Molecular Cancer Therapeutics CTRC-AACR San Antonio Breast Cancer Symposium
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
Molecular Cancer Therapeutics 6, 1175-1179, April 1, 2007. doi: 10.1158/1535-7163.MCT-06-0674
© 2007 American Association for Cancer Research
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Braiteh, F.
Right arrow Articles by Kurzrock, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Braiteh, F.
Right arrow Articles by Kurzrock, R.

Editorial/Perspectives

Uncommon tumors and exceptional therapies: paradox or paradigm?

Fadi Braiteh and Razelle Kurzrock

Phase I Program, Division of Cancer Medicine, The University of Texas, M. D. Anderson Cancer Center, and the University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas

Requests for reprints: Razelle Kurzrock, Phase I Program, Division of Cancer Medicine, M. D. Anderson Cancer Center, Unit 422, 1515 Holcombe Boulevard, Houston, TX 77030-4009. Phone: 713-794-1226; Fax: 713-745-2374. E-mail: rkurzroc{at}mdanderson.org

Abstract

Why does it seem that, repeatedly, when a new treatment with a striking effect is discovered in the cancer field, it is effective for a very rare cancer type? For example, groundbreaking therapeutic discoveries have been made for extremely uncommon malignancies such as hairy cell leukemia, chronic myelogenous leukemia, seminoma, gastrointestinal stromal tumor, (del)5q myelodysplastic syndrome, and acute promyelocytic leukemia. In contrast, progress in the most common and most intensively studied tumors—lung, breast, prostate, and colon cancer—has been slow and incremental. We hypothesize that the reason for this phenomenon is that the pathophysiologic basis for a tumor being rare is one and the same as the reason that it may ultimately be so treatable. That is, if a cancer can be derived only via a single aberrant molecular genetic aberration, then it should be both rare and easily targeted by a molecular cancer therapeutic approach. If, on the other hand, many distinct pathways can lead to the development of a specific tumor type, it should occur much more commonly and be significantly more difficult to treat. The corollary to our hypothesis is the prediction that new therapies will continue to show their most salutary effects in rare cancers. Furthermore, only by stratifying the common tumors, especially when using targeted agents, into the molecular subsets of diseases that compose them are we likely to achieve a substantial effect in these disorders. [Mol Cancer Ther 2007;6(4):1175–9]

Currently, cancer is the second leading cause of death in the United States (1). Prostate, breast, lung, and colon cancers constitute more than half of the new cases of malignancies. These four malignant categories attract the major share of preclinical and clinical drug development research efforts, at least in part because of the financial incentive to address the most prevalent diseases. Yet, over the last three decades, remarkable progress has been made in the medical treatment of several of the rarest cancers, whereas only incremental therapeutic progress has occurred in the most common tumors.

Rare disorders are defined as those with a prevalence of <0.07% in the Unites States and <0.05% in Europe.1 Because of their low prevalence, by definition, there is much less expectation that the cost of developing a drug will be recovered from sales. Further, patients with common cancers are more likely to be represented in clinical trials than patients with rare tumors. Research in uncommon cancers also suffers from relatively fewer trials devoted to them. Indeed, the Orphan Drug Act was introduced in 1982 because it was felt that government incentives, such as 7 years of exclusive marketing, were needed to encourage research efforts in rare diseases (2). It is therefore rational to assume that the most striking therapeutic successes would be in the most common diseases. However, this is not so. Indeed, the paradox of cancer research is that the most dramatic treatment discoveries cluster in some of the least common cancers.

Our definition of a dramatic medical discovery is one in which a relatively simple systemic treatment produces responses (often complete or near-complete remissions) and/or markedly improves survival (by several years) in the majority of patients with that cancer. Examples of such therapeutic advances in very rare cancers include cisplatinum for seminomas (3), imatinib mesylate in gastrointestinal stromal tumors (4–6) and chronic myelogenous leukemia (5, 7–9), and lenalidomide in del(5q) myelodysplastic syndrome (refs. 10, 11; Table 1 ; refs. 12–20). Further, several very rare tumors show marked responses to several drugs. For example, idarubicin, all-trans retinoic acid, and arsenic are each extremely effective as single agents for the treatment of acute promyelocytic leukemia (21–24). Hairy cell leukemia is a very rare malignancy (25, 26) that occurs in only ~600 new cases per year in the United States. There are now at least three treatments for hairy cell leukemia, each with striking therapeutic efficacy as monotherapy: IFN-{alpha} (27), 2-chlorodeoxyadenosine (19, 20, 28–31), and pentostatin (12, 16, 32, 33). In the meantime, whereas some therapeutic advances have occurred in more common cancers, their effect is limited to smaller subsets of patients, less striking responses, and more modest extension of survival. For many patients, metastatic disease in these tumors remains difficult to treat and still portends a dismal prognosis.


