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Old 08-18-2008, 05:49 PM
gdpawel gdpawel is offline
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Default Functional Tumor Cell Profiling for Gastric CA

Functional profiling consists of a combination of a (cell morphology) morphologic endpoint (DISC) and one or more (cell metabolism) metabolic endpoinsts (MTT, ATP, resazurin). It studies cells in small clusters or microspheroids (microclusters). The combination of measuring morphologic (structural) effects and metabolic effects constitutes the measuring of a profile at the whole cell level.

Functional profiling (whole cell profiling) with cell culture assays for targeted drug therapy

Recent findings presented at the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium in Orlando, Florida concluded that "Functional Profiling" with cell culture assays is relevant for the study of both "conventional" and "targeted" antineoplastic drug agents.

Cell Culture Assays with "cell-death" endpoints can show disease-specific drug activity, are useful clinical and research tools for "conventional" and "targeted" drugs, and provide unique information complementary to that provided by "molecular" tests. There have been more than 25 peer-reviewed publicatons showing significant correlations between cell-death assay results and patient response and survival.

The "Functional Profiling" technique is a cell-death endpoint assay in which drug effect upon cancer cells is visualized directly. Photomicrographs of actual tumor cells sometime show that the exact same identical individual culture well, shows some clusters have taken up vast amounts of a drug, while right next door, clusters of the same size, same appearance, same everything haven't taken up any of the drug.

So it doesn't matter if there is a "target" molecule (protein or receptor) in the cell that the targeted drug is going after, if the drug either won't "get in" in the first place or if it gets pumped out/extruded or if it gets immediately metabolized inside the cell, drug resistance is multifactorial. The advantage of the "Functional Profiling" technique is that it can show this in the "population" of cells.

The "Functional Profiling" technique makes the statistically significant association between prospectively reported test results and patient survival. It can correlate test results which are obtained in the lab and reported to physicians prior to patient treatment, with significantly longer or shorter overall patient survival depending upon whether the drug was found to be effective or ineffective at killing the patient's tumor cells in the laboratory.

This could help solve the problem of knowing which patients can tolerate costly, new treatments and their harmful side-effects. These "smart" drugs are a really exciting element of cancer medicine, but do not work for everyone, and a test to determine the efficacy of these drugs in a patient could be the first crucial step in personalizing treatment to the individual.

Functional profiling (FP) with cell culture assays for targeted drug therapy.
Sub-category: Translational research
Category: Colon and Rectum
Meeting: 2007 Gastrointestinal Cancers Symposium

Abstract No: 440
Author(s): L. M. Weisenthal

Abstract: Introduction: We studied the relevance of FP for standard and targeted drugs.

Methods: Drugs were tested against fresh human tumor microclusters, with 96 hr drug exposures and multiple FP endpoints (MTT, DISC, resazurin, and/or ATP).

Results: In 65 previously chemonaive stage 4 colon cancer patients, those with FP assays showing 5FU results in the most resistant tertile had inferior overall survival, compared to pts without 5FU resistance (303 days vs. 686 days, H.R. 2.1, 95% C.I. 1.2 - 5.0, P2=0.011). In subset analysis restricted only to 53 pts who subsequently died (eliminating potential surgical cures), the respective results were 292 vs 493 days, HR 1.5 - 6.9, P2=0.0021. We applied FP to test targeted agents, including gefitinib, erlotinib, sunitinib, sorafenib, and bevacizumab. Gefitinib was tested against > 700 fresh tumor specimens; we reported striking correlations between gefitinib activity and overall pt survival in non-small lung cancer (2006 ASCO Annu Mtg, Abst 17117). Gefitinib and erlotinib are moderately cross resistant (R2=0.48, n paired comparisons=190). Gefitinib/sunitinib (R2=0.20, n=46) and erlotinib/sunitinib (R2=0.12, n=44) are largely non-cross resistant. We also developed a new microvascular viability assay (MVVA) to test microvascular cells present in tumor clusters. In the MVVA, bevacizumab was tested in 81 fresh tumor specimens (including 15 GI). Bevacizumab was nontoxic to the tumor cells, but often strikingly toxic to microvascular cells present within the same tumor clusters. Grading on a 0-4 scale, there was absent (Gr 0) effect in 23 specimens, weak (Gr 1-2) effect in 28, and a strong (Gr 3-4) effect in 26. In contrast to bevacizumab, neither sunitinib (n=87) nor sorafenib (n=20) showed selective effects against microvascular cells compared to tumor cells.

