I’m currently attending the 2009 American Society of Clinical Oncology (ASCO) breast cancer symposium, in San Francisco.
The Keynote Address (by Martine PIccart-Gebhart of the Jules Bordet Institute) was very relevant to Individualized Tumor Response Testing (ITRT). The speaker made the point that only 8% of new drugs entering Phase I trials ever make it to marketing and that this percentage is even lower for cancer drugs, because “current drug testing is inefficient, with many drugs failing late in development,” with “these expensive failures” owing, in large measure, to “ineffective drugs” and “poor patient selection (i.e, lack of prognostic and predictive markers for response to therapy).”
The speaker went on to note that “little progress has been made in identifying which therapeutic strategies are likely to be effective for individual patients.” The speaker concluded that “identifying markers that can predict response to a particular drug remains a great challenge.”
To my knowledge, there is absolutely nothing being presented at this meeting which reports any progress at all in drug selection through the use of molecular profiling. Perhaps I’ve missed something. There is another half day remaining.
When microarrays and high throughput RT-PCR emerged some years back, I’d have predicted quite a bit of progress by now. Instead, there were a couple of early clinical studies, and virtually no follow up by now. Certainly, the sum total of the cell culture-based literature is vastly superior, taken as a whole, to the sum total of the molecular profiling-based literature for drug selection. One would think that there would be at least equal interest in cell culture-based approaches. Sadly, no.
I presented what I think was an important study in a poster session. It attracted virtually no interest. I’d like to briefly go through the most important points here. I’d be very interested in feedback, comments, and/or criticism, preferably on this blog, but, if preferred, as a private email: mail@weisenthal.org
The problem I addressed is that of so-called “triple negative” breast cancer (TNBC), which is: Estrogen Receptor Negative (ER-), Progesterone Receptor Negative (PR-), and Her2 Negative (H2-).
When breast cancer presents as locally advanced disease, it is customarily treated with neoadjuvant (preoperative) chemotherapy, followed by definitive surgery. At the time of surgery, the specimen is assessed to determine if all visible tumor has been destroyed by chemotherapy. When this happens, it is said to be a “pathological complete response” (pCR). The Kaplan-Meier curves below show survival in Non-TNBC and TNBC, as a function of whether or not preoperative chemotherapy produced a pCR.
In the figure below, the yellow line is the survival for non-TNBC patients who achieved a pCR; the blue dashed line is the survival of TNBC patients who achieved a pCR; the black dashed line is for non-TNBC who did not achieve a pCR; and the red dashed line is for TNBC patients who did not achieve a pCR.
These data show that obtaining a pCR is everything. Get a pCR, and the survival is excellent. Don’t get a pCR and the survival, especially for TNBC patients, is very poor.
So the issue is this: what can we do to improve the pCR rate in TNBC?
I began by going through our database of breast cancer cell culture assays (using cell death endpoints) and trying to see if there were any drugs which appeared to be uniquely active in TNBC vs non-TNBC. Here’s a representation of what I found:
The horizontal bars show percent control cell survival for drug exposed cultures. The shorter the bar, the more active the drug. Error bars represent 95% confidence limits. These are representative data for a few of the more important drugs.
Essentially, there are no major differences between the activity of most drugs in TNBC vs non-TNBC, with one glaring exception: cisplatin, which was dramatically more active in TNBC than in non-TNBC.
I went on to present a lot of data further dissecting which specific markers were most associated with TNBC sensitivity to cisplatin. These data will shortly appear on the ASCO website, when they post slide presentations from the 2009 Breast Cancer Symposium. But the following were the most important “take home” messages:
Major markers for platinum sensitivity in breast cancer were:
1. Estrogen Receptor negativity
2. Bloom-Richardson (Nottingham) score of 9/9 (i.e. very poorly differentiated tumors.
Minor markers for platinum sensitivity in breast cancer were:
1. Her2 negativity
2. Progesterone receptor negativity
The following puts the findings into a useful perspective:
These data compare TNBC to other types of tumors. It’s known that renal cell carcinomas are very resistant to cisplatin (less than 10% response rate), and that is reflected by the cell culture (cell death endpoint) data. It’s known that previously-untreated, poorly differentiated ovarian cancers tend to be very sensitive to cisplatin (70% response rate), and that’s also reflected by the cell culture data. When ovarian cancer patients relapse soon (0 to 6 months) after discontinuation of chemotherapy, they have only a 25% response rate to re-treatment with platinum. When ovarian cancer patients relapse greater than 6 months following discontinuation of chemotherapy, they have a 50% response rate to re-treatment with platinum. These clinical findings are also nicely recapitulated by the cell culture assay data.
