Every Cancer Patient’s Outcome is Important

Clinical oncologists can be divided into different camps. There are those who see patient outcomes as a means-to-an-end. Each clinical response provides a data point and when those data points reach critical mass they become reportable. These are the trialists. They see the world through a utilitarian lens. They use aggregate data, through sufficient patient accrual, to achieve significance. This, they hope, will lead practice-changing observations. Trialists populate academic centers and an ever-expanding number of “mega medical groups” that are now gobbling up private oncology practices. They apply metrics to gauge success, as their focus has moved away from individual patient needs toward the achievement of a “greater good” for the population as a whole. Statistical significance is the currency of their realm and clinical protocols their preferred tool.

In the other camp reside physicians, that dwindling cadre of doctors whose principal focus is the good response of each individual patient. They are the practitioners who eke out a living in an environment of diminishing returns. Having relinquished both autonomy and income over recent years, their one remaining reward is the benefit they can bring to each patient. With neither the desire nor ability to publish their results, individual patient survival becomes their paramount goal. Their job is to alleviate suffering, provide comfort and sponsor the health of their clients. Patients preparing to meet with a cancer specialist should consider carefully who is treating them – and why.

I was reminded of this when a 48-year-old gentleman recently requested an opinion. He had presented to an emergency room with a month-long history of sharp abdominal pain. The CT scan revealed extensive intra-abdominal disease, which upon endoscopic biopsy, proved to be of gastric (stomach) origin. He was immediately referred to an accomplished university-based clinical investigator for consultation.

Metastatic gastric cancer is a very difficult disease to treat. One bright spot has been the discovery that 20 percent of patients carry an epidermal growth factor receptor (HER-2) mutation that enables them to receive Herceptin-based therapy. As luck would have it, this patient did not carry the HER-2 mutation. The university investigator explained that there were limited treatment options. In light of his metastatic presentation, the doctor felt that aggressive, multi-agent chemotherapy might only engender toxicity. The patient was offered either single agent 5-FU for palliation or the opportunity to participate in a clinical trial. The patient considered his options and chose to seek an opinion with me.

20 percent response rateI reviewed the patient’s status and explained that while the opinion of the university investigator was valid it might underestimate the patient’s individual chance of response. I explained that gastric cancer statistics, like all medical statistics, are population based. That is, a 20 percent response rate does not mean that every patient gets 20 percent better, but instead, that 20 out of every 100 respond while 80 do not. Our job was to find out which group he belonged to.

The patient decided to undergo a biopsy and submitted tissue to Rational Therapeutics for EVA-PCD® analysis. The results were strikingly favorable with several drug combinations revealing both activity and synergy. After careful comparison, I recommended the combination of a Cisplatin, Taxotere and 5-FU (DCF), a regimen originally developed at the MD Anderson almost 10 years earlier.

On March 12th, the patient began treatment on an every-other-week schedule. As he did not circulate tumor markers like CEA or CA 19-9, there was no easy measure of his response so I elected to repeat the PET/CT after just two cycles. Much to my delight, the patient had achieved a complete remission with resolution of all measurable disease, including the bulky abdominal masses, numerous lymph nodes and the stomach. As I described the remarkable PET/CT results, the patient’s wife began to weep. Her husband, the father of their two young children, wasn’t dying after all. He was no longer a grim cancer statistic. With mother’s day approaching, this was the first good news that they had received in six months. At once, the patient began to discuss business trips, travel plans and family outings. He breathed a slow sigh of relief as he realized that, once again, he had a life.

Good outcomes, even in the worst diseases, occur in all oncology practices. Every doctor can regale you with the story of a patient who responded beautifully and went on to survive years beyond everyone’s expectations. The reason we remember these stories is because they occur so infrequently. Complete remissions in metastatic gastric cancer are vanishingly rare. That is the reason that the university investigator offered single agent 5-FU. It’s easy, nontoxic, well tolerated, but it also cures no one. The rationale is well established: Why poison patient’s you cannot cure? Playing the averages, this strategy is a winner. Yet, on an individual patient basis it may, in fact, be a very big loser.

What are we to do with the “non-average” patient? What about the outliers? Should we not, at least, try to find them? We do it with stocks, racehorses, Indy-drivers, real-estate investments and every underdog sports team in every league. It’s the outliers after all that we call winners.

Cancer patients are not clinical trial subjects. They are unique individuals with their own very unique biology. Every patient is an experiment in real time, an “N of 1.” We must respect the dignity of each individual and we are duty-bound to apply every tool at our disposal to assist him or her in the pursuit of his or her own very personal best outcome – providing truly personalized cancer treatment. This patient did not have a 20 percent response. Instead, he was one of the fortunate few who responded very well. And for him that response was 100 percent.

A New Target in Breast Cancer Therapy

In many ways the era of targeted therapy began with the recognition that breast cancers expressed estrogen receptors, the original work identified the presence of estrogen receptors by radioimmunoassay. Tumors positive for ER tended to be less aggressive and appear to favor bone sites when they metastasized. Subsequently, drugs capable of blocking the effects of estrogen at the estrogen receptor were developed.  Tamoxifen competes with estrogen at the level of the receptor. This drug became a mainstay with ER positive tumors and continues to be used today, decades after it was first synthesized.

Recognizing that some patients develop resistance to Tamoxifen, additional classes of drugs were developed that reduced the circulating levels of estrogen by inhibiting the enzyme aromatase, this enzyme found in adipose tissue, converts steroid precursors to estrogen.  Despite the benefits of these classes of drugs known as SERMS (selective receptor modulators), many patients break through hormonal therapies and require cytotoxic chemotherapy.

With the identification of HER-2 amplification, a new subclass of breast cancers driven by a mutation in the growth factor family provided yet a new avenue of therapy – trastuzumab (Herceptin). For HER-2 positive breast cancers Herceptin has dramatically changed the landscape. Providing synergy with chemotherapy this monoclonal antibody has also been applied in the adjuvant setting offering survival advantage in those patients with the targeted mutation.

Reports from the San Antonio breast symposium held in Texas last December, provide two new findings.

The first is a clinical trial testing the efficacy of pertuzumab. This novel monoclonal antibody functions by preventing dimerization of HER-2 (The target of Herceptin) with the other members of the human epidermal growth factor family HER-1, HER-3 and HER-4. In so doing, the cross talk between receptors is abrogated and downstream signaling in squelched.

The second important finding regards the use of everolimus. This small molecule derivative of rapamycin blocks cellular signaling through the mTOR pathway. Combining everolimus with the aromatase inhibitor exemestane, improved time to progression.

While these two classes of drugs are different, the most interesting aspect of both reports reflects the downstream pathways that they target. Pertuzumab inhibits signaling at the PI3K pathway, upstream from mTOR. Everolimus blocks mTOR itself, thus both drugs are influencing cell signaling that channel through metabolic pathways PI3K is the membrane signal from insulin, while mTOR is an intermediate in the same pathway. Thus, these are in truest sense of the word, breakthroughs in metabolomics.