Gastric Cancer (May 2016): Molecular Oncology Tumor Boards

ASCO University
May 11, 2016 9:46 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. Angela Bartley (St. Joseph Mercy Hospital) and Timothy Price (The Queen Elizabeth Hospital).

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Please see attached for supplemental resources related to the case.

Comments

12606

ASCO University
Re: Gastric Cancer (May 2016): Molecular Oncology Tumor Boards
May 11, 2016 9:48 AM

Patient Case

Age/sex: 65yo Caucasian male patient

Medical History/comorbidities: Prior myocardial infarction 2012, small vessel disease, no indication for stent/surgery. No recent angina. Type 2 diabetes for 10 years compliant on oral hypoglycemic and diet. Non-smoker, weekly alcohol intake 60 mL (2 ounces). No family history.

Prior cancer history: November 2013 underwent gastrectomy for T3, N1 adenocarcinoma of stomach (intestinal-type). No molecular markers performed. Preoperative CT scan and laparoscopy negative for advanced disease. Proceeded to adjuvant chemo/radiotherapy per the “Macdonald protocol” of combined intravenous fluorouracil and radiotherapy, completing June 2014 with 20% dose reduction of final cycles of fluorouracil.

Presentation: Presents now with right upper quadrant pain requiring paracetamol, and an elevated Ca 19.9. LFT is as follows; AST/ALT normal, ALP 210 (range 30-110 U/L) and GGT 115 (range <60 U/L). No weight loss or other symptoms. CT staging reveals low volume liver metastasis (x4) localized to the right side, and borderline para-aortic lymph node enlargement.

12611

ASCO University
Re: Gastric Cancer (May 2016): Molecular Oncology Tumor Boards
May 11, 2016 9:49 AM

Discussion Questions

  1. Would further imaging be required before discussing a plan for systemic therapy?
  2. Which of the available tissue specimen/sites would be appropriate for HER2 testing: tissue from the primary resection specimen, metastasis from the para-aortic lymph nodes or liver, or can all be considered? Why?
  3. If proceeding to chemotherapy/systemic therapy, what treatment options would you consider if the patient were HER2 positive?
  4. Any additional work up before starting chosen systemic therapy in this setting?

12616

Kamal Kishore Mandalapu, MD
Re: Gastric Cancer (May 2016): Molecular Oncology Tumor Boards
May 11, 2016 3:29 PM

 1. No need for further testing

2. Liver or para-aortic lymph nodes are ideal for HER2 testing as this will give the current molecular charecterstics of the tumor.

3. TCH or Cisplatin, 5-FU and Trastuzumab ( would prefer TCH as the patient as recent Angina and 5-FU can cause serious angina though the incidence is low)

4. Need to order 2D Echo and cardiology clearance. 

12621

Leandro Brust, MD
Re: Gastric Cancer (May 2016): Molecular Oncology Tumor Boards
May 12, 2016 9:58 PM

Hi

I think we can find in different metastasis different molecular profile, BUT at this scientific moment, I would prefer obtain tissue only from the most accessible lesion.

12626

Timothy Jay Price, MBBS, FRACP, D.H.Sc
Re: Gastric Cancer (May 2016): Molecular Oncology Tumor Boards
May 16, 2016 9:16 AM

Course Faculty Response

This patient raises the question of whether there is any role for liver resection in gastric cancer. The disease isolated to the right side of liver may lead to further assessment of the borderline lymphadenopathy. PET scanning would be one option. However, we know that not all gastric cancer is PET avid, in particular certain histologies (e.g. signet cell, mucinous) (Hopkins). Furthermore, there is likely to be significant debate as to whether there is a survival gain to this approach regardless of node status. Currently, the evidence is not as compelling as it is for colorectal cancer but recent pooled analysis does raise the potential for hepatic resection to improve outcome in selected patients (Sheraz). However, ultimately this must be seen as investigational and systemic therapy is likely to be the treatment offered in this clinical situation.

Systemic therapy will be guided by the HER2 result and Dr. Bartley will discuss issues around HER2 testing. Our focus here is the molecular options and therefore what is the optimal therapy for HER2 positive advanced gastric cancer. If HER2 negative, the options are limited to chemotherapy outside of a clinical trial based on current evidence. The questions of doublet versus triplet, the role of anthracyclines, etc., are questions that remain topics of debate but there is no role for a molecular agent in this patient group outside of clinical trials.