Conclusions: We cannot rule out a cytostatic effect of sunitinib or sorafenib on tumor microvascular cells. However, our results imply that the antitumor effects of bevacizumab are predominately mediated through antimicrovascular effects, while effects of sunitinib and sorafenib may be mediated largely through tumor cell apoptosis. We conclude that FP is relevant for the study of both traditional and targeted antineoplastic agents.

Last edited by gdpawel : 07-14-2011 at 10:37 PM. Reason: additional info
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Old 09-05-2010, 05:38 PM
gdpawel gdpawel is offline
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Default What is the precedent for using cell culture assay tests?

There isn't one paper, or two, which by itself, makes a case for or against cell-based assays. Nor does the proposition that the whole thing depends on one study or even one review. You've got to consider the body of literature as a whole.

The fact that none of this exists as one neat, convenient paper in the New England Journal of Medicine does not, in any way, negate the existence of this body of information. It has been found that newer methods of "cell-death" assays have an overall predictive accuracy of 98.2% concerning treatment response, which compares favorably with older, previously published data ranging from 75% to 92%. (Staib,P.et al. Br J Haematol 128 (6):783-781, March 2005)

We have tests such as estrogen receptor, progesterone receptor, Her2/neu, BCR-ABL, C-KIT, CD-20, etc., and panels of immunohistochemical stains for subclassifying tumors. All of these tests are used to select chemotherapy in precisely the same manner as cell culture assay tests are used.

Also, we have the use of additional medical tests, such as serial CT, MRI, and PET scans, performed for the purpose of monitoring the size of the tumor to determine if it is shrinking or growing with chemotherapy. The purpose of this testing is to determine if chemotherapy with specific drugs should be continued or changed to different drugs. These radiographic tests are also used as an aid in making clinical decisions about the choice of chemotherapy.

So yes, there is precedent for using cell culture assays.

The June issue of Oncology News International (June 2010, V 19, No 6) quotes a Duke University study of the use of high-tech cancer imaging, with one representative finding being that the average Medicare lung cancer patient receives 11 radiographs, 6 CT scans, a PET scan, and MRI, two echocardiograms, and an ultrasound, all within two years of diagnosis. A study co-author (Dr. Kevan Schulman) asks: "Are all these imaging studies essential? Are they all of value? Is the information really meaningful? What is changing as a result of all this imaging?"

Why is it that oncologists are so accepting of high tech, expensive imaging studies, yet so reluctant to consider the use of cell culture diagnostic tests? For one thing, clinical trials virtually always have time to disease progression as a primary endpoint. Without the imaging studies, one can't get accurate time to progression data. So these are tests performed for the benefit of drug companies seeking new drug approval, for clinical investigators seeking contracts and publications, and for clinicians seeking an easy way to make clinical decisions (and, occasionally, seeking income enhancement).

In the absence of information provided by cell culture testing, oncologists have complete freedom to choose between a myriad of drug regimens. The proven basis on which they make these selections, by and large, is on the benefit a given regimen provides to the oncologist (or academic institution). Cell culture testing threatens this freedom of choice. There's absolutely nothing in it for the oncologist or academic medical center (unlike, for example, imaging studies).

Lecture on issues related to cell culture testing

A 33 minute lecture on functional profiling of human cancer, using cell culture drug resistance testing on fresh human tumor specimens obtained by surgical biopsy. This lecture was given at Charite University Medical Center in Berlin, Germany on March 19, 2009 by Larry Weisenthal, M.D., PhD. The audience consisted primarily of oncologists and surgeons working in the field of gynecologic oncology. Thanks to Dr. Frank Kischkel, TherapySelect GmbH & Co. KG, Heidelberg, Germany [url]http://vimeo.com/7577309
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Last edited by gdpawel : 03-01-2013 at 02:12 AM. Reason: additional info
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  #3  
Old 09-24-2010, 06:24 PM
gdpawel gdpawel is offline
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Default Microspheroids - Microclusters

There are any number of variables that affect drugs. These include the rate of excretion of the drugs by the kidneys and liver, protein binding and a myriad of other biological factors.

