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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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)


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.



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


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?


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


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. 


ASCO University
Re: Head and Neck (September 2017): Molecular Oncology Tumor Boards
Sep 18, 2017 9:36 AM

Dr. Anthony Snow: 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.


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



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?


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.