Platinum-Based Treatment of Triple-Negative Breast Cancer

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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/40486-70

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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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Direct anti-tumor and anti-vascular effects were studied of Tykerb, Nexavar and Avastin in fresh biopsy specimens of breast cancer and presented at the American Society of Clinical Oncology Breast Cancer Symposium on September 5, 2008.

While the other clinically-available 'nib' drugs have been shown to have anti-vascular activity, anti-vascular activity of Tykerb has not been previously reported.

Angiogenesis studies are limited by the clinical relevance of laboratory model systems. They don't do "real world" studies under "real world" conditions. Patient outcomes need to be reported in real-time, so patients and cancer physicians can learn immediately if and how patients are benefiting from new drug therapies.

Cell culture detection of microvascular cell death in clinical specimens of human neoplasms and peripheral blood can identify the activity of both single drugs and combinations of drugs at the level of individual patients with individual cancers. It works by measuring drug effects (real-time) upon endothelial cells which make up blood vessels.

Drugs like Avastin had striking anti-microvascular effects but minimal anti-tumor effects. Tarceva and Gleevec had mixed antitumor and anti-microvascular effects. Anti-microvascular effects of Tarceva and Iressa were equal to those of Sutent and Nexavar. Anti-microvascular additivity was observed between Avastin and other drugs on an individual basis.

Conclusions of the study had shown that Tykerb has antivascular activity superior to that of Nexavar. Avastin + Tykerb may be the first clinically-exploitable antivascular drug combination. High dose, intermittent 'bolus' schedules of Tykerb to coincide with Avastin administration may be clinically advantageous, even in HER2-negative tumors.

The system utilized for the study was a functional profiling assay, which may be used to individualize antivascular therapy. It can be adapted for simple, inexpensive and sensitive/specific detection of tissue and circulating microvascular cells in a variety of neoplastic and non-neoplastic conditions, for drug development, and individualized cancer treatment.

It can accurately sort drugs into categories of above average probability of providing clinical benefit on one hand and below average probability of providing clinical benefit on the other hand, based both on tumor response and patient survival.

http://www.weisenthal.org/Weisenthal_ASCO.pdf
http://onlinelibrary.wiley.com/doi/1...8.01955.x/full

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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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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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A new study strengthens the evidence that pathological complete response (pCR) is a good surrogate marker of longer-term efficacy in the neoadjuvant drug treatment of breast cancer.

pCR, which is defined as the absence of invasive cancer in the breast and lymph nodes after treatment, can be measured within weeks of starting a drug. Thus, it can provide a very early indicator of efficacy.

However, here at the 36th Annual San Antonio Breast Cancer Symposium (SABCS), investigators reported that short-term pCR results also correlate with longer-term event-free survival in the neoadjuvant setting.

At a meeting press conference today, Martine Piccart-Gebhart, MD, PhD, illustrated this using data from the Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization (NeoALTTO) trial.

She explained that the combination of lapatinib (Tykerb, GlaxoSmithKline) and trastuzumab (Herceptin, Genentech) provided significantly better 3-year event-free survival than either agent alone in women with early-stage HER2-postive disease.

Notably, this improvement correlated with pCR in the 455-patient trial, said Dr. Piccart-Gebhart, who is chair of the Breast International Group in Brussels.

At 3 years, there was a 62% reduction in the risk for an event, such as disease recurrence or a second primary tumor, among the 137 patients who had a pCR compared with the 274 patients who did not (hazard ratio [HR], 0.38; P = .0003).

The correlation between pCR and 3-year event-free survival is especially important because NeoALTTO is one of the first randomized trials to prospectively evaluate pCR in breast cancer, said Jennifer Litton, MD, from the University of Texas M.D. Anderson Cancer Center in Houston. She moderated the meeting press conference.

Multiple retrospective studies in the neoadjuvant setting have shown that pCR correlates with long-term outcomes, she explained. "We have been looking at it for decades," said Dr. Litton about pCR.

Thus, NeoALTTO extends the evidence that pCR is a "strong surrogate marker," she told Medscape Medical News.

"For me, that's the story of NeoALTTO: pCR shows benefit, and it's persisting [at 3 years]," Dr. Litton summarized.

She also explained that regulators have contributed to the emerging status of pCR. The US Food and Drug Administration (FDA) "has now looked at the totality of evidence and realized that pCR is an important surrogate end point."

This fall, the FDA approved pertuzumab (Perjeta, Genentech) for the neoadjuvant treatment of early HER2-positive breast cancer on the basis of pCR results. In other words, the drug was approved based on short-term efficacy findings using a surrogate marker. The drug, which received accelerated approval, will need to eventually show a longer-term survival benefit to keep its indication in this setting.

Approval on the basis of pCR results signaled a new day in drug approval in the United States.

"We have a whole new tool to get drugs to patients faster," said Dr. Litton.

Industry has also been understandably appreciative of the shift in FDA drug evaluation criteria in this setting.

"If we can shorten the time it takes to determine whether a breast cancer medicine works, that is clearly good news for patients," said Dietmar Berger, vice president of clinical hematology/oncology at Genentech, in a press statement earlier this year when the FDA was considering the use of pCR as a marker in breast cancer drug approval in the neoadjuvant setting. The agency has since issued a draft guidance on the use of the measure in trials in this setting.

Differing Opinions

In NeoALTTO, an international team of researchers led by Dr. Piccart-Gebhart randomized 455 women with HER2-positive primary breast cancer to lapatinib, trastuzumab, or a combination of the 2 for 6 weeks, followed by surgery, chemotherapy, and then 48 more weeks of the original neoadjuvant therapy.

At the 2010 SABCS, the investigators revealed that the combination of trastuzumab and lapatinib completely wiped out tumor cells in the breast, and thus achieved pCR, in 51.3% of women — about twice the rate of response seen with either drug alone. The difference was statistically significant (P =.001).

However, at that time, a number of experts said that pCR was not ready to be used as a surrogate marker.

pCR was "not ready for prime time" as a measure to be used for drug approval because it is not always correlated with improved disease-free and overall survival, said Eric Winer, MD, from the Dana-Farber Cancer Institute in Boston, at the 2010 meeting.

Another expert agreed with Dr. Winer at that time. "Complete pathological response is not a perfect surrogate for long-term survival," said Leif Ellisen, MD, PhD, from the Gillette Center for Breast Cancer at Harvard Medical School in Boston.

"It's predicted survival in some trials of breast cancer, but not in all," Dr. Ellisen said. "And the FDA has said that it will not allow pCR to be used as an end point."

How quickly things have changed.

The study was funded by GlaxoSmithKline. Dr. Piccart-Gebhart reports financial ties to Roche and GlaxoSmithKline.

36th Annual San Antonio Breast Cancer Symposium (SABCS): Abstract S1-01. Presented December 11, 2013.

Citation: pCR Arrives as a Standard Measure in Breast Cancer. Medscape. Dec 11, 2013.