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Platinum-Based Treatment of Triple-Negative Breast Cancer

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gdpawel
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Larry Weisenthal, MD, PhD

The last issue of The ASCO Post reports encouraging results with platinum-based treatment of triple-negative breast cancer (September 15, 2013).

We predicted these findings 4 years ago in a presentation at the 2009 Breast Symposium.1 We compared the activity of a series of agents (platinum, taxane, alkylating agent, and anthracycline) tested in cell cultures of fresh biopsy specimens of triple-negative breast cancer, in comparison with the activity in non–triple-negative breast cancer, previously untreated ovarian cancer, platinum-resistant ovarian cancer, and late-relapse ovarian cancer.

We reported the following conclusions:

1. Estrogen receptor (ER)-negative breast cancer is dramatically more sensitive to cisplatin than is ER-positive breast cancer.

2. HER2-negative breast cancer is slightly more sensitive than is HER2-positive disease.

3. ER-negative/HER2-negative breast cancer is more sensitive than is ER-negative/HER2-positive disease.

4. Poorly differentiated breast and ovarian tumors are more sensitive than are moderate and well-differentiated tumors.

5. Non–triple-negative breast cancer subsets are more resistant to cisplatin than are cases of platinum-resistant ovarian cancer.

6. Triple-negative breast cancer is equally sensitive to cisplatin as is previously untreated ovarian cancer, and cisplatin is the most active of the four tested drugs in triple-negative breast cancer.

It is gratifying to see the clinical validation for our prediction based on cell culture testing. With regard to the “exciting new assays coming down the pike to help us identify which patients may respond to platinum agents,” there is a very impressive peer review literature confirming the predictive value of fresh tumor cell culture assays with cell death endpoints to reliably predict for the clinical benefit of platinum agents in human neoplasms. These latter tests are already available from licensed clinical laboratories; however, in the absence of results from individualized cell culture testing, the markers that best identify breast cancer patients for platinum therapy are ER-negative, HER2-negative, and Bloom-Richardson Grade 9/9 (data shown in abstract.1)

Disclosure: Dr. Weisenthal reported no potential conflicts of interest.

Reference

1. Weisenthal L: Activity of cisplatin in triple-negative breast cancer in comparison to other cancer types in fresh tumor cell culture assay using a cell death endpoint. 2009 Breast Cancer Symposium. Abstract 61. Presented October 8-10, 2009.

Citation: Larry Weisenthal, MD, PhD. The ASCO Post, October 15, 2013, Volume 4, Issue 16

http://meetinglibrary.asco.org/content/336

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gdpawel
Posts: 549
Joined: May 2001

As our understanding of breast cancer biology continues to advance, this disease has come to be understood as many different diseases. Original categorizations based on histology lead to lobular versus ductal subtypes. Thereafter, recognition of estrogen and progesterone status, and finally HER2 status provided further subcategorizations.

Over the past decade, molecular subtypes have characterized this disease into a series of signatures characterized by luminal, basal and other groupings with distinct prognoses. Within the context of these categories, the triple negative breast cancers have emerged as an important target.

These patients whose tumors do not mark for estrogen, progesterone, or HER2 on immunohistochemical or FISH analyses, appear to carry features that segregate them into a BRCA1-like biology. This is of great interest clinically for it offers the opportunity to treat these patients with drugs found active in the BRCA mutant populations.

Among the most active drugs in these patients are the PARP inhibitors. The excellent results with PARP inhibitors and BRCA mutants have been followed by striking response and survival data combining PARP inhibitors with carbo-platinum and gemcitabine. PARP inhibitors by inhibiting DNA damage response can enhance the effects of ionizing radiation, mustard alkylators, topoisomerase inhibitors, platins, and intercalating agents.

We have explored the biology of PARP inhibitors in breast and other cancers. In these investigations, our lab to applies the functional profiling platform to understand how PARP inhibitors enhance the effects of drugs and drug combinations.

To date, we have observed good activity for the PARP inhibitors as single agents in BRCA1 positive patients, and in some triple negative patients. More interesting, will be the results combining the PARP inhibitors with mustard alkylators, platins, and drug combinations to optimize PARP inhibitor combinations.

This work is ongoing in triple negative and BRCA positive patients as well as other tumor types where the PARP inhibitors may prove useful in the future.

[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.]