View this table:
[in this window]
[in a new window]

  		Table 1. Agents approved by the Food and Drug Administration between 1990 and 2005 with a response rate of >70%

 
We postulate that the advances in rare tumors are not simply a paradox but rather that these are physiologically preordained and therefore represent a paradigm for understanding responses in cancer and, hence, for future therapeutic research. Indeed, our hypothesis is that the physiologic basis for tumors being rare is one and the same as the reason that they are ultimately so treatable. That is, these cancers are driven by a single aberrant mechanism, such as a single gene anomaly (Table 1; ref. 5). If a particular cancer can develop as a result of only a single, specific molecular abnormality, it is likely to be rare, and it is also more likely that therapy that effectively targets this aberration will have a significant effect on the majority of patients. On the other hand, if numerous distinct molecular defects can result in a certain type of tumor, as is likely in lung, colon, prostate, or breast cancer, then that type of tumor should occur commonly; at the same time, it is unlikely that a single, relatively simple therapy will have a dramatic effect on most of the patients being treated.

Between 1990 and 2005, the Food and Drug Administration in the United States approved 51 claims for new antineoplastic drugs (small molecules, antibodies, or cytotoxic), of which only 12 (21%) were initially indicated for the treatment of one of the four leading cancers (Table 2 ).2 The majority of new treatments were, however, approved for rare or very rare tumors (Fig. 1A and B ). The introduction in 1982 of the Orphan Drug Act could have facilitated the emergence of some of these drugs, but would not account for their predominance (34). Furthermore, the response rates for agents eventually approved were generally in the 5% to 40% range for common cancers, but were much higher for rare tumors (Fig. 2 ), easily exceeding 70% for some of them (Table 1). It could be argued that because of the small number of patients available to be enrolled in clinical trials of orphan drugs, only new treatments with a very high efficacy would successfully show a statistically significant benefit adequately to allow their approval. However, this does not explain why so many successful compounds cluster in the rare or very rare cancers.


View this table:
[in this window]
[in a new window]

  		Table 2. Agents approved, the initial cancer approval, average response rate, and success rate (SS = n / N x 1,000)

 

Figure 1
View larger version (26K):
[in this window]
[in a new window]

  		Figure 1. A, a review of all the new agents approved for the first time by the Food and Drug Administration between 1990 and 2005 and their initial indication. We excluded hormonal therapy agents, supportive therapy drugs, and newer indications for previously approved agents. We identified 51 agents approved for 21 different cancers. Additionally, we plotted in red the estimated incidence of these 21 cancers in the United States for the year 2005, in the order of from the most to the least frequent (1). This figure illustrates the disproportionately high number of agents approved for rare cancers compared with the most common types. B, calculation for each of the 21 cancer categories of the success rate SS as the ratio of the number (n) of new agents approved for that cancer over the number (N) of estimated new cases in the United States in 2005 (SS = n / N x 1,000). The ratio is inversely proportional to the incidence of cancers, showing an inverse relationship between the number of drugs approved and the incidence of that cancer (a mirror image) with a strong Spearman rank correlation test (R's = –0.94, P < 0.05).

 

Figure 2
View larger version (28K):
[in this window]
[in a new window]

  		Figure 2. Using the same 51 identified Food and Drug Administration–approved agents over the period 1990 to 2005, we calculated the average individual response rates for each cancer, the mean of response rates of all new agents approved for that particular malignancy.

 
Although superficially it may seem that common tumors will remain difficult to treat, our hypothesis, in fact, has a more important therapeutic research implication. That is, it is likely that common tumors are composed of numerous distinct "molecular" subsets of disease, and therapy that yields a robust response in a small percentage of patients (e.g., 2–10%) should not be abandoned, as has previously happened. Nor should a randomized survival study of the entire population of patients take place because an unselected group would almost certainly obscure the responsive subset, unless there were thousands of participants. Research investigators should be redirected to an intense effort to identify the molecular characteristics that are the hallmark of the responders. A recent example that highlights this issue involves epidermal growth factor receptor (EGFR) inhibitors. Gefitinib (35) and erlotinib (36) induce responses in about 10% (8.9% and 12%, respectively) of all enrolled patients with advanced non–small cell lung cancer. Yet, in patients not selected based on their EGFR mutation status, gefitinib provided no survival advantage despite remarkable salutary effects in some patients (37). More recently, it has been shown that the response to gefitinib (38) and the sensitivity to erlotinib (39) in patients with non–small cell lung cancer are pronounced in those individuals whose tumors bear mutations in the tyrosine-kinase domain of the EGFR gene (which occurs in ~10% of the lung cancer population; refs. 40–44).

Our hypothesis therefore suggests that the current strategy of treating entire populations of patients with what we think is a single tumor type in a similar fashion and abandoning therapy because of low response rate will continue to yield slow progress in cancer drug development. If the expectation that highly effective therapies will affect only small subsets of patients is accepted, a paradigm shift toward intense studies of these subsets, or indeed more personalized therapy, will be important if we are to make leaps, rather than small steps, in the field of molecular cancer therapeutics.

Footnotes

1 http://rarediseases.info.nih.gov/; accessed on 3-1-2006. Back

2 http://www.fda.gov/cder/cancer/approved.htm; accessed on 3-2-2006. Back

Received 10/31/06; revised 1/17/07; accepted 2/23/07.

