Gastric Cancer (December 2016): Molecular Oncology Tumor Boards

ASCO University
Dec 07, 2016 8:16 AM

Learner 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. Ian Chau (Medical Oncologist from The Royal Marsden Hospital) and Jaclyn Hechtman (Pathologist from Memorial Sloan Kettering Cancer Center).

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

13686

ASCO University
Re: Gastric Cancer (December 2016): Molecular Oncology Tumor Boards
Dec 07, 2016 8:18 AM

Patient Case

Age/Sex:  55-year-old Caucasian male

Presentation: 2 months’ history of shortness of breath, lethargy, anemia with 6kg weight loss

Medical history/comorbidities:  Hypertension well controlled on losartan.  No other co-morbidities.  

Family history: No relevant family history

Social history: Non-smoker, weekly alcohol intake 6 units.  Worked as local general practitioner.  Patient had a 19-year-old daughter who died from acute lymphocytic leukemia 4 years ago.

ECOG performance status =1

Clinical examination was unremarkable.  

Presenting hemoglobin 85g/L, normal renal, liver and bone profile in routine blood tests

Upper gastrointestinal endoscopy showed 6cm ulcer in gastric fundus

Biopsy showed poorly differentiated intestinal type adenocarcinoma; HER2 negative
 
CT scans showed T4N1M1 gastric adenocarcinoma with coeliac axis and retroperitoneal lymphadenopathy (View CT Scans)

13691

ASCO University
Re: Gastric Cancer (December 2016): Molecular Oncology Tumor Boards
Dec 07, 2016 8:18 AM

Discussion Questions

1.    Would you consider further imaging such as PET scanning before formulating a treatment plan?
2.    Is further tissue needed to confirm radiologically presumed metastatic disease or for repeat HER2 testing?
3.    What systemic therapy option would you recommend for confirmed HER2 negative metastatic gastric cancer?
4.    What is the role of molecular profiling for this patient’s tumor to guide treatment now or in the future?

13696

Cem Mirili
Re: Gastric Cancer (December 2016): Molecular Oncology Tumor Boards
Dec 07, 2016 2:18 PM

1no

2no

3cisplatin 5fu and may be add docatakse

4 targeted therapy

13701

Joao Ribeiro, MD
Re: Gastric Cancer (December 2016): Molecular Oncology Tumor Boards
Dec 09, 2016 3:15 PM

To the questions 1 and 2 my answer is no. If possible I would consider inclusion in a clinical trial. If this is not an option I would propose modified DCF (as published in JCO) in first line. This is a young man without significant co-morbidities.

Based in the molecular profile I also could also a clinical trial. 

13706

Tony Philip, MD
Re: Gastric Cancer (December 2016): Molecular Oncology Tumor Boards
Dec 09, 2016 6:20 PM

1.    No PET but CT chest if not done already to complete staging.  
2.    If retroperitoneal node is only site of M1 disease, then I would biopsy to confirm before deeming this otherwise healthy person as incurable.  and would repeat HER2 testing on the metastasis if confirmed - can have heterogeneity(see below).

   Extra-gain of HER2-positive cases through HER2 reassessment in primary and metastatic sites in advanced gastric cancer with initially HER2-negative primary tumours: Results of GASTric cancer HER2 reassessment study 1 (GASTHER1)

3.    I use mFOLFOX6 in first line metastatic gastric adeno that is HER2 negative
4.    I  would check MSI status and PDL1 status to plan ahead.  

13711

Timothy Jay Price, MBBS, FRACP, D.H.Sc
Re: Gastric Cancer (December 2016): Molecular Oncology Tumor Boards
Dec 09, 2016 9:29 PM

I woud not perform PET scan, but as already mentioned CT Chest would complete staging. The CT scan looks fairly conclusive with enlarge necrotic para aortic node so would not biopsy and Her 2 status unlikey to be discordant, at least at diagnosis.

Chemotherapy options are quite open, and FOLFIRI through to ECX cold be discussed. The other question is whether claudin 18.2 targeted trial is worth considering (if available). For later therapy PDL1 and MSI would be important. 

