of the TCGA HNSCC cohort.  Other common pathway alterations include reduced PTEN expression (~30% of patients) and AKT amplification (~5%).  EGFR and AKT mutations are rare in HNSCC.
PIK3CA mutation or amplification was more frequent in HPV-positive tumors in the TCGA cohort (56% HPV-positive vs 34% HPV-negative) although the number of tested HPV positive tumor samples was small.  PIK3CA is often the only mutated oncogene in HPV-positive tumors.

PIK3CA is a known oncogene. The protein product of this gene (phosphatidylinositol 3-kinase or PI3K) has many functions, but can be conceptually simplified by describing its role in the activation of downstream effector molecules including AKT. An important function of PI3K is to phosphorylate phosphatidylinositol 4, 5-bisphosphate (PIP2) to create the active molecule phosphatidylinositol 3, 4, 5-trisphosphate (PIP3) in direct opposition to PTEN, which acts to reverse this phosphorylation event. Activating mutations of PIK3CA are the most common type of variant in this pathway in the setting of HNSCC and tip the scale toward the active PIP3 molecule and net activation of downstream effectors including AKT. This has many repercussions including a decrease in apoptosis secondary to interactions between AKT and FOXO and increased cell proliferation secondary to interactions between AKT and mTOR. There are small molecule inhibitors of activated PIK3CA and downstream effectors of the PI3K pathway including AKT1/2/3 and mTOR, which have been developed. However, to date there is insufficient evidence of clinical effectiveness to currently recommend therapy with any of the existing drugs. There are clinical trials recruiting in this clinical context, but none appear to fit this patient with respect to inclusion/exclusion criteria and regional access. I would defer to the oncology team to confirm this assessment. As clinical trials continue and data are gathered, these PIK3CA molecular lesions may become actionable in the future.   TP53 is commonly mutated in HPV negative but not in HPV positive HNSCCs.  TP53 is a tumor suppressor gene with many functions including a large role in regulating the cell cycle. It is among the most common somatically mutated genes across tumor types. Mutations can occur anywhere in the gene and can be nonsense or missense mutations.

Nonsense mutations usually result in total loss of gene function as tumors progress and develop loss of heterozygosity (loss of the wild-type allele via progressive somatic changes). Missense mutations commonly cause loss of tumor suppressor function and gain of multiple oncogenic functions.  Tumors of with variants of this type will frequently show over expression of p53 protein in the nucleus. The variant identified in this case has been associated with HNSCC and reported as pathogenic in previous studies with some retained expression of protein identified by immunohistochemistry.  However, gain of function activity has not been definitively demonstrated in vivo or in vitro. Therefore, I would consider this variant pathogenic and associate it with other TP53 mutated squamous cell carcinomas of the head and neck. This type of variant is commonly seen in sporadic cancers associated with tobacco and alcohol use. This mutation in combination with clinical history can assist in placing the neoplasm in an etiologic group, but there are no approved therapies for variants of this type in this clinical setting. Study is ongoing to develop therapies in the setting of TP53 variants including those with gain of function.

15037

Roger B. Cohen, MD
Re: Head and Neck (September 2017): Molecular Oncology Tumor Boards
Sep 27, 2017 10:01 AM

Faculty Case Summary

  • Treatment with PD-1 mAbs has become standard of care therapy for patients with R/M HNSCC failing to respond to platin-based therapies or cetuximab.
  • It is feasible to perform next generation sequencing from a variety of archival tumor specimens, including formalin fixed specimens and cytology preparations.
  • Next generation sequencing is an efficient approach to detection of less common alterations in HNSCC and may detect tumor suppressor gene alterations with potential implications for response to targeted therapies.
  • PI3K mutations are common in HNSCC and are more common in HPV positive HNSCC
  • PI3K targeting is still investigational with some early evidence of clinical activity in patients with refractory HNSCC.
  • Other clinical trials for patients failing PD-1 antibodies might include experimental “post-PD-1 therapies” looking at combinations of experimental immune modulating drugs added to pembrolizumab or nivolumab or completely novel immunotherapy strategies.

15042

Anthony N. Snow
Re: Head and Neck (September 2017): Molecular Oncology Tumor Boards
Sep 27, 2017 10:04 AM

Faculty Case Summary

  • Next generation sequencing can be performed from commonly collected pathology specimens including formalin fixed paraffin embedded tissue and cytology smears and is an efficient method of interrogating multiple targets in one assay.
  • NGS is a technique, not a specific test. There is wide variety in test choices available and each provides distinct information.
  • Multidisciplinary assessment of the clinical context and availability of clinical trials can assist in identification of potential molecular targets and appropriate test selection when approved therapies have failed.
  • There are currently no FDA approved targeted therapies for patients with PIK3CA activating mutations in the setting of R/M HNSCC. Clinical investigation is in progress.
  • Evaluation of PD-L1 expression by immunohistochemistry is not required before application of anti-PD-1 monoclonal antibodies in the setting of HNSCC.
  • TP53 mutations are common in the setting of HNSCC particularly in the context of alcohol and/or tobacco as etiologic factors. FDA approved targeted therapies are not currently available in this context.

15047

ASCO University
Re: Head and Neck (September 2017): Molecular Oncology Tumor Boards
Sep 27, 2017 10:07 AM

Thank you to Drs. Cohen and Snow 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-October for a new case in this series.


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