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gdpawel
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Joined: May 2001

A study was presented at the 2009 American Society of Clinical Onocology (ASCO) breast cancer symposium in San Francisco about progress in drug selection through the use of cell-based functional profiling. It delt with the so-called "triple negative" breast cancer (TNBC), which is estrogen receptor negative (ER-), progesterone receptor negative (RP-), 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).

Data shows 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. How can the pCR rate be improved in TNBC?

The speaker went through all the database of breast cancer cell culture assays (using cell death endpoints) and tried to see if there were any drugs which appeared to be uniquely active in TNBC vs non-TNBC.

There were 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.

The speaker went on to present a lot of data further dissecting which specific markers were most associated with TNBC sensitivity to cisplatin. 

But, essentially, the major markers for platinum sensitivity in breast cancer were estrogen receptor negativity and very poorly differentiated tumors. The minor markers for platinum sensitivity in breast cancer were Her2 negativity and progesterone receptor negativity.

The data compared 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.

The data clearly showed 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 is hard to see how molecular profiling tests could have produced similar insights.

Genomics is far too limited in scope to encompass the vagaries and complexities of human cancer biology when it comes to drug selection. Efforts to administer targeted therapies in randomly selected patients often result in low response rates at significant toxicity and cost.

While researchers continue to develop molecular probes to select candidates, the cell culture analysis platform serves as a functional profile capable of examining the nuances of cellular response to drugs. To exploit the full potential of targeted anticancer therapies, physicians will need laboratory tests that match patients to specific drugs.

Cell culture assays are able to accurately predict how an individual patient's cancer cells will respond to an array of drug combinations. It is able to quantify synergistic drug combinations and individually tailor treatment.

Activity of cisplatin in triple-negative breast cancer in comparison to other cancer types in fresh tumor cell culture assay using a cell death endpoint

http://meetinglibrary.asco.org/content/40486-70

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gdpawel
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Robert A. Nagourney, M.D.
Medical and Laboratory Director
Rational Therapeutics, Inc.
Long Beach, California

I recently had an interesting conversation with a physician regarding her patient with an aggressive breast cancer.

A portion of tumor had been submitted to our laboratory for analysis and we identified activity for the alkylating agents and the Taxanes, but not for Doxorubicin. After our report was submitted to the treating physician she contacted me to discuss our findings, as well as the results from a genomic/proteomic laboratory that conducted a parallel analysis upon a portion of the patient’s tumor. The physician was kind enough to forward me their report. Their results recommended doxorubicin while ours did not. The treating physician asked for my input. Here, I thought, was a “teachable moment.”

Our discussion turned to the profound difference between analyte-based laboratory tests e.g. genomic and proteomic, and functional platforms like our own (EVA-PCD). Genomic, transcriptomic and proteomic platforms measure the presence or absence of genes, RNA or protein. Gene amplification, deletions or mutations and protein and phosphoprotein expressions are examined. These platforms dichotomize patients into those who do and those who do not express the given analyte, with cutoffs for gene copy number or intensity of staining.

These platforms have worked very well in diseases where there is a linear connection between the gene (or protein) and the disease state, e.g. BCR-ABL in CML for which imatinib has proven so effective. These tests have worked reasonably well in EGFR mutated and ALK gene rearranged in lung cancer, but even here response rates and response durations have been less dramatic. However, they have not worked very well at all for the vast majority of cancers that do not carry specific and well-characterized targets. These cancers reflect polygenic phenomena and are not defined by a single gene or protein expression.

Functional platforms look at cellular response to injury at the systems level and measure the end result of drug exposure to gauge the likelihood of a clinical response. Our focus on cell biology allows us to determine whether a drug or combination induces programmed cell death. After all, regardless of what gene elements are operational, it is the ultimate eradication of the cancer clone (its loss of viability) that results in clinical response.

As we reported in a recent paper in non-small cell lung cancer, patients who revealed the most sensitive ex-vivo profile to erlotinib (Tarceva) lived far longer than the general clinical experience for those patients who were selected for erlotinib by EGFr mutation analysis alone. Some of these patients are alive at 5, even 9 years since diagnosis.

We live in a technocracy where process has taken precedence over results. We are enamored with complex scientific technologies sometimes at the expense of simple answers. A metallurgist, familiar with every last detail of the alloys used in a Boeing 747 wouldn’t necessarily be your first choice for pilot. A skilled pathologist, intimately familiar with the most detailed intricacies of human diagnostics would not likely be your preferred surgeon for cardiac bypass.