This patient has intestinal type adenocarcinoma which made up the majority of HER2 positive patients within the ToGA trial of chemotherapy with or without trastuzumab, reinforcing that there is a potential this patient has HER2 positive disease (Bang). For HER2 positive advanced gastric cancer, the ToGA trial demonstrated that the addition of trastuzumab to cisplatin and fluoropyrimidine chemotherapy improved survival (13.8 months v 11.1 moths, HR 0.74, CI 0.6-0.91, p=0.0046). The size of the benefit did differ based on the HER2 subgroups, with the largest gain in those with HER2 3+ by IHC and FISH positive (OS 17.9 months v 12.3 months, HR 0.58, CI 0.41-0.81). Relevant to this patient, prior fluoropyrimidine chemotherapy as part of an adjuvant schedule was allowed in the ToGA trial as long as 6 months had elapsed prior to metastatic disease and the schedule did not include a platinum agent (the numbers were small [9% and 4% in each arm]. There is an additional Japanese Phase II trial of cisplatin, S-1 and trastuzumab which had similar survival outcomes but other phase III trials with alternate chemotherapy backbones are awaited (Kurokawa). 

Ongoing research is underway assessing alternate methods of targeting HER2 including combination therapy with trastuzumab and pertuzumab which is now accepted as a standard of care in HER2 positive breast cancer (Swain). A phase II trial in gastric cancer has already completed enrollment with very high response rates seen (RR 86%) (Kang). Phase III trial results are awaited to define the role of this regimen  however. Other agents used in breast cancer which could be considered in HER2 positive gastric cancer include lapatinib which also binds HER2 in addition to EGFR, and trastuzumab emtansine. Both have been primarily studied in advanced gastric cancer in second-line this far. Lapatinib was assessed first line in the LOGiC study (capecitabine, oxaliplatin and trastuzumab); however, no benefit was seen with addition of trastuzumab (Hecht)

Our patient has a cardiac history and thus a cardiac assessment would generally be recommended in patients receiving trastuzumab prior to therapy and at regular intervals depending on regional guidelines, although the rates of cardiac adverse events in ToGA were similar between the arms (6% v 6%). A drop of >10% in LVEF to below 50% was also low in both arms (5% v 1%) (Bang). This may reflect the low rate of prior anthracycline exposure which may explain a difference to the results seen in breast cancer. Herceptin should not be used if LVEF is <45% or a drop of > 10% occurs.

12631

Angela Nicole Bartley, MD
Re: Gastric Cancer (May 2016): Molecular Oncology Tumor Boards
May 16, 2016 9:29 AM

Course Faculty Response

Our patient has three possible candidate specimens available for HER2 testing: the primary gastric resection specimen and possible biopsies from the para aortic lymph nodes or liver metastasis.  Although a biopsy from the metastatic liver or lymph node tissue may be preferable, all specimen types are acceptable for testing.  There are several issues to consider when choosing the most appropriate specimen to test if multiple are available.  Unlike in breast cancer, tumor heterogeneity is well documented in gastroesophageal adenocarcinoma, and is often seen with an incomplete membranous and basolateral pattern by immunohistochemistry (IHC). (Albarello)  In this instance, slides from both the resection specimen and biopsy specimen should be examined microscopically on the hematoxyin and eosin (H and E) slides and the best area marked for examination.  The definitive number of biopsy cores that is optimal for HER2 testing in gastroesophageal adenocarcinoma is not currently known, however it has been recommended that a minimum of 5 (Gullo) and preferably, 6-8 cores (Ruschoff, Van Custem) of neoplastic tissue be obtained for testing. These ideally would contain minimal to no tissue necrosis or crush artifact.  Alternatively, the resection specimen could contain a greater portion of neoplastic tissue and allow the pathologist to discern whether different morphologies are present (in this case moderately-differentiated intestinal type) and to choose the best representative block for testing.  Testing on additional blocks may be performed if more than one morphology is present (intestinal versus diffuse/signet-ring cell type).  If two morphologies are present in either the biopsy or resection specimen, selection of the areas with the lowest grade tumor differentiation is recommended, as HER2 positivity has been shown to be greater in intestinal and low-grade morphologies than in tumors that are poorly differentiated (diffuse-type).  (Ajani) Overexpression of HER2 has also been shown to be slightly greater at the gastroesophageal junction in comparison to the stomach (Albarello)

