Originally published as JCO Early Release 10.1200/JCO.2008.20.0683 on December 8 2008

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Time to Shift the Focus of the War: It Is Not All About the Enemy

John L. Marshall

Division of Hematology/Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Hospital, Washington, DC

Since the war on cancer was declared in 1971 by Richard Nixon, we have made significant strides in the treatment of cancer. As in traditional wars, our primary strategy has been to understand and control the behavior of the tumor—or the enemy—itself. We began by using simple histopathology as a means to distinguish one cancer type from another. In this way, we have distinguished tumors on the basis of differentiation, invasiveness, signet rings, large cells, small cells, clear cytoplasm, no cytoplasm, necrosis, mitosis, lymph nodes positive, and lymph nodes negative. Histopathology has proved extremely useful in determining prognosis, but rarely has it taught us anything about treatment choices. More recently, we have shifted our focus to the molecular analysis of tumors at both protein and genetic levels. The molecular profile of tumors has provided us with an improved prognostic ability, but more importantly, it has provided us with more refined, targeted therapies. As the best example, no physician would attempt to fight a battle against breast cancer without knowing the hormone receptor and human epidermal growth factor receptor 2 status of the enemy: the patient's tumor. As we uncover new enemy targets and new weapons to match, we fully anticipate that we will eventually win the war; it is merely a matter of finding the right targets and the right weapons. We have invested heavily in trying to uncover the secrets of the enemy. New technologies, such as gene microarrays, proteomic analyses, and the measurement and analysis of circulating cancer cells, have all been developed so we can better understand the tumor itself in the hope of developing better therapeutics. In fact, the entire focus of translational research is to analyze what is happening at the tumor level, and make therapeutic decisions on the basis of this. In the drug development world, the holy grail of obtaining paired tumor biopsies has proved difficult, not only because patient compliance with this approach is poor, but also because the data obtained from this process are often limited. In obtaining a tumor biopsy, we have caught the enemy, but we are not sure what questions we should be asking, or even how to interpret the answers we obtain. We have often followed small leads obtained from such analyses (for example, epidermal growth factor receptor expression as a determinant of epidermal growth factor receptor antibody efficacy), and discovered years later that we had it all wrong. In fact, the more we understand about the molecular pathways of cancer, the more complicated and redundant they seem.

One of the more dramatic examples of our lack of progress in understanding the enemy has been in the world of adjuvant therapy. We continue to attack (treat) a large number of patients in the hope that they are harboring the enemy (micrometastatic disease). Our ability to measure and determine who should get treatment in this setting, and which treatment should be delivered, continues to fall far short of our goals as officers in the war, and would be unacceptable in any other area of medicine. As we have come to recognize in our current global military efforts, we in cancer research must increase the focus on the internal role we play in the conflict with regard to the host response to the tumor.

The lay literature is full of references to a deficient immune system as a cause of cancer, and any number of remedies to enhance one's immune response. In fact, we are frequently called on by patients to evaluate over-the-counter supplements that claim to enhance immune response. I feel quite uneducated when explaining to a patient that I simply do not understand the immune system well enough to answer. Is the vocal majority correct? Is cancer caused by a deficient immune system?

What we must first remember is that the immune system is designed to detect foreign invaders, and avoid our own cells. With few exceptions, the immune system does not appear to recognize cancers within an individual as foreign, because they are actually part of the self. (The parallel to our current military efforts to recognize the enemy is noteworthy.) There are those within the oncologic community who believe that immune therapies and the immune system can play an important role in the treatment and prevention of cancer. There are others who believe that the immune system is never going to play an important role, a belief supported by decades of failed clinical trials. However, those of us who have focused on this area are encouraged by the rare but consistent durable responses that have been observed in patients with advanced cancer using immune-based therapies. It is these events that drive us to believe that the immune system could be harnessed and used as an effective anticancer therapy, if we could only gain a better understanding of its mechanisms of action. A logical place to start is at the tumor-host interface, to see what, if anything, the immune system is doing.

For 20 years, relatively simple histopathologic investigations have suggested that immune response does help predict outcomes in patients.¹ In the last decade, we have made additional improvements in our understanding of the function and regulation of the immune system. Key among these discoveries is the importance of T regulatory cells in controlling the immune system. A series of recent publications has emphasized the importance of T regulatory cells in patients with a variety of cancers. Research has demonstrated that T regulatory cells correlate with angiogenesis and prognosis in endometrial adenocarcinomas;² T regulatory cells worsen the prognosis of hepatocellular carcinoma;³ important interactions occur between T regulatory cells and CTLA4, a new therapeutic target;⁴ and the percentage of T regulatory cells before therapy predicts outcome in patients who are undergoing immune-based therapies.^5,6 Before that time, a series of interesting studies had demonstrated that the lymphocytic infiltrate and type of lymphocytes within the infiltrate were strong predictors of outcome in patients who had resected cancers. In these studies, it was found that a high density of forkhead box protein P3–positive (FOXP3+) T regulatory cells was associated with poor outcome. The presence of T regulatory cells in the tumor was believed to be a negative prognostic indicator, because of their negative impact on immune response, in general, thus equating to a higher recurrence rate. Most recently, Graziano et al⁷ demonstrated again that low levels of FOXP3+ cells in gastric cancers predict significantly improved outcome, a more powerful predictor than anything but stage. This T regulatory story is beginning to look rather consistent.