Cancer diagnosis and cancer treatment are two distinctly different disciplines. While we use the ER (estrogen receptor) status in breast cancer to select treatment, few oncologists would select Tamoxifen for their NSCLC patients even though many NSCLC patients express ER in their tissue. ER + NSCLC does not respond to tamoxifen and V600E BRAF mutated (+) colon cancer patients do not respond to vemurafenib, the very drug that works so well in BRAF V600E (+) melanoma.

Cancer is contextual and responses are not solely predicated upon the presence or absence of a gene element alone. We must use a broader brush when we paint the likeness of our patients in the laboratory, one that encompasses the vicissitudes of human biology in all of its complexities.

Where I took issue with the report, however, was its “evidence-based” moniker. The evidentiary manuscripts cited to support the drug recommendations, with titles like “Overexpression of COX-2 in celecoxib-resistant breast cancer cell lines” provided little evidence that a (+) COX-2 finding by IHC on this patient’s biopsy specimen would offer any real hope of response. It seemed that with all of the really interesting science going on here, no one had taken the time to do the hard work to figure out whether any of these observations had a basis in reality. The failure of ERCC1 expression in lung cancer to correlate with response and survival or the Duke University debacle with gene profiling in NSCLC are just the most recent examples of how “lovely theories can be spoiled by a little fact.”

As we and our colleagues in cell profiling have actually taken the time to correlate predictions with clinical outcomes we have shown a 2.04 fold higher objective response rate (p 0.001) and significantly improved 1-year survival (p=0.02). (Apfel, C. et al Proc ASCO, 2013). To the contrary, it is of interest to examine the comparatively scant published literature on genomic and IHC profiling for drug selection under similar circumstances. While one group reported an underwhelming objective response rate of 10 percent in their study, (Von Hoff, J Clin Oncol 2010) a more recent study is even more illuminating. A Spanish group used genomic profiling in 254 colon cancer patients to select candidates for gene-targeted agents (KRAS/BRAF/PI3K/PTEN/MET) and provided therapy for 82. They reported a significantly shorter time to progression for targeted treatments compared with conventional therapies 7.9 vs 16.3 week (P<0.001) and an overall objective response rate of 1.2 percent, yes that’s 1.2% (1/82).

Human tumor biology is many things, but simple is not one of them. Reductionist thinking is not providing the insights that our patients desperately need. While we await the arrival of a perfect test for the prediction of response to cancer therapy, perhaps we as physicians and our patients should use a good one, one that works.

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gdpawel
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Joined: May 2001

Replies to comments regarding personalized cancer treatment, as published in the December 15, 2013 "ASCO Post" (American Society of Clinical Oncology publication).

By Larry Weisenthal, MD
December 15, 2013, Volume 4, Issue 20

Dr. Mason states that I implied that Dr. Telli supports the routine application of chemosensitivity assays. I have no knowledge regarding Dr. Telli’s views on this subject, nor did I in any way attempt to represent her views, much less imply that she was supportive of anything relating to chemosensitivity assays.

Dr. Mason also raises the issue of conflict of interest. I am an expert in chemosensitivity testing, with 35 years of largely full-time experience with the relevant technologies. Dr. Telli stated that her group was working on predictive markers to identify the best candidates for platinum treatment in breast cancer. I quoted our data presented at the 2009 Breast Cancer Symposium, which prospectively identified the best candidates for such treatment as being patients with triple-negative disease and a Bloom-Richardson score of 9/9. My laboratory provides neither marker studies for triple-negative disease nor Bloom-Richardson scoring.

Obvious vs Nonobvious Conflicts

Let’s imagine that I were a pathologist, who pointed out to Dr. Telli that there was prior work suggesting that the above routine pathology markers could be useful in identifying candidates for platinum treatment. Would this be a conflict of interest?

Dr. Mason seems to be implying that any expert/specialist who provides a service related to his/her comment should declare a conflict of interest. Thus, a radiotherapist commenting on a surgical study should declare a conflict of interest, a chemotherapist commenting on a radiotherapy study should declare a conflict of interest, and so forth.

In my case, it was obvious from my letter that I performed chemosensitivity testing, as I quoted my own work in this field! In a similar vein, pathologists, radiotherapists, and chemotherapists generally make note of their own specialties in their comments, as workers in a particular field typically have the most relevant knowledge base, and their conflicts of interest are likewise obvious. One generally makes a formal conflict of interest declaration when one’s conflict is not obvious, eg, most typically in disclosing a relationship to an entity not obviously related to one’s medical practice, such as a relationship with an outside pharmaceutical company. 