A number of studies have examined whether it is best to select the biopsy or resection specimen from the primary or metastatic site.  One study evaluated patient biopsy or resection specimens showing 92.9% concordance between the biopsy and resection specimens. (Okines)  In the ToGA trial, the positivity was similar in biopsy versus resection specimen (23.3 and 19.7%) (Bang).  Another study showed no difference in HER2 positivity between resection specimens or biopsies from primary or metastatic site (Janjigian).  Other studies have found relatively fair concordance between biopsy and resection specimen. (Grillo, Pirrelli)  In many instances however, only one of the specimen types is available.

Several groups have also investigated HER2 expression in specimens from the primary tumor and metastasis (lymph node or distant metastasis) in the same patient.  These have shown good concordance between HER2 expression in the primary specimen and lymph node metastasis. (Selcukbiricik, Qui) Similarly, those who have compared HER2 expression between the primary tumor and the distant metastasis also showed good concordance (Bozzetti, Saito) although there are documented cases of discordance between the primary specimen and the metastasis. (Fusco, Schoppmann)  Given the overall high rate of concordance, HER2 testing may be performed on the primary or metastatic site when available.

12636

ASCO University
Re: Gastric Cancer (May 2016): Molecular Oncology Tumor Boards
May 16, 2016 9:35 AM

Patient Case Update

The patient's tissue was tested for HER2 expression by IHC and found to be equivocal (2+). Subsequent ISH testing revealed HER2 amplification (positive) and cisplatin/capecitabine/trastuzumab was commenced with an initial partial response. Pain resolved and no dose adjustments required. Capecitabine and trastuzumab were continued after 6 doses of cisplatin. Subsequent progression in liver and peritoneum was noted 13 months after initial diagnosis. Patient remains well and active.

12641

ASCO University
Re: Gastric Cancer (May 2016): Molecular Oncology Tumor Boards
May 16, 2016 9:36 AM

Discussion Questions

  1. What is the best testing algorithm from a laboratory standpoint to determine HER2 status in this patient?
  2. What is the role of anti-HER2 therapy in second line?
  3. What systemic therapy schedule would be an appropriate choice now?
  4. Do you see a role for palliative care at this time?

12646

Li Xu, MD, PhD
Re: Gastric Cancer (May 2016): Molecular Oncology Tumor Boards
May 19, 2016 7:56 AM

1. FISH test result is proper for this patient.

2. there are some report that use anti-HER2 therapy in second line or third line.

3. since the patient responsed to cisplatin + Capecitabine and trastuzumab treatment well enough and cisplatin had been stop for more than 8 months,  cisplatin + Capecitabine and trastuzumab treatment could be reintroduced.  if biopsy from new liver and peritoneum metastasis loci could be obtained to test for Her2, it would be helpful to decide should we continue to use anti-HER2 therapy.

4. since the patient remains well and active, no palliative care needed at this time.

 

12656

Angela Nicole Bartley, MD
Re: Gastric Cancer (May 2016): Molecular Oncology Tumor Boards
May 20, 2016 9:14 AM

