Two Women with Metastatic Breast Cancer – Same Age, Same Disease, Two Very Different Functional Profiles

A day in the life of advanced breast cancer. Two different 37-year-old breast cancer patients, both mothers of young children, were seen in consultation on the same day.

The first had been referred by a colleague who was concerned that the patient’s ER positive breast cancer had disseminated to her brain despite aggressive standard chemotherapy. She was to undergo a craniotomy and a portion of fresh tumor would be submitted from the surgery to Rational Therapeutics for EVA-PCD functional profiling.

The second mother had metastatic triple negative breast cancer, which recurred after aggressive standard chemotherapy. She underwent neo-adjuvant treatment (preoperative) but at the time of her surgery, there was no evidence of response to the treatment. By the time we met her, only months into her diagnosis, new areas of metastatic disease were cropping up daily.

Microscope Detail2-lo resThe EVA-PCD assay results on these two “similar” patients were entirely different.

The results of the first patient with the ER positive tumor and brain metastases clearly identified treatments directed toward the PI3K pathway, with or without chemotherapy. We are recommending a combination of Everolimus plus chemotherapy.

The second patient had a completely different profile. Indeed, the degree of drug resistance was quite striking. A three-drug combination was among the most active from almost two dozen drugs tested.  The other option appeared to be a new class of drugs called the cyclin dependent kinase (CDK) inhibitors.

On a functional level, we used targeted drugs to probe for sensitivity to inhibitors of these cancer signal pathways. Unlike genomic profiles that tell you whether the gene is present or absent, we can tell whether the gene is driving the tumor. Functional profiling.

One patient is now under my care and the other will begin treatment under the care of a colleague in Orange County, CA. We will await results of these assay-directed therapies and wish these two young patients every success.

Rare Tumors – Challenges and Triumphs

When I am asked how our EVA-PCD laboratory platform might best be applied, I have several responses.

On the one hand, there is my catchphrase, “we cure the curable, treat the treatable and avoid futile care.” What I mean by this is that patients with potentially curable malignancies, e.g., small cell lung cancer, previously untreated ovarian, non-Hodgkin lymphoma, and some leukemias should receive the most effective treatment first line, in order to enhance the likelihood of a cure.

The majority of our patients fall into the second category, those whose tumors can be treated but are less likely to be cured. They include recurrent breast, newly diagnosed lung or pancreas, and colorectal cancer among others.

Finally, in those patients for whom very few options exist, it is arguable that they are best served, when found drug resistant, by avoiding the toxicity of ineffective therapy, or what is known as futile care.

The other way I describe our platform is to explain its capacity to explore treatment options where no reliable guidelines exist. These rare malignancies offer the opportunity to examine a broad array of treatment options, including signal transduction inhibitors in pursuit of heretofore-unrecognized therapeutic directions. Just such a case was submitted to our laboratory this spring

The patient, a 56-year old woman from Brazil, presented in February with a large mass in the left axilla. Biopsy confirmed for an ER, PR and HER2 negative (triple negative) epithelial neoplasm with a proliferative index of 80 percent. The only positive findings were p63 antigen and cytokeratins. Work-up revealed extensive metastatic disease but no other primary could be identified.

The patient underwent surgery followed by aggressive multi-agent chemotherapy. The disease rapidly progressed. Second line therapy proved ineffective. At this point a tissue sample was submitted to our lab. The EVA-PCD analysis revealed an unusual profile with a high degree of activity for sorafenib combinations.  Sorefenib was originally developed as BRAF inhibitor and ultimately received FDA approval for the treatment of advanced kidney and liver tumors, associated with the drugs cross reactivity as a VEGF inhibitor. The patient’s study also revealed persistent activity for the beta tublin inhibitors vinorelbine and paclitaxel. The treating physician used our profile to create a novel combination of vinorelbine, paclitaxel combined with sorafenib.

The pretreatment PET CT obtained in June, revealed complete replacement of the liver and extensive soft tissue and nodal metastasis to the lungs, mediastinum, retroperitoneum, as well as innumerable boney metastasis. After failing the previous chemotherapies the patient began this novel drug combination in mid June.