Some anticancer drugs are actually pro-drugs: they need to be first activated in the liver before becoming biologically active. So in vitro testing must administer the active forms of these agents, not the pro-drug form that is given to patients.

In the body, these cells interact with and supported by other living cells, both malignant and non-malignant cells. That is why cell-death functional profiling assays study cancer cells in small clusters, or microspheroids.

Analysis of these microspheroids provides a snapshot of cancer's behavior within the human body and provides a more accurate representation of how cancer cells are likely to respond to treatment in the clinic.

It is crucial that there is no manipulation of isolated cancer cells to make them grow, which was an important point of distinction with earlier cell-growth assays.

Drs. Larry Weisenthal and Robert Nagourney adopted this concept and began applying the term microclusters.

Real-life cancers grow as a complex organism that includes both malignant and non-malignant components. It may include fibrous tissue, mesothelial cells, fibroblasts, endothelial cells, etc.

In order to exhibit its most characteristic behavior patterns, a cancer cell needs to be surrounded by a colony of other cells, both normal and malignant.

Human tumors represent micro-ecosystems composed of transformed cells, stroma, fibroblasts, vascular elements, extra-cellular protein matrices and inflammatory elements.

The behavior of human cancers and their reponse to therapy reflect the complex interplay between humoral, vascular, adhesion and cytokine-mediated events acting in concert.

Tumors are very complex organisms. Ignoring this complexity, most studies of human cancer in culture have focused upon individual tumor cells that have been removed from their complex microenvironoment.

Cells are routinely broken up by mechanical and enzymatic means, which alters their subsequent behavior. Some previous methods of assays limited their analysis only to isolated tumor cells and failed to incorporate the crucial contribution of non-tumorous elements to the cancer phenomenon.

When allowed to grow in vitro, living cancer cells develop into these tiny micro-spheroid clusters that form a complex biosystem in which each malignant cell reacts upon its fellow colonists in subtle but important ways.

Each of these microspheres contains all the complex elements of tumor biosytems that are found in the human body and which can impact clinical reponse.

Source: Nagourney RA, Kollin CA, Sommers B, Su Y-Z, Evans SS. Functional profiling of human tumors in primary culture: a platform for drug discovery and therapy selection, AACR abstract #1546, 2008
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  #4  
Old 03-16-2011, 03:32 PM
gdpawel gdpawel is offline
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Default Is there more to Gastrointestinal Cancer Managment than FOLFOX?

[Dr. Nagourney is medical and laboratory director at Rational Therapeutics, Inc., in Long Beach, California, and an instructor of Pharmacology at the University of California, Irvine School of Medicine. He is board-certified in Internal Medicine, Medical Oncology and Hematology]

One example of the functional tumor cell profiling approach represents a novel opportunity to explore the biology of gastic cancer.

Case Report


A 58-year-old male with a very bad diagnosis — a bout of gastrointestinal bleeding that had lead to an upper GI endoscopy. It wasn’t an ulcer, or even gastric cancer, but a very rare form of cancer arising in the duodenum. Adenocarcinoma of the duodenum is very uncommon.

In addition to the bleeding, he had lost a substantial amount of weight, was in pain and had a very large tumor that was nearly obstructing his upper GI tract. After getting the patient stabilized, he was referred to a surgeon who conducted an aggressive surgical resection. The recovery was difficult, prolonged and accompanied by additional GI bleeding. By the time the patient had recovered adequately enough to consider additional therapy, his PET scan revealed extensive re-growth.