Course Faculty Response

HER2 testing is currently primarily being performed on formalin fixed and paraffin embedded tissue specimens using immunohistochemistry (IHC) and/or in situ hybridization (ISH).  Fluorescence in situ hybridization (FISH) or a bright-field method (silver in situ hybridization or SISH, chromogenic in situ hybridization or CISH, or dual in situ hybridization or DISH) are available.  The biopsy specimen should be placed in fixative ideally within 1 hour (cold ischemic time) and fixed in 10% neutral buffered formalin for 6-72 hours.  Routine processing should be performed according to analytically validated protocols with established policies.  The National Comprehensive Cancer Network (NCCN) recommends that HER2 testing be performed by IHC first, followed by ISH if the result by IHC is 2+ or equivocal.  An IHC result of 0 or 1+ is considered negative, a result of 2+ is considered equivocal, and a result of 3+ is considered positive. (Ajani)  A scoring system for IHC was developed by Ruschoff/Hoffman et al (used in the ToGA trial) with separate categories for surgical and biopsy specimens. (Ruschoff) Surgical specimens should contain 10% or greater staining for a result, and biopsy specimens should contain at least a small cell cluster (or greater than or equal to 5 cells) for a result.  A negative result contains no staining in any of the neoplastic tissue.  A 1+ negative result contains weak or barely perceptible membranous basolateral to lateral staining, a 2+ or equivocal contains weak to moderately weak membranous basolateral to lateral staining, and a 3+ or positive result contains strong membranous staining.  Assurance of proper positive and negative controls is always important.

If an equivocal (2+) result is found by IHC, testing for HER2 amplification by ISH is indicated.  In FISH, a spectrum orange directly labeled fluorescent DNA probe specific for the HER2 gene locus on chromosome 17, and a spectrum green, or CEP17 probe, specific for the alpha satellite DNA sequence at the centromeric region of Chromosome 17 is used.  At least 20 non-overlapping nuclei of tumor cells are evaluated for the HER2 and CEP 17 probes.  A HER2 to CEP17 ratio of > 2.0 is considered positive (amplified) and a HER2 to CEP17 ratio of < 2.0 is considered negative (not amplified). In our patient, the biopsy specimen from the metastasis revealed weak to moderately weak incomplete membranous staining in a cluster of 15 neoplastic cells with good staining controls consistent with a 2+ equivocal result.  Subsequent FISH testing revealed an average of 10 HER2 signals to 2 CEP17 signals for a ratio of 10:2 = 5 which is amplified.  The patient would therefore be eligible for trastuzumab therapy.

12661

Timothy Jay Price, MBBS, FRACP, D.H.Sc
Re: Gastric Cancer (May 2016): Molecular Oncology Tumor Boards
May 20, 2016 9:14 AM

Course Faculty Response

Firstly, it is important to be clear that based on the evidence we now have from three randomized trials that there is a survival benefit to second-line chemotherapy (Galdy). The options are irinotecan, docetaxel and paclitaxel. For this patient there are two points to theoretically consider specific to the HER2 positive status. Firstly, one approach considered may be to continue Herceptin into second-line therapy with an alternate chemotherapy backbone or to switch to second-line chemotherapy and add an alternate anti-HER2 agent, e.g. lapatinib. There is currently no evidence for the first option of continuing trastuzumab. Regarding the second consideration, the TyTAN trial which compared paclitaxel with or without lapatinib (anti-HER2 and EGFR) reported no overall survival gain (Satoh). Therefore, outside of ongoing trials there is no evidence in gastric cancer to maintain HER2 blockade when switching to second-line therapy.

In regard to a second-line chemotherapy choice the main evidence to guide us comes from the ramucirumab trials which show a survival benefit to both single agent ramucirumab and ramucirumab combined with paclitaxel (Fuchs, Wilke). The overall gain in terms of PFS and OS is greater in the REGARD trial with combination therapy. Importantly, HER2 positive disease was included in these trials (8-9% in REGARD). Otherwise, patients with contraindications to an anti-angiogenic agent could be considered suitable for any of the three recognized chemotherapy options. The other exciting area of research for gastric cancer is immunotherapy and agents targeting PD-1/PD-L1 pathway. There is no definitive evidence as yet but consideration of relevant clinical trials is very appropriate.

Palliative care referral will always be a difficult discussion but given the relatively short PFS and subsequent OS seen in the second-line population a discussion of all options would seem appropriate. This will always be based on patient and clinician discussions of course but important aspect of care. 

12666

Aditya Bardia, MD, MPH
Re: Gastric Cancer (May 2016): Molecular Oncology Tumor Boards
May 22, 2016 6:51 PM

Great discussion. It is interesting to note that as opposed to HER2+ breast cancer, where maintaining HER2 blockade is the norm in 2nd line setting and beyond, things are different in gastric cancer as supported by TyTAN results reviewed by Dr. Price. However, the choice of 2nd line anti-HER2 therapy in TyTAN was lapatinib and it is unclear whether the negative results represent failure of the broad biological concept of "maintaining HER2 blockade" in gastric cancer, or the choice of specific anti-HER2 therapy (lapatinib). With the availability of multiple other anti-HER2 therapies such as pertuzumab or T-DM1 or neratinib, it would be great if the faculty could provide general comments on this issue and whether there are any clinical trials that could be considered for this patient. 

12671

Timothy Jay Price, MBBS, FRACP, D.H.Sc
Re: Gastric Cancer (May 2016): Molecular Oncology Tumor Boards
May 23, 2016 10:50 AM

Course Faculty Response

Thank you Dr. Bardia for your comments:

  • The question of reintroducing a platinum agent is an interesting one. There may be two options, firstly to switch the platinum to oxaliplatin where there is some evidence for non cross resistance and the synergy of fluoropyrimidine and oxaliplatin may be beneficial (Tsuji). As the patient had not failed cisplatin reintroduction may also be reasonable option if there is a PFS > 3 months (Waddell). That said there is no randomized evidence of survival over best supportive care alone for these approaches.
  • The difference between breast and gastric cancer for HER2 positive disease is interesting and the benefit of continuing trastuzumab into second line with a switch of chemotherapy remains unclear. As noted before there are also alternate anti-HER2 agents now available (e.g. pertuzumab and trastuzumab-emtansine). Pertuzumab, as in breast cancer, is currently being tralled primarily in first line. There are however currently trials planned/open in second line comparing taxane to trastuzumab-emtansine which could be considered (Clinicaltrials.gov NCT01641939) however the evolving evidence around immunotherapy and the trials underway would mean that these studies may still be an option if available.

12676

Angela Nicole Bartley, MD
Re: Gastric Cancer (May 2016): Molecular Oncology Tumor Boards
May 25, 2016 9:24 AM

Course Faculty Summary

Thank you to everyone who participated in this discussion. In summary, these are my individual interpretations based off of the available information:

  • HER2 testing may be performed on the primary or metastatic site when available (biopsy of resection specimen).
  • Tumor heterogeneity is well documented in gastroesophageal adenocarcinoma, and is often seen with an incomplete membranous and basolateral pattern by immunohistochemistry (IHC). Neoplastic tissue should be examined microscopically and the best area marked for examination.
  • If two different morphologies are present (ie cases with both intestinal and diffuse/signet-ring cell types) in either the biopsy or resection specimen, selection of the areas with the lowest grade tumor differentiation is recommended, however both areas may be tested.
  • HER2 testing should be performed first by IHC followed by in-situ hybridization (ISH) if the result is equivocal (2+) by IHC. If the IHC yields a negative (0 or 1+) or positive (3+) result, no further testing by ISH is necessary.

12681

Timothy Jay Price, MBBS, FRACP, D.H.Sc
Re: Gastric Cancer (May 2016): Molecular Oncology Tumor Boards
May 25, 2016 9:26 AM

Course Faculty Summary

Thank you for the robust discussion. Some of the key lessons relate to the following;

  • For HER2 positive disease the optimal therapy currently based on available evidence is a combination of cisplatin, fluoropyrimidine and trastuzumab. 
  • Currently there is no data to support an alternate HER2 targeted approach in first line although trials of new combinations are ongoing.
  • Second line chemotherapy has been shown to improve OS in advanced gastric cancer.
  • The addition of a HER2 targeted agent in second line is not supported based on current data however ongoing trials could be considered
  • The addition of ramucirumab to paclitaxel does improve overall survival and thus should be considered in second line as long as there are no contraindications to anti-angiogenic therapy
  • Treatment beyond second line is often considered in fit patients although currently there is little data beyond randomized phase II trials where PFS was the primary endpoint and the population was mixed.
  • Patients having third line therapy should therefore be considered for a clinical trial where appropriate.
  • There does appear to be activity of immunotherapy in gastric cancer and ongoing clinical trials will help define its role.

12686

ASCO University
Re: Gastric Cancer (May 2016): Molecular Oncology Tumor Boards
May 25, 2016 9:30 AM

Thank you to Drs. Bartley and Price 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-June for a new case in this series related to CNS tumors.    

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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