In this issue, Salama et al⁸ have published their study to determine the prognostic significance of FOXP3 lymphocytes in colorectal cancers. They analyzed a large data set of 593 stage II and 374 stage III colorectal cancers. These tumors were then analyzed for a variety of prognostic markers (typical histopathology except for microsatellite instability), and most importantly, for the tumor-infiltrating lymphocytes within the tumor, compared with those in the normal surrounding stroma. Their findings are the opposite of those of others, in that patients who had a high density of FOXP3+ cells within their tumors had better outcomes. Why their results are different from those of prior studies is still unclear. However, their data carry strong clinical implications for decision making. At the least, their data tell us that the host immune response to the tumor plays an important role in prognosis for patients with stage II and stage III colorectal cancer. The data also tell us that the host is interacting with the tumor, and influencing the outcome.

Should we start testing colon cancer specimens for FOXP3+ lymphocytes? The authors themselves suggest that this type of analysis would be useful in decision making on an individual-patient basis. However, because of broad skepticism about immune response and the unusual results that were observed, it is my prediction that this kind of analysis will not be routinely incorporated into decision making in patient care in the near future. For the present, we will continue to rely on our histopathologic view of cancer in an individual as our primary data source for treatment decisions.

Molecular markers are making their way into colon cancer treatment. On the basis of an analysis of the tumors of slightly more than 100 patients obtained nearly two decades ago, Sargent et al⁹ demonstrated that patients with stage II cancer with a high-frequency microsatellite instability genotype failed to benefit from chemotherapy, and in fact, may have been harmed by chemotherapy. This is a provocative observation, and many are changing their practice patterns immediately, before the completion of the ongoing prospective randomized trial, which would give us a clearer answer. Salama et al⁸ have provided us with a large data set that could add to our current definitions of high-risk colon cancer and chemotherapy decision making. However, I know of no prospective colon cancer trial that plans to analyze tumors for FOXP3+ or any host response measures. The fact that these new data are in stark contrast to prior findings should increase our zeal to understand the host response to the tumor.

In summary, I believe our increased understanding of the immune system and our increasing recognition of the importance of host-tumor interaction are leading us to develop new strategies and improvements in both prediction and therapeutic choices for patients with cancer. The deeper we probe the molecular changes in tumors, the more complicated our effort becomes. I suspect that the same will not be true for the host response to the tumor. There we will find a more predictable world that will be easier to control. The vast majority of our research and focus remains concentrated on the tumor itself and, based on the report by Salama et al and others, I believe that it is time to increase our focus on the host response to the tumor, and on our role in the war on cancer.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

NOTES

published online ahead of print at www.jco.org on December 8, 2008

REFERENCES

1. House AK, Watt AG: Survival and the immune response in patients with carcinoma off the colorectum. Gut 20:868-874, 1979[Abstract/Free Full Text]

2. Giatromanolaki A, Bates GJ, Koukourakis MI, et al: The presence of tumor-infiltrating FOXP3+ lymphocytes correlates with intratumoral angiogenesis in endometrial cancer. Gynecol Oncol 110:216-221, 2008[CrossRef][Medline]

3. Kobayashi N, Hiraoka N, Yamagami W, et al: FOXP3+ regulatory T cells affect the development and progression of hepatocarcinogenesis. Clin Cancer Res 13:902-911, 2007[Abstract/Free Full Text]

4. Kavanagh B, O'Brien S, Lee D, et al: CTLA4 blockade expands FOXP3+ regulatory and activated effector CD4+ T cells in a dose dependent fashion. Blood 112:1175-1183, 2008[Abstract/Free Full Text]

5. Leffers N, Gooden MJ, de Jong RA, et al: Prognostic significance of tumor infiltrating T-lymphocytes in primary and metastatic lesions of advanced stage ovarian cancer. Cancer Immunol Immunother [epub ahead of print on September 13, 2008]

6. Wada J, Yamasaki A, Nagai S, et al: Regulatory T-cells are possible effect prediction markers of immunotherapy for cancer patients. Anticancer Res 28:2401-2408, 2008[Abstract/Free Full Text]

7. Graziano F, Ruffini PA, Perrone G, et al: Association of intratumoral FOXP3-positive regulatory T cells (Tregs) with adverse prognosis in radically resected (R0), stage II-III gastric cancer (GC). J Clin Oncol 26:219s, 2008 (suppl; abstr 4527)

8. Salama P, Phillips M, Grieu F, et al: Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol [epub ahead of print on December 8, 2008]

9. Sargent DJ, Marsoni S, Thibodeau SN, et al: Confirmation of deficient mismatch repair (dMMR) as a predictive marker for lack of benefit from 5-FU based chemotherapy in stage II and III colon cancer (CC): A pooled molecular reanalysis of randomized chemotherapy trials. J Clin Oncol 26:180s, 2008 (suppl; abstr 4008)

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