I am going to hazard a guess that Dr. Mason would state that the difference between an oncologist providing chemosensitivity testing and a pathologist providing estrogen receptor testing is that the former testing is considered to be “investigational/not recognized by ASCO,” whereas the latter is considered to be noninvestigational/recognized. But is this a fair distinction?

Double Standard?

To date, ASCO has provided two formal reviews of chemosensitivity testing.1,2 In both reviews, the sole criterion being assessed was “efficacy,” meaning the existing data relating to the question of whether the use of this testing improves clinical outcomes. In both reviews, no attempt was made to assess the considerable data documenting the accuracy of chemosensitivity testing, where test accuracy is the only criterion ever used to “validate” any predictive laboratory technology, specifically including the triple-negative tests (ie, for estrogen receptor, progesterone receptor, and HER2).

This double standard has had the effect of halting virtually all progress in the field of chemosensitivity testing since the late 1980s. Critics have labeled the technology “investigational” and have then failed to support the investigations they have demanded, as readily evidenced by the complete absence of NIH grant–supported publications in the American literature over the past 2 decades. The technologies are largely in the public domain and labor-intensive, and there has accordingly been no serious private sector money to compete with pharmaceutical company funding for clinical trials.

New Development

Just this year, however, there has been a new development. A large-scale (777-patient) prospective, randomized trial in chronic lymphocytic leukemia was published, supported by the British Leukemia Research Fund.3 I would ask fair reviewers to compare and contrast the quality and results of this trial with what is the self-proclaimed “best” trial ever performed to “validate” estrogen receptor testing4 (estrogen receptor negativity being the most powerful contributor to platinum sensitivity in patients with triple-negative disease in our 2009 study).5

Comparing the chemosensitivity test study with the estrogen receptor study, the former had a greater number of patients and stronger predictive correlations, and used real-world test conditions (real-time processing and prospective reporting, as opposed to post hoc batch-processing and retrospective reporting). Additionally, for the first time ever in all studies of predictive markers used for treatment selection in cancer, the chemosensitivity study showed an improved clinical outcome for patients randomly assigned to test-guided treatment selection vs non–test-guided treatment selection. (Patients in the empiric therapy arm had a 2.5-fold greater probability of being dead at 1 year, compared to the patients in the test-directed arm.)

Lost Opportunity

I view the lack of support and overt hostility to chemosensitivity testing as being the single greatest lost opportunity in clinical cancer research over the past 25 years.

As a postscript, there was a nonfunctioning link to our 2009 ASCO Breast Symposium presentation relating to platinum therapy in triple-negative breast cancer in my original comment, as published. Here is the correct link, presenting our abstract and most important data: 

http://meetinglibrary.asco.org/content/40486-70 

—Larry Weisenthal, MD
Huntington Beach, California

References

1. Schrag D, Garewal HS, Burstein HJ, et al: American Society of Clinical Oncology Technology Assessment: Chemotherapy sensitivity and resistance assays. J Clin Oncol 22:3631-3638, 2004.

2. Burstein HJ, Mangu PB, Somerfield MR, et al: American Society of Clinical Oncology clinical practice guideline update on the use of chemotherapy sensitivity and resistance assays. J Clin Oncol 29:3328-3330, 2011.

3. Matutes E, Bosanquet AG, Wade R, et al: The use of individualized tumor response testing in treatment selection: Second randomization results from the LRF CLL4 trial and the predictive value of the test at trial entry. Leukemia 27:507-510, 2013.

4. Elledge RM, Green S, Pugh R, et al: Estrogen receptor (ER) and progesterone receptor (PgR), by ligand-binding assay compared with ER, PgR and pS2, by immuno-histochemistry in predicting response to tamoxifen in metastatic breast cancer: A Southwest Oncology Group Study. Int J Cancer 89:111-117, 2000.

5. Weisenthal L: Activity of cisplatin in triple-negative breast cancer in comparison to other cancer types in fresh tumor cell culture assay using a cell death endpoint. 2009 Breast Cancer Symposium. Abstract 61. Presented October 8-10, 2009.

Disclaimer: This letter represents the views of the author and may not necessarily reflect the views of ASCO.

Citation: The ASCO Post. Dr. Weisenthal Replies. December 15, 2013, Volume 4, Issue 20

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