Now, breast cancers which are either estrogen receptor positive and/or more than very poortly differentiated (Bloom Richardson score of 4 to eight) tend to be even more resistant to cisplatin than are previously treated ovarian cancer which relapse soon (0 to 6 months) after discontinuation of chemotherapy. In contrast, Triple Negative Breast Cancers tend to be as sensitive or more sensitive (especially when also Bloom Richardson 9/9) to cisplatin than are previously-untreated, poorly-differentiated ovarian cancers.
I think that these data clearly show the utility of cell culture assays in “targeting” chemotherapy to patient sub-groups who are most likely to benefit from treatment with given individual drugs. It’s hard to see how “molecular” profiling tests could have produced similar insights.
The following were my summary conclusions, comparing cell culture profiling versus “molecular” profiling:
So the question is this: Why is there absolutely no interest in cell culture tests?
- Larry Weisenthal/Huntington Beach, CA
Very interesting that there was no work presented on “drug selection through the use of molecular profiling” despite the keynote address.
One of the things that lead to the closure of Bath Cancer Research was the refereeing of a grant application of mine by a leading UK Oncologist who said something along the lines of:
“This is old hat. We are now going to select drugs by molecular profiling.”
I do not agree with one thing you said:
These data show that obtaining a pCR is *everything*. Get a pCR, and the survival is excellent. Don’t get a pCR and the survival, especially for TNBC patients, is very poor.
There is a subtle difference between this and:
Those who got a pCR did better than those who did not.
Those who did not get a pCR, even if had been given drugs that gave them a pCR, might have done just as badly. Although what you say may be true, these data do not *necessarily* show that obtaining a pCR is everything.
Excellent summary slide at the end. And what *is* the answer to your question:
Why is there absolutely no interest in cell culture tests?
Andrew Bosanquet
Just as a post-script: By the end of the symposium, there were absolutely NO reports or reviews of molecular-based technologies which had any promise whatsoever for use in drug selection in breast cancer, beyond prognostic tests which might be used to identify sub-groups of patients who don’t require chemotherapy at all, in very localized disease. – Larry Weisenthal/Huntington Beach, CA
It’s not a case of no interest in cell culture tests, patients (and even some oncologists) don’t know about them. In the last few years, since Medicare approved the coverage of this testing (Oncologic In Vitro Chemoresponse Assays) on a non-investigational basis, more and more of these patients are questioning why they are not used routinely, and some are demanding it be used in their cancer treatment.
The question should be, “Why was nothing presented at the ASCO meeting with regard to drug selection through the use of molecular profiling?” Sad to say, there has not been any progress with it. Is molecular profiling ready for prime-time use in clinical decision making?
http://theoncologist.alphamedpress.org/cgi/content/full/12/3/301
H. Jack West, MD, Medical Director, Thoracic Onc, Swedish Cancer Inst, Seattle, WA posted this on the Medscape blog, November 17, 2009.
Over the last couple of years, there has only been mounting interest in treating NSCLC in a new, more intelligent way by using molecular testing to tailor our therapy. In fact, I’ve been among the people hailing the wondrous promise of a new age in which we can deliver response rates of more than 50% by identifying a targeted population for a targeted therapy. From where I’m standing, though, the reality hasn’t measured up that well.
For starters, getting tissue has been a pain, at least for me. A large number of my patients come from outside institutions, so getting tissue from another hospital sent for EGFR mutation testing adds a major layer of obstruction and delays, and that’s even presuming that there’s enough tissue. I’ve come to the conclusion that it can be easier to get tissue at my own institution, which is I believe what Memorial Sloan-Kettering, MD Anderson, and other places have concluded as well. It’s a little troubling that we need to submit patients to an additional invasive procedure, but it can be a delay of weeks otherwise, and sometimes it just seem like pathology departments can’t handle the simple task of sending slides elsewhere.
On the other hand, I can’t say that my own institution has done a much better job. Three weeks ago, I saw a woman with a rapidly recurring effusion and thought it would be easier to get the effusion drained at my own place and have the cell block sent for mutation testing. Great, and within 2 days that had been performed, but my center’s pathology department is part of a national mega-group that contracts with a lab in North Carolina for their mutation testing and didn’t want to send it to Response Genetics, which is about the only place I’ve found that makes any real effort to get EGFR mutation testing done within a week. I agreed to let them try, but now I’m still waiting and told I won’t get the result until more than three weeks after the test went out. I’ve had to use words like substandard to convey that this is unacceptable from a clinical standpoint. But I think this kind of runaround is probably pretty common right now.