When I arrived in my office this week, I was met with an email that had as an attachment a slide set from a tumor board presentation that described this patient. The introductory slide was, “Tumores Raros.”(Portuguese for Rare Tumors)  Included in the presentation was the patient’s history, pathology, immunohistochemistry, treatment overview and serial CT/PET scans. The final slide compared June 2013 PET CT (taken before she began our combination) with an August 2013, (taken after 2 cycles of therapy). The results could not have been more different.  The patient had achieved a complete remission. Gone was the extensive hepatic disease. Gone were the boney metastasis. Gone were the dark nodal mets that had scattered across her torso and abdomen like shotgun pellets on an x-ray image. Contrary to every expectation this patient had responded to a drug combination that no one had ever heard of.  No one including her treating physician and me.

These experiences remind us that every patient is a unique story, unfolding in real time. This is a stellar example of personalized cancer care, a gleaming testament to the laboratory’s capabilities and even more so to the dedication of the treating physician who broke with all tradition to treat this patient correctly. I am honored to work with this courageous colleague and delighted by this spectacular outcome.

Do We Already Have the Tools We Need to Cure Cancer?

The rapid-fire sequence of the annual American Association of Cancer Research (AACR) meeting, held in May, followed by the annual American Society of Cllinical Oncology (ASCO) meeting, held in June, provides the opportunity to put scientific discoveries into perspective as they find their way from theoretical to practical.

Members of AACR, the basic science organization, ponder deep biological questions. Their spin-offs arrive in the hands of members of ASCO as Phase I and Phase II trials, some of which are then reported at ASCO meetings.

Many of the small molecules my laboratory has studied over the years are now slowly making their way from “Gee Whiz” to clinical therapy. At the ASCO meeting I attended many of the Phase I sessions, where alphabet soup compounds had their first “in-human” trials. As most of these compounds are familiar to me, I was very interested in these early, though highly preliminary, results.

Departing from one Developmental Therapy (Phase I) session, with visions of signal transduction pathways in my head, I attended a poster discussion on triple negative breast cancer. For those of you unfamiliar with the term, it refers to an increasingly common form of breast cancer that doesn’t mark for the usual estrogen, progesterone, or HER-2 features. Often occurring in younger patients, this form of breast cancer can be aggressive and unresponsive to some forms of therapy. Much work has gone into defining sub-types of this disease and slow progress is being made.

As I examined the posters, one caught my eye, “Clinical Characteristics and Chemotherapy Options of Triple Negative Breast Cancer: Role of Classic CMF regimen. (Herr, MH et al, abstract #1053, ASCO 2012.) What these investigators showed in a series of 826 breast cancer patients was that those treated with the oldest drug combination for breast cancer (CMF) did better than those who received the more modern and more intensive anthracycline or taxane-based regimens. CMF, originally developed by Italian investigators in the 1970s, was the principal therapy for this disease for two decades before it was replaced, first by anthracycline and later by taxane-based treatments. What struck me was the unexpected superiority of this old regimen over its more modern, toxic and expensive brethren.

I began to wonder about other modern therapies and their real impact upon cancer outcomes. One study in HER-2 positive patients revealed relative equivalency between weekly taxol, every three-week Taxotere and Abraxane-based therapy. Once again, the cheaper, older, less toxic Taxol regimen proved superior. While most of the attendees at the ASCO meeting were considering how the newest VEGF inhibitor Regorafenib, or the addition of aflibercept, might impact their practices, I was somewhat underwhelmed by the results of these statistically significant, but clinically marginal survival advantages, all associated with great expense.

As I pondered the implications of the CMF results in triple negatives and those of the taxol results in HER-2 positives, I considered other old-fashioned therapies with newfound potential. Among them, losartan, the angiotensin antagonist that influences tumor stroma or the results of an earlier published study that identified intraconazole (a widely available anti-fungal therapy), as an inhibitor of the hedgehog pathway. While the pharmaceutical industry promotes the use of vismodegib, a hedgehog inhibitor for basal cell skin cancer, and dozens of trials examine VEGF and FGF inhibitors, I wondered whether losartan or intraconazole or other simple compounds and combinations might not already provide many of the tools we need. Is it possible that effective treatments for cancer are at hand?

Lacking the tools to decipher the signals and combine the agents to greatest effect, are we destined to continue to blindly administer increasingly expensive, toxic, yet arguably no more effective therapies? With the myriad of drugs and combinations available today, might it be that we “can’t see the forest for the trees.”

Emerging Therapies in Breast Cancer: a Focus on Triple Negative Disease

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 EVA-PCD™ 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.