13726

Osbert Luis Mejia Palomino, MD
Re: Gastric Cancer (December 2016): Molecular Oncology Tumor Boards
Dec 12, 2016 12:51 AM

with data it's unresectable, then question 1 answer is no. The same with question 2, For question 3, many schemas are useful inside chemo. I'd prefer DCF even if it's toxic because patiente is in ECOG 1 and his age.

additional tissue if necessary could be obtained for PD1 or other target.

13731

Jaclyn Frances Hechtman, MD
Re: Gastric Cancer (December 2016): Molecular Oncology Tumor Boards
Dec 12, 2016 9:57 AM

Course Faculty Response

1. No further imaging required from a pathology point of view in light of confirmed metastases.

2. No further tissues are required for HER2 testing. HER2 testing may be performed if additional tumor material from metastatic sites becomes available due to the fact that gastric carcinoma often displays heterogeneity in HER2 overexpression/ amplification. However, repeat testing of metastases is not required for patients who receive non HER2-based treatments and have a sample with no HER2 overexpression.

3. While molecular profiling can assist with choosing the most appropriate clinical trial, I would defer to Dr. Chau for this question.

4. Broad molecular profiling with a next generation sequencing assay that can assess fusions, missense and indel mutations, and copy number alterations.

13736

Ian Chau, MD
Re: Gastric Cancer (December 2016): Molecular Oncology Tumor Boards
Dec 12, 2016 10:00 AM

Course Faculty Response

1. There is distant retroperitoneal lymphadenopathy evident on CT scan.  This would be deemed as metastatic and therefore further PET scanning is not required at this stage.  In a recent randomized controlled trial, REGATTA, patients with metastatic gastric cancer and single non-curable factor were randomized to have gastrectomy followed by systemic chemotherapy or systemic chemotherapy alone (Fugitani, 2016).  There was no survival advantage to undertake gastrectomy up front and therefore it weakens the need to obtain a PET scan in this scenario.

2. Although there is heterogeneity in HER2 expression in gastric cancer, there is generally a high concordance of HER2 status between primary tumor and metastatic sites (Kim, 2011) (Bozzetti, 2011).  Therefore, no further tissues are required.  

3. For patients with HER2 negative metastatic gastric cancer and good performance status, the standard first line chemotherapy would be a combination of platinum compound + fluoropyrimidine.  Examples of regimens would include XP (capecitabine + cisplatin), FOLFOX (oxaliplatin, 5-FU), CAPOX (capecitabine + oxaliplatin).  If platinum compound is contraindicated, one could consider first line FOLFIRI (irinotecan +5-FU).  In addition, triplet chemotherapy including anthracycline and taxanes can also be considered.  Examples include ECX (epirubicin, cisplatin, capecitabine), EOX (epirubicin, oxaliplatin, capecitabine), DCF (docetaxel, cisplatin, 5-FU) and FLOT (oxaliplatin, docetaxel, 5-FU).  Patient factors to be considered for first line chemotherapy choice include performance status, co-morbidities, patient preference, toxicity especially peripheral neuropathy if future second line therapy would include paclitaxel + ramucirumab.

4. Currently there is no other routine molecular testing aside from HER2 for gastric cancer.  However, with the recent publication from The Cancer Genome Atlas and the Asian Cancer Research Group (TCGA, 2014) (Cristescu, 2015), molecular subgrouping have been proposed for gastric cancer.  Next generation sequencing assay, mismatch repair testing , and testing for Epstein-Barr Virus (EBV) have been proposed to broaden the opportunity for patient to participate in relevant clinical trials, but currently these are not routine tests.

13741

ASCO University
Re: Gastric Cancer (December 2016): Molecular Oncology Tumor Boards
Dec 12, 2016 10:07 AM

Patient Case Update

Patient was commenced on ECX.  After 4 cycles of chemotherapy, CT scan showed disease progression in primary tumor, malignant lymphadenopathy plus new peritoneal deposits. His performance status remained at ECOG 1.

Pre Treatment:    CT scan 1    CT scan 2                               

Post 4 Cycles of ECX:   CT scan 1     CT scan 2

The patient decided to participate in anti-PD-L1 antibody/CTLA4 antibody combination trial.