Finally, my center is one of the earliest places activated for the EML4-ALK mutation testing as part of the trials with the agent PF-02341066. The agent is only available for people who have the mutation, and the test isn’t commercially available. Pfizer had promised up and down that they’d guarantee that they can get the test turned around in 5 days. Well, now that I’ve consent a bunch of patients who are sitting by the phone waiting to find out if they have the mutation, Pfizer calls to say that the guy who runs their lab isn’t going to be able to do it for another two weeks at least. I have patients on hold waiting for this, and this kind of crap undermines my relationship with them. Even if they know it’s not my fault, it’s frustrating for all involved, and it just underscores how Pfizer has already bungled this process terribly, with just two sites active in the country. How will they manage when they get another 20 sites activated?
Sorry to rant, but the truth is that our system doesn’t have the infrastructure to deal with a roll-out of molecularly-defined treatment of lung cancer yet. The idea is great, but I don’t think we can execute this yet in a way that makes it broadly clinically applicable. And it’s pretty disappointing to know the data but not be able to act on it.
It was hoped some day that Genomic Analyses of cancer tumors would be able to identify in advance which patients will benefit from use of cancer drugs (clinical responders). A new draft report from the Agency for Healthcare Research and Quality (AHRQ) suggests that day is still a ways off.
The study looked at whether the presence of specific mutations in people who had breast and colon cancer and chronic myeloid leukemia determined if patients would respond to expensive new drugs commonly used to fight the diseases. Only in colon cancer did the mutation matter and in that case, while it ruled out the effectiveness of drug therapy, the relevant mutation only appears in a small percentage of cases.
In the finding most likely to cause controversy, the AHRQ report found there was “no consistent associations” between breast cancer patients with the relevant CYP2D6 polymorphism and the outcome of tamoxifen therapy, whether as primary treatment or in as post-operative adjuvant therapy. Estimates vary, but anywhere from 10 to 40 percent of women have the gene variant of CYP2D6 that is believed to slow the metabolism of tamoxifen and make it less effective. A number of companies sell a $300 test that can show if women have the allegedly telltale CYP2D6 polymorphism.
As is often the case, the 13 studies identified by the systematic review didn’t contain enough data to draw definitive conclusions. “Most studies were relatively small and thus underpowered to detect what would be a plausible effect size for the modification of response to tamoxifen by a single polymorphism,” the report noted.
Numerous studies in recent years have noted that colon cancer patients with the KRAS mutation do not respond to epidermal growth factor receptor inhibitors like cetuximab (Imclone Systems/Bristol Myers Squibb’s Erbitux) and panitumumab (Amgen’s Vectibix). The Food and Drug Administration, the European Medicines Agency and the American Society of Clinical Oncology have issued guidelines suggesting patients with the mutation shouldn’t be given the drugs.
The AHRQ-sponsored review confirmed that finding. “Patients with KRAS mutations were less likely to experience treatment benefit, compared to patients whose tumors were wild-type for KRAS mutations,” the report said. About 20 percent of patients have KRAS mutations, which generally signal a more virulent form of the disease.
Chronic myeloid leukemia is one of the great success stories for targeted chemotherapy drugs and imatinib (Novartis’ Gleevec) has been a godsend for patients with CML since it came on the market a decade ago. But resistance is growing, and at least two similar drugs are now on the market, dasatinib (Bristol-Myers’ Sprycel) and nilotinib (Novartis’ Tasigna).
Some mutations of the BCR-ABL1 gene make the cancer resistant to imatinib (Gleevec), which is designed to block the action of the hyperactive tyrosine kinase receptors in people with CML. But don’t look to any tests currently on the market to determine what they are. The review of 31 studies found that “the presence of any BCR-ABL1 mutation does not appear to predict differential response to treatment in CML patients treated with imatinib-, dasatinib- (Sprycel), or nilotinib- (Nilotinib) based regimens.”
Indeed, the report said there is “no evidence that presence of any BCR-ABL1 mutation can differentiate response to tyrosine kinase inhibitor therapies.”
“It is possible that pharmacogenetic (how our inherited genes affect the way we respond to drugs) testing and the subsequent use of targeted therapies will add cost without producing clinically meaningful improvements in patient outcomes,” the report said.
http://www.ahrq.gov/clinic/ta/pharmgentest.pdf
Source: Gooznews on Health
Molecular Oncology (Germany)
http://www.biofocus.de/data/biofo/en/data/Link_1273_download.pdf
tamoxifen and breast cancer…
I always like to search on UTube for videos on tamoxifen and breast cancer, you can learn a lot about tamoxifen and breast cancer although like blogs you have to filter out the dross. This was a better article than most. Thanks….