Less is More in the Management of Breast Cancer

According to a study reported in the Journal of the American Medical Association, a randomized clinical trial that compared axillary lymph node removal to no lymph node removal in patients with node-positive breast cancer, there was no advantage for the more aggressive lymph node removal in terms of survival. The study reported by principal investigator Armando Giuliano has created a stir in the surgical, radiation and medical oncologic communities.

But, in the global scheme of breast cancer management, it really should not have.

The history of breast cancer management is one of diminishing returns. In the beginning of the turn of the last century, breast cancer was managed by the Halsted radical mastectomy. This procedure removed the breast, lymph nodes and pectoral muscle, skeletonizing the chest wall. Following that, Hagenson, Crile and other early pioneers documented the equivalence of the Halsted technique and the modified radical mastectomy. Decades later, Veronese at the National Cancer Institute of Italy proved that a quadrantectomy was equivalent to a modified radical mastectomy. This gave rise to the lumpectomy and finally the lumpectomy with sentinel lymph node dissection.

What we have learned, painfully, is that breast cancers have a trajectory all their own. Those tumors with a propensity for dissemination are likely to progress despite aggressive surgery and the associated morbidity and disfigurement while those tumors unlikely to recur cannot possibly benefit from more therapy. To some degree the outcome was independent of the aggressiveness of the surgery.

For years, tumor biologists have recognized that the process of dissemination and metastasis can begin when some cancers are less than 1/8 cm3 in volume — well below the level able to be detected by most diagnostic tools. What Dr. Giuliano’s study has shown us is that cancer biology determines the cancer outcome. The scalpel blade, however sharp, is a blunt instrument in the management of micro-metastatic disease. The cure of this and other solid tumor malignancies will increasingly depend upon effective systemic therapies and judicious use of local measures. Recognizing the fundamental role of systemic management, optimization of drug selection becomes only that much more important.

When all Else Fails, Do a History and Physical Examination

A few weeks ago, I was apprised of a 58-year-old gentleman with what appeared to be advanced lung cancer. He was scheduled for a diagnostic CT-guided biopsy and a core of tissue was being submitted to my laboratory. He was considering participating in our assay-directed clinical trial in which we test FDA approved drugs for lung cancer and selects the most active ones for each patient’s therapy. Although we hadn’t met, I knew that he had advanced disease and that he would likely be in need of chemotherapy.

The tissue sample as sometimes happens with core biopsies (as opposed to open surgeries), was too small for a full analysis. We focused only upon the principle platinum-based doublets and a few wells to test the EGFR TKI drugs (erlotinib and gefitinib). Unfortunately, the results did not reveal significant activity for the chemotherapy drugs tested. We did, however, suggest possible targeted therapy approaches. I was concerned that our consultation would consist of the option of experimental drugs or that he go on to a conventional standard drug combination off-study. The final option would be to consider an additional biopsy.

The patient arrived and a careful history and physical revealed that he was a strapping athlete and participant in triathlons — indeed, his symptoms of shortness of breath occurred during a recent 5K. He also said that he had gained weight, which I found surprising. I took the patient into the exam room and conducted a careful physical examination. No sooner did he remove his shirt but I noticed a strikingly protuberant “beer belly.” I was shocked, a tri-athlete? I asked if his feet swelled. He said no, but when I compressed his ankles my fingers left deep impressions. I weighed him, 216 lbs. He had been 199 lbs just two weeks earlier.

Then, I checked his pulse. The problem was I couldn’t really feel it; at least not when he took a breath. It came back only thready with expiration. I checked his blood pressure. He had a systolic pressure of about 88, which fell to undetectable with each inspiration. I looked to his neck and could see the jugular veins prominently distended. I walked with him back to the conference room where his two sons and wife awaited.

I told him that as a medical student at McGill University, the Canadian medical system was not as flush as the American. As such, we were taught the age-old art of physical diagnosis. And I told him that I had just clinically diagnosed cardiac tamponade — the phenomena when fluid, usually malignant, sometimes infectious surrounds the heart and compresses it so severely that it cannot marshal a blood pressure. Left untreated the patient will decompensate and if not attended to, often collapses and dies. To my estimation, he was close. I told him to go directly across the street to the hospital for an immediate x-ray, echocardiogram and fluid aspiration known technically as pericardiocentesis.

I told him not to stop to pay for my consultation; that we could take care of that another time. Upon arrival at the Emergency Department he was in florid tamponade with renal failure, hypotension and an almost unattainable pulse. The cardiac specialist arrived, the patient was taken to the cath lab and two liters of bloody fluid were removed from his pericardial sack. Twelve hours later, I visited this very nice patient in the Critical Care Unit, fluid draining from a catheter in the middle of his chest. He was a different person. Good color, average blood pressure, normal pulse, kidney function almost back to normal.

I shudder to think what might have happened if even a single additional day had passed. Oddly, when I arrived in the cardiac lab that night, the cardiologist congratulated me on the diagnosis and handed me 1.5 liters of fluid from the chest. The next morning, under the microscope, we isolated more cancer cells from his fluid than we could ever need, enabling us to test all the possible drugs and combinations for his treatment.

While I cannot say what the results will show, or whether I will find an active treatment for him, I can say with certainty that diagnostic skills drilled into me by the excellent clinicians at McGill School of Medicine, made it possible for this very pleasant gentleman to live to fight another day.

When Fluff Isn’t Enough

Recent press coverage from the San Antonio Breast Cancer Symposium (SABCS) touched upon the development of multi-gene predictors for clinical response in breast cancer. One report from that meeting described correlations between a laboratory assay model in use at the University of Pittsburgh and microarray analyses. However, the suggestion that this laboratory technique — described by its proponents as a chemosensitivity assay — could accurately identify gene profiles that would predict response seems at odds with the current literature.

Although the press coverage concluded that this technique showed “promising performance” it was largely exploratory and defined by the authors as a “validation study.” What is interesting is that a team of highly reputable investigators from M.D. Anderson recently reported a very negative study using a similar approach of identifying target genes in cell lines and then correlating them with patient outcomes. In the paper, published in the June 2010 issue of Breast Cancer Research and Treatment (Liedtke, C. et al. Breast Cancer Res Treat. 2010 Jun; 121(2):301-9) the authors reported “cell line derived predictors of response to four commonly used chemotherapy drugs did not predict response accurately in patients.”

Indeed, differential gene expression seemed only to correlate with paclitaxel. The authors found that false discovery rates were high for all other drugs tested. Thus, the report from the SABCS will need to be carefully examined to determine whether truly relevant clinically predictive information can be provided by this particular laboratory platform.

Renal Cancer Patient Update

A few weeks ago, I discussed the case of a patient with metastatic renal cell carcinoma who upon arrival in my office for a consultation, appeared to be too ill to even consider further treatment. Determined to persevere, he provided us with a sample to test and underwent our suggested regimen. As was mentioned previously, the patient was delighted with his response and has now returned to many normal activities, including working out at the gym.

What I did not expect was to receive a letter a few weeks later from his treating oncologist in Northern California. He was thrilled with the patient’s “massive” response, even commenting that the carcinoma had reacted more like a lymphoma than the typically aggressive and non-responsive renal cancer. In fact, the patient is doing so well he is being considered for a kidney removal (a procedure that he couldn’t have possible survived just weeks earlier).

Working in tandem with treating physicians is a partnership that benefits patients. It is exhilarating for myself and my team to hear about such favorable outcomes.