13746

ASCO University
Re: Gastric Cancer (December 2016): Molecular Oncology Tumor Boards
Dec 12, 2016 10:08 AM

Discussion Questions

1.    What would you recommend for his clinical management now?
2.    Molecular profiling of his tumor showed an increased number of mutations, specifically frameshift mutations. What might this result signify?
3.    What immunotherapy-related adverse effects would you discuss with patient and which one would you highlight to him specifically? (Figure 1) (Molecular Report) (Figure 2)

13751

Anis Toumeh, MD
Re: Gastric Cancer (December 2016): Molecular Oncology Tumor Boards
Dec 14, 2016 2:53 PM

It is important to determine how high the mutational load is when tested. Trials of anti PD1 are starting to be reported for GI malignancies with high mutational load/MSI-H as well as specifically for gastric/GE junction. If available, would enrol in a trial. Outside a protocol I would consider Taxane plus Ramucirumab. 

13756

Kate Young
Re: Gastric Cancer (December 2016): Molecular Oncology Tumor Boards
Dec 14, 2016 5:41 PM

What is the significance of PD-L1 positivity in gastric cancer treated with checkpoint inhibition?

13761

Jaclyn Frances Hechtman, MD
Re: Gastric Cancer (December 2016): Molecular Oncology Tumor Boards
Dec 15, 2016 8:39 AM

There is insufficient evidence to support the role of PD-L1 expression screening as a biomarker to predict response to immunotherapy specific to gastric carcinoma at this time. Results from the KEYNOTE-012 trial did not show evidence that higher expression of PD-L1 in tumor cells lead to response. However, all patients in this trial had tumors with some expression of PD-L1. This inclusion criterion of PD-L1 positivity for this gastric carcinoma trial was based on data showing that pembrolizumab has higher efficacy in lung cancer patients when PD-L1 is expressed in at least 50% of tumor cells. A comparison of PD-L1 positive and PD-L1 negative gastric carcinoma patients who receive immune checkpoint inhibition will be necessary to assess the significance of PD-L1 in gastric carcinoma patients. (Muro 2016, Garon 2015)

Whereas there was a general trend towards higher response rate in patients with positive PD-L1 expression,  objective responses were observed in patients with negative PD-L1 expression especially when PD-L1 antibody was combined with CTLA-4 antibody.  Furthermore there was even less correlation between PD-L1 expression and both progression free and overall survival. (Janjigian 2016)

13766

Jaclyn Frances Hechtman, MD
Re: Gastric Cancer (December 2016): Molecular Oncology Tumor Boards
Dec 16, 2016 9:02 AM

Course Faculty Response

1. I would recommend molecular testing to assess mutation load and any specific actionable targets. I would also recommend PD-L1 IHC as this has been shown in some studies to correlate with response to immune checkpoint inhibitors.

2. This result may signify a defect in the mismatch repair (MMR) system, resulting in a microsatellite-high (MSI-H) phenotype. The defect in the mismatch repair system causes insertions and deletions in areas where genetic material is rich in short nucleotide repeat sequences, or microsatellites.  These patients with MMR deficiency have increased mutations and their tumors may be rich in neo-antigens that results from proteins that are slightly different due to mutations. These neo-antigens can signal that the tumor is foreign/ abnormal to the patient’s immune system.

3. I would tell him that immune checkpoint inhibitors are associated with pneumonitis, colitis, rash, thyroiditis, and liver enzyme abnormalities. He will be monitored for these side effects.

13771

Ian Chau, MD
Re: Gastric Cancer (December 2016): Molecular Oncology Tumor Boards
Dec 16, 2016 9:07 AM

Course Faculty Response

1. For a patient who progressed on first line platinum + fluoropyrimidine chemotherapy, one standard option would be paclitaxel plus ramucirumab.  However, there has been recent enthusiasm in participating in clinical trials with immune checkpoint inhibitors, especially as these trials have a limited recruitment period.  The clinical dilemma is whether to participate in clinical trial first and receive paclitaxel + ramucirumab after the clinical trial or proceed to standard paclitaxel + ramucirumab first.  The current experimental nature of using checkpoint inhibitors in gastric cancer need to be discussed carefully with patient.

