At the Breast Cancer Symposium 2009

[gdpawel]

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. The data will shortly appear on the ASCO website. When they post slide presentations from the 2009 Breast Cancer Symposium, I'll post it here.

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://www.asco.org/ASCOv2/Meetings/...stractID=40486

[gdpawel]

At 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.

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, and Chas Bountra of the Structural Genomics Consortium (SGC) raises the sobering fact that 90% of Phase II compounds failbecause 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.

Why was nothing being presented at this meeting which reports any progress at all in drug selection through the use of molecular profiling? When microarrays and high throughput RT-PCR emerged some years back, you'd think that there would be quite a bit of progress by now. Sad to say, there has not.

http://theoncologist.alphamedpress.o.../full/12/3/301

[Rich66]

Any discussion there about cancer stem cells? Max Wicha walking about? I would think ongoing support for metformin as an available, safe, cheap and stem cell degrading agent would be generating big buzz.

[gdpawel]

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://www.asco.org/ASCOv2/Meetings/...stractID=40486

[gdpawel]

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.

Source: http://www.weisenthal.org/Weisenthal_ASCO.pdf

[Jackie07]

Remember the Human Genome project? The attempt to map all the genes in the human body had a slow start. The traditional steps taken by the government agencies - with the best brain and top scientists - was so slow that Craig Venter finally took off and formed his own company to 'speed things up'. And he succeeded - several years before the predicted time.

Hopefully the current debate will continue and help speed things up...

[gdpawel]

They may have to wait awhile longer.

http://her2support.org/vbulletin/showthread.php?t=46200

[gdpawel]

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

[gdpawel]

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.]