References

  1. Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA Cancer J Clin 2005;55:10–30.[Abstract/Free Full Text]
  2. Orphan Drug Act. No. 97-414. 1983. Pub. L.
  3. Einhorn LH, Williams SD. Chemotherapy of disseminated seminoma. Cancer Clin Trials 1980;3:307–13.[Medline]
  4. Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002;347:472–80.[Abstract/Free Full Text]
  5. Tibes R, Trent J, Kurzrock R. Tyrosine kinase inhibitors and the dawn of molecular cancer therapeutics. Annu Rev Pharmacol Toxicol 2005;45:357–84.[CrossRef][Medline]
  6. Shinomura Y, Kinoshita K, Tsutsui S, Hirota S. Pathophysiology,diagnosis, and treatment of gastrointestinal stromal tumors. J Gastroenterol 2005;40:775–80.[CrossRef][Medline]
  7. Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 2001;344:1038–42.[Abstract/Free Full Text]
  8. Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002;346:645–52.[Abstract/Free Full Text]
  9. Kurzrock R, Kantarjian HM, Druker BJ, Talpaz M. Philadelphia chromosome-positive leukemias: from basic mechanisms to molecular therapeutics. Ann Intern Med 2003;138:819–30.[Abstract/Free Full Text]
  10. Giagounidis AA, Germing U, Strupp C, Hildebrandt B, Heinsch M, Aul C. Prognosis of patients with del(5q) MDS and complex karyotype and the possible role of lenalidomide in this patient subgroup. Ann Hematol 2005;84:569–71.[CrossRef][Medline]
  11. Rajkumar SV, Hayman SR, Lacy MQ, et al. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood 2005;106:4050–3.[Abstract/Free Full Text]
  12. Annino L, Ferrari A, Giona F, et al. Deoxycoformycin induces long-lasting remissions in hairy cell leukemia: clinical and biological results of two different regimens. Leuk Lymphoma 1994;14 Suppl 1:115–9.[Medline]
  13. Berman E, Heller G, Santorsa J, et al. Results of a randomized trial comparing idarubicin and cytosine arabinoside with daunorubicin and cytosine arabinoside in adult patients with newly diagnosed acute myelogenous leukemia. Blood 1991;77:1666–74.[Abstract/Free Full Text]
  14. Fenaux P, Le Deley MC, Castaigne S, et al.; European APL 91 Group. Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia. Results of a multicenter randomized trial. Blood 1993;82:3241–9.[Abstract/Free Full Text]
  15. Frankel SR, Eardley A, Heller G, et al. All-trans retinoic acid for acute promyelocytic leukemia. Results of the New York Study. Ann Intern Med 1994;120:278–86.[Abstract/Free Full Text]
  16. Golomb HM, Dodge R, Mick R, et al. Pentostatin treatment for hairy cell leukemia patients who failed initial therapy with recombinant {alpha}-interferon: a report of CALGB study 8515. Leukemia 1994;8:2037–40.[Medline]
  17. Grever M, Kopecky K, Foucar MK, et al. Randomized comparison of pentostatin versus interferon {alpha}-2a in previously untreated patients with hairy cell leukemia: an intergroup study. J Clin Oncol 1995;13:974–82.[Abstract]
  18. Piro LD, Ellison DJ, Saven A. The Scripps Clinic experience with 2chlorodeoxyadenosine in the treatment of hairy cell leukemia. Leuk Lymphoma 1994;14 Suppl 1:121–5.[Medline]
  19. Robak T, Krykowski E, Blasinska-Morawiec M, Urbanska-Rys H. Treatment of patients with hairy cell leukemia with 2-chloro-2'-deoxyadenosine (2-CdA). Arch Immunol Ther Exp (Warsz) 1994;42:25–9.[Medline]
  20. Vogler WR, Velez-Garcia E, Weiner RS, et al. A phase III trial comparing idarubicin and daunorubicin in combination with cytarabine in acute myelogenous leukemia: a Southeastern Cancer Study Group Study. J Clin Oncol 1992;10:1103–11.[Abstract]
  21. Soignet SL, Frankel SR, Douer D, et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 2001;19:3852–60.[Abstract/Free Full Text]
  22. Wiernik PH, Banks PL, Case DC, Jr., et al. Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia. Blood 1992;79:313–9.[Abstract/Free Full Text]
  23. Ohno R, Yoshida H, Fukutani H, et al.; Leukaemia Study Group of the Ministry of Health and Welfare. Multi-institutional study of all-trans-retinoic acid as a differentiation therapy of refractory acute promyelocytic leukemia. Leukemia 1993;7:1722–7.[Medline]
  24. Ohno R, Ohnishi K, Takeshita A, et al. All-trans retinoic acid therapy in relapsed/refractory or newly diagnosed acute promyelocytic leukemia (APL) in Japan. Leukemia 1994;8 Suppl 3:S64–9.[Medline]
  25. Bernstein L, Newton P, Ross RK. Epidemiology of hairy cell leukemia in Los Angeles County. Cancer Res 1990;50:3605–9.[Abstract/Free Full Text]
  26. Staines A, Cartwright RA. Hairy cell leukaemia: descriptive epidemiology and a case-control study. Br J Haematol 1