2. As this patient has MSI-high tumor, there is perhaps a greater chance of response to PD1/PDL-1 inhibitor based on current limited data (Le, 2015).  In patients whose tumor expressed >1% PD-L1, single agent pembrolizumab resulted in an objective response rate (ORR) of 22%, 6-month progression free survival of 26% and 12-month overall survival of 42% (Muro, 2016).  In addition, for all comers regardless of PD-L1 expression, nivolumab resulted in an ORR of 14%, 6-month PFS of 18% and 12-month OS of 36% whereas nivolumab + ipilimumab resulted in an ORR of 26%, 6-month PFS of 24% and 12 month OS of 34% (Janjigian, 2016).  Avelumab also demonstrated similar level of efficacy in second line setting (Chung, 2016).  

3. The safety profile for the combination of PD-1/ PD-L1 antibody plus CTLA 4 antibody is dependent on the dose of CTLA 4 antibody which is more likely to be the dominant cause of immune-related side effects.  In the CHECKMATE 032 study, the combination of nivolumab (1mg/kg) and ipilimumab (3mg/kg) resulted in 45% of any grade 3/4 toxicities – of which the proportion of toxicities were diarrhea 12%, Fatigue 4%, Hypo or hyperthyroidism 4%.  However, there were also grades 1-2 toxicities observed with pneumonitis, rash, liver enzyme abnormalities and other hormonal disturbances such as adrenal insufficiency (Janjigian, 2016).

13776

Timothy Jay Price, MBBS, FRACP, D.H.Sc
Re: Gastric Cancer (December 2016): Molecular Oncology Tumor Boards
Dec 19, 2016 5:10 AM

The idea of a clinical trial with checkpoint inhibitor would certainly be a discussion and the toxicity as allude to by Prof Chua very imortant. We know that there is "positive" data coming at ASCO GI so this will highten patient interest. Agree the biomarker for checkpoint inhibition remains controversial. Outside of a trial, second line paclitaxel plus or minus ramucirumab will be standard of care noting not all countries can acces ramucirumab.

13791

Jaclyn Frances Hechtman, MD
Re: Gastric Cancer (December 2016): Molecular Oncology Tumor Boards
Dec 21, 2016 8:46 AM

Course Faculty Summary

Here, we manage a patient with metastatic gastric carcinoma. His tumor is negative for HER2 overexpression, which makes him ineligible for HER2 inhibitors such as trastuzumab. His tumor is mismatch repair-deficient, reflected by a molecular profile that shows hypermutation. PD-L1 is expressed by immunohistochemistry in his tumor. He is counseled on potential side effects and undergoes treatment with an immune checkpoint inhibitor. We learn that:

  • In HER2-negative patients with advanced gastric carcinoma, treatment options are limited to conventional chemotherapy and clinical trials such as immune checkpoint inhibitors
  • PD-L1 expression may be predictive of response to immune checkpoint inhibitors
  • Microsatellite-instability high status/ mismatch repair deficiency may be associated with response to immune checkpoint inhibitors
  • Adverse effects of immune activation can affect multiple symptoms and include pneumonitis, colitis, liver enzyme abnormalities, thyroiditis, and rashes

13796

Ian Chau, MD
Re: Gastric Cancer (December 2016): Molecular Oncology Tumor Boards
Dec 21, 2016 8:49 AM

Course Faculty Summary

In a patient with HER2 metastatic gastric adenocarcinoma, the standard first line therapy is a combination of platinum compound and fluoropyrimidine.  Early molecular profiling of his tumor would broaden his opportunity to participate in clinical trials including novel genomically determined therapeutic targets and agents targeting the tumor microenvironment such as immunotherapy.  Even in the presence of standard second line treatment option, clinicians should still discuss the relative merits and risk of participating relevant clinical trials to further improve survival for patients with metastatic gastric cancer. We learn about:

  • Potential biomarker for PD-1 antibody including MSI status and PD-L1 expression
  • Emerging efficacy data from several PD1/PD-L1 antibodies.  Currently these agents are considered experimental and should not be used outside the context of clinical trials.
  • Safety profile of combination immune checkpoint therapy

13801

ASCO University
Re: Gastric Cancer (December 2016): Molecular Oncology Tumor Boards
Dec 21, 2016 8:52 AM

Thank you to Drs. Chau and Hechtman 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-January for a new case in this series related to melanoma.

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