If you were to ask medical oncologists in the United States what to give such a patient, 99% would recommend FOLFOX or some variation thereof. But, FOLFOX wasn’t the right treatment for this patient. Instead, he had a strong signal for Irinotecan, which was further enhanced by the addition of an EGFR inhibitor. Based on this, the patient was treated with Erbitux + Irinotecan. Before starting therapy, his CA 19-9 was 354. Although his signal for the EGFr inhibitor was very favorable in the cell function analysis, he was screened for K-ras mutation. It seemed evident from his dose response curves and clear synergy between Irinotecan and the EGFR inhibitors that he would be K-ras wild type.

Indeed, he was K-ras wild type and was treatment was started with Erbitux + Irinotecan. Other than the rash associated with the Erbitux, the tolerance was good. The bleeding stopped immediately, the CA 19-9 plummeted with the first dose to 71 and the patient then returned every other week for therapy.

Three cycles later, the PET/CT was repeated. The phrase “marked interval regression” of measurable disease was noted. Also noted was the normalization of his CA 19-9. The patient had gained weight and returned to normal activities. With the exception of a small and diminishing rash, he looks quite normal. In fact, with the rather modest dose of Irinotecan used in his schedule, he hasn’t even suffered any hair loss.

What is most interesting about this patient is that FOLFOX, the most widely used regimen in this setting, wasn’t anywhere on the radar screen. It wasn’t active, it wasn’t recommended and wouldn’t have worked. However popular FOLFOX may have come to be in patients like this, it doesn’t fit everyone.
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Old 06-28-2013, 03:14 PM
gdpawel gdpawel is offline
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Default What is the role of targeted therapies in treating gastric (stomach) cancer?

Here is a list of drugs which one laboratory oncologist tests for gastric (stomach) cancer. It's limited by the yield of viable tumor (adenocarcinoma) cells. With a large specimen, containing large numbers of viable (living) tumor cells, he tries to test:

5FU (fluorouracil/Capecitabine)
5FU/leucovorin
doxorubicin
cisplatin
oxaliplatin
gemcitabine
gemcitabine + cisplatin
gemcitabine + oxaliplatin
irinotecan
topotecan
mitomycin c
cyclophosphamide
docetaxel
temsirolimus
everolimus
vinorelbine
vinorelbine + gefitinib
vinorelbine + gefitinib + high dose tamoxifen
etoposide
gefitinib
erlotinib
sorafenib
sunitinib
lapatinib
dasatinib
crizotinib
pazopanib
imatinib
vismodegib
vemurafenib
axitinib
selumetinib
vandetinib
bevacizumab (Avastin)

He tests the "targeted" agents for both direct antitumor activity and for antivascular (antiangiogenic) activity.
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Old 08-06-2013, 01:04 AM
gdpawel gdpawel is offline
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Default Cancer chemotherapy chemosensitivity testing

Anticancer Res. 2003 Jan-Feb;23(1B):583-7.

Cancer chemotherapy chemosensitivity testing is useful in evaluating the appropriate adjuvant cancer chemotherapy for stages III/IV gastric cancers without peritoneal dissemination.

Kubota T, Egawa T, Otani Y, Furukawa T, Saikawa Y, Yoshida M, Watanabe M, Kumai K, Kitajima M.

Department of Surgery, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. [email]tkubota@sc.itc.keio.ac.jp[/email]

Abstract

BACKGROUND:

Because of the low chemosensitivity of gastric cancer to conventional antitumor agents, the role of adjuvant chemotherapy for patients with advanced gastric cancer is controversial. We have previously proposed the necessity to evaluate the appropriateness of particular adjuvant cancer chemotherapies in individual advanced gastric cancer patients using chemosensitivity testing. In the present study, we compared the chemosensitivity and clinical outcomes of patients with Stages III and IV gastric cancer.

PATIENTS AND METHODS:

A total of 282 patients with advanced gastric cancer were analyzed retrospectively in terms of chemosensitivity as detected by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and survival outcome after surgery. Patients were split into groups according to Stage III or IV gastric cancer, then categorized into those that received surgery without chemotherapy (surgery-alone), and those that received adjuvant chemotherapy, for which all the evaluable cases were further divided into sensitive and resistant cases as determined by MTT assay.

RESULTS:

For Stage III gastric cancer patients, the sensitive group had a more favorable survival outcome than the other two groups. For Stage IV gastric cancer patients, the sensitive groups, had a more favorable survival outcome than the other two groups, but only in the absence of peritoneal dissemination.

CONCLUSION:

Chemosensitivity testing, based on the MTT assay, was useful in evaluating the appropriate cancer chemotherapy for patients with Stages III/IV gastric cancer without peritoneal dissemination.

PMID: 12680150 [PubMed - indexed for MEDLINE]

[url]http://www.ncbi.nlm.nih.gov/pubmed/12680150
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Old 08-06-2013, 01:06 AM
gdpawel gdpawel is offline
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Default Chemotherapy sensitivity and resistance testing

Gastric Cancer. 2006;9(2):82-7.

Chemotherapy sensitivity and resistance testing: to be "standard" or to be individualized, that is the question.

Kubota T, Weisenthal L.

Center for Advanced and Comprehensive Medicine, Keio University Hospital, 35 Shinanomachi, Tokyo 160-8582, Japan.

Abstract

Radical surgery with extended lymph-node dissection is the treatment of first choice and the only curative treatment for locally advanced gastric cancer. While recent combination chemotherapy with S-1 (a combination of tegafur with two biomodulators, gimeracil and oteracil) has achieved high response rates, controversy still remains regarding the significance of adjuvant cancer chemotherapy after surgery. We have been applying chemosensitivity testing in evaluating the appropriate adjuvant cancer chemotherapy for advanced gastric cancer. Our multiple studies have indicated that this chemosensitivity testing would be useful to improve the results of adjuvant chemotherapy, by increasing survivals in the sensitive group. The chemosensitivity testing is approved as "advanced clinical medicine" by the Japanese Ministry of Health, Welfare, and Labor at 11 institutes at present. While complete lymph-node dissection and chemosensitivity test-guided adjuvant chemotherapy has been reported to result in a survival benefit for patients with advanced gastrointestinal cancer, the clinical utility of the testing should be established by means of prospective, randomized clinical trials. Two pivotal clinical trials have been initiated to clarify the utility of chemosensitivity testing in the selection of the appropriate adjuvant cancer chemotherapy for gastric cancer.

PMID: 16767362 [PubMed - indexed for MEDLINE]

[url]http://www.ncbi.nlm.nih.gov/pubmed/16767362

Functional profiling for traditional and targeted antineoplastic drugs

Plenary lecture on cell culture functional profiling in cancer treatment and research presented at the 5th International Symposium on Cancer Research and Treatment, presented in Tokyo, Japan November 25, 2006.

A PDF file containing the PowerPoint slides: [url]http://www.weisenthal.org/Tokyo_Cancer_Symposium_Nov_2006_Weisenthal.pdf
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Old 12-04-2013, 05:10 PM
gdpawel gdpawel is offline
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Default Gastric Cancer: A Call for Patient Selection

Robert A. Nagourney, M.D.

Gastric cancer is the fourth most common cancer worldwide with more than 930,000 diagnoses and 800,000 deaths attributed to this disease each year. Although relatively uncommon in the U.S., constituting only 2 percent of new cancers, in countries like Korea it makes up 20 percent of all new malignancies.

Among the causes are Helicobacter pylori infection, diets rich in smoked food, a high intake of nitrates and nitrites and cigarette smoking. A rare but aggressive form of the disease is associated with a gene mutation known as CDH1. The high frequency of metastatic disease at the time of initial diagnosis often precludes surgery, leaving systemic chemotherapy as the principal treatment option.

A recent report in The Annals of Oncology (No improvement in median survival for patients with metastatic gastric cancer despite increased use of chemotherapy: Bernards N. et al, Annals of Oncology. November, 2013) describes a retrospective analysis by Dutch investigators who examined the use of chemotherapy in patients with inoperable gastric cancer.

[url]http://annonc.oxfordjournals.org/content/24/12/3056.abstract?sid=25563c49-c8db-4fa5-b03d-ee7f3493a33b

In total, 4,797 cases were examined from 1990 to 2011. Over this time, the proportion of patients presenting with metastatic disease increased from 24 percent in 1990 to 44 percent in 2011. At the same time, palliative chemotherapy use increased from 5 percent to 36 percent. Younger patients and those of higher socioeconomic status had the largest increase in chemotherapy use, while older patients, those with linitis plastica and those with multiple metastases had lower chemotherapy use. Despite the significant increase in the use of chemotherapy, the median survival for patients was unchanged at 15 weeks in 1990 and 17 weeks in 2011 (P = 0.1).

Over this period, early treatment regimens like 5-fluorouracil (5FU) and FAM were largely replaced by combinations like Docetaxel/Cisplatin/5-FU (DCF), Cisplatin/Irinotecan, Epirubicin/Oxaliplatin/Capecitabine (EOX) and Carboplatin/Taxol. While response rates and palliative benefits have continued to improve, this has not translated into improved overall survival. This reflects a dilemma that has confronted medical oncologists for decades.

For many years, clinical trialists have held that one cannot assess the benefit of a treatment by comparing responders to non-responders. That is, time to progression and survival must compare all patients on a given treatment arm to those on the control arm. Their rationale was that “one must treat all patients to obtain the benefit seen in some.” Put differently you cannot “cherry pick” your winners and losers. It was said that this proscription was needed to avoid selection bias. But as any medical or nonmedical person would recognize, people who respond to treatment do better than those who do not. Lacking the ability to identify responders upfront, these trialists have insisted upon a one-size-fits-all approach to the detriment of clinical therapeutics and drug development.

With the dawn of the molecular era we see chinks in the armor of these trial designs as investigators now question why everyone should receive a treatment if only a small percentage will benefit. In gastric cancer, HER2 over-expression, found in 20-25 percent of patients, is now routinely used to identify patients who will respond to trastuzumab. But what of the other 75-80 percent of patients who do not carry HER2 and for whom there are no widely used determinants of clinical response? Do the results of Bernard article suggest that these patients should not receive therapy?

The Bernard article offers an interesting insight into what may be the future of medical oncology. As cancer therapy is increasingly scrutinized, not only for response or palliation but also for overall survival, patients may soon be denied treatments unless the results of the therapy rise to this, the highest level of evidence, for the entire population of treated patients.

Would it not be preferable to use laboratory analyses, like the EVA-PCD®, to select among treatment candidates before subjecting all patients to the risk and expense of toxic chemotherapy? In this regard, the author’s comments are poignant: “Identification of the subgroup of patients which benefit from palliative chemotherapy is of the utmost importance to avoid unnecessary treatment.” As a laboratory investigator engaged in the field of drug selection science (functional profiling), I couldn’t agree more.
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Old 07-22-2016, 11:32 PM
gdpawel gdpawel is offline
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Default Is Stage 4 Gastric Cancer Curable?

Robert A. Nagourney, M.D.

In February 2016, I met with a 57-year-old gentleman who presented with weight loss. An endoscopy revealed gastric (stomach) carcinoma. With the tumor causing progressive obstruction, he was taken to surgery and tissue was submitted to our laboratory for EVA-PCD functional profiling.

[url]http://www.rational-t.com/what-we-do/functional-profiling

The findings revealed several active drug combinations.

The patient obtained an opinion from a cancer center that offered participation in a 3-arm clinical trial comparing Pembroluzumab (Keytruda), a PD-L1 antibody, to FOLFOX chemotherapy or to the combination of FOLFOX plus Pembroluzumab. I encouraged him to pursue the trial.

After all, I knew that he was sensitive to the “control arm” (FOLFOX) and because Pembroluzumab is not FDA approved for gastric cancer, the trial offered him the opportunity to receive this novel immunotherapy agent alone or in combination with FOLFOX.

Unfortunately, he did not qualify for the study as he did not express the PD-L1 protein.

With Pembroluzumab removed from the equation, chemotherapy was now his only chance and he needed the best. That option, from the EVA/PCD function profile was FOLFOX & Irinotecan, known as FOLFIRINOX.

His trial physician didn’t agree.

He recommended FOLFOX alone suggesting that the Irinotecan should be kept as a fall back for future need. With the stakes so high, I had no intention of compromising. I again recommended FOLFIRINOX and the patient agreed.

The patient tolerated the first dose but several days later developed intense crampy abdominal pain. Concerned that there might be a post-operative complication, I obtained x-rays and blood tests. All were unrevealing. Despite having undergone a CT scan only 8 days earlier I repeated the CT to rule out a perforation, diverticular abscess or other complication.

The results were surprising, shocking even. The tumor had disappeared!

I examined the CT’s side-by-side. The large para-aortic and peri-caval lymph nodes were gone. Gone! The tumor markers reflected this, falling from 1237 to 59. The pain, it seemed was not a bad thing. It was actually a good thing reflecting rapid tumor lysis, a condition that can happen when cancer treatment causes cancer cells to die quickly.

The rapidity of response presumably caused an inflammatory reaction. As the chemotherapy drugs that he received are not highly immunosuppressive, that same inflammatory response likely contributed to the tumor shrinkage. We adjusted the doses and proceeded to cycle II, which he tolerated much better.

It now appears that he will achieve a complete remission reflected by his most recent CA19.9 of 22 (normal <34) and the soon to be conducted PET/CT. We are conferring with surgery for possible re-exploration and intra-peritoneal chemotherapy (HIPEC).

Several interesting points are raised:

- Every cancer patient deserves the right treatment the first time, every time. It is better to prevent a relapse than to withhold effective therapy and accept its inevitability. Modern oncologists, trained to opt for palliation, too often remove the words “cure” and “complete remission” from their vocabulary.

- Stage 4 gastric cancer may be a curable malignancy, at least in some patients. This is not the first time that we have managed a patient with Stage 4 gastric cancer, given no hope for cure, and achieved a complete remission. J.T. remains in complete remission 2˝ years after receiving a different chemotherapy regimen identified by our EVA-PCD functional profile.

- Finally, cancers like gastric, pancreatic, lung, recurrent breast or ovary may be incurable in some but not in all patients. The so-called “tail” of the survival curve reflects that percentage of patients who beat the odds.

Using our functional laboratory platform to enrich our skills, we can tip the scales in favor of our patients. Why should we or our patients accept anything less?

Yes we do test each agent individually and then in combination. This allows us the opportunity to examine true drug synergy, a unique aspect of functional analyses. The data upon ERCC1, GST and other enzymatic DNA repair phenomena have been mixed. In fact, ERCC1 expression has not been found to be a good correlate in NSCLC response and survival.

The observed activity for FOLFIRINOX ultimately reflects the dynamic interactions between DNA excision repair, Topoisomerase I activity and anti-metabolite drug incorporation. All of which is beyond the capacity of static platforms like gene profiles that can only measure presence or absence of genes not their real time activity at the the cellular level.

Indeed, over-expression of ERCC1, the DNA repair gene has actually been shown to paradoxically confer greater sensitivity to some drug combinations, completely contrary to it's putative role as a drug resistance phenomenon. This further supports the use of real-time cellular analyses like EVA/PCD to interrogate these complex events.
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Old 04-19-2017, 06:39 AM
gdpawel gdpawel is offline
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Default For Stage 4 Stomach Cancer Old Drugs May Be Better

Robert A. Nagourney, M.D.

The accelerating pace of scientific discovery, profusion of genetic advances and explosion of big data has led to a sense that the cure for all disease is at hand. Every day we are offered the opportunity to explore our genetic heredity, measure our telomeres or perform a buccal smear (mouth swab) to predict our future response to drugs.

In cancer, this has been associated with the explosive growth of genomic analyses that analyze patient’s paraffin-fixed (wax embedded) tumor blocks in the hope of identifying targets for the newest classes of drugs that block mutations, amplifications and duplications.

We can imagine a future when patients will arrive at their doctor's office and instruct their physicians on exactly the drugs and doses that they should receive.

Despite the promise, the reality has been somewhat disappointing.

Medical oncologists are coming to realize that gene profiles usually provide more questions than answers. The impressive collection of mutational findings is generally not associated with actionable “targets”, effective drug choices or available clinical trials for patient accrual. So what’s a patient to do?

Looking at the Newest Targeted Drugs

Some years ago we reported our observations with the newest targeted agents. We were interested to see how drugs that inhibited specific cell pathways worked in different tumor types. As a backdrop, we already knew that some cancers responded very well to conventional chemotherapies.

Among them were small cell lung, leukemia, lymphoma and ovarian cancers. When we examined these chemo-responsive tumors we found, in some cases, that the tumors for which current chemotherapies worked very well were often less likely to respond to the newer classes of “targeted” agents.

Our observations suggested that there were really two types of cancer.

One group behaves like the model cell lines that were used for many years in drug development. These cancers tend to grow rapidly and often carry DNA-repair defects that make them responsive to conventional drugs.

The second group is those historically drug resistant tumors that we now understand carry unique drivers rendering them more responsive to the new “targeted” inhibitors.

I was reminded of this dichotomy by a recent patient.

Diagnosis - Stage 4 Stomach Cancer

This 53 year old gentleman presented with a rapidly growing gastric (stomach) cancer and transfusion-dependent bleeding. After undergoing a diagnostic endoscopy, confirming the mass in the stomach, he travelled to LA to seek opinions. He was offered chemotherapy by one qualified oncologist in LA and then requested a consultation with me shortly thereafter.

He was a healthy, vigorous and youthful gentleman who looked well despite his diagnosis of metastatic stomach cancer.

He was very familiar with our functional profiling assay technique (we call it EVA-PCD) that uses tissue analysis and requested a biopsy. At the patient and his family’s request we also submitted a portion of the biopsy specimen for genomic analysis. While we awaited the gene profile results, our EVA-PCD test was completed.

Although there are many treatment options for stomach cancer, this patient’s profile perfectly matched one drug combination known by the acronym FOLFOXIRI. In light of his advanced condition, we recommended that treatment begin immediately.

The patient required another blood transfusion before we could begin treatment and the first days of therapy were a bit rocky. But, by the second week, as cycle 2 began, he looked and felt much better. His pain had resolved and the evidence of stomach bleeding had ceased. When I inquired, he described himself as "10 out of 10."

Results of His Gene Profile

With Cycle 2 of FOLFOXIRI underway, the results of the gene profile arrived. They were disappointing, but not unexpected. The tumor carried no actionable mutations.

Although there were several interesting changes like a chromosome remodeling gene often found in uterine cancers or changes in a DNA-related-protein gene, sometimes seen in leukemia, absolutely nothing could be directly targeted with an available drug.

Nothing!

His Cancer Doesn't Fit the Fashionable Trend

With a 50% decline in tumor marker after a single cycle of therapy, this patient is a living, breathing example of exactly what we had observed years earlier.

He is one of the many patients whose cancers don’t fit the current trend in “targeted therapy”. These patient’s tumors proliferate rapidly or use DNA in ways that make them targets for conventional chemotherapy. After all, he carries no actionable mutations.

For him and patients like him the new era of targeted therapy left them behind. His tumor, it seems, only responds to what, in the current parlance, would be unfashionable drugs.

What Can We Learn?

There are many implications.

The first is that new drugs aren’t always better drugs.

The second is that patients must receive those drugs and combinations that work best for them, regardless of how in vogue those treatments may be.

The third is that cancer patients may represent distinct sub-groups. Older drugs, originally designed to stop cell proliferation may, in some patients, be just right. On the contrary, those tumors with specific drivers, that utilize nutrients differently, alter cell receptors or respond differently to survival signals may be quite resistant to classical cytotoxic drugs and can benefit from the newest agents.

Our job is to decide “who is who” before we treat them.

The take home message is that each patient must receive the right treatment for them the first time, every time.

Forcing patients to behave according to our current scientific dictates serves no one's purpose - not the patient, not the doctor, not the third party reimburser nor the pharmaceutical industry. Good medicine is good for everyone.
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Gregory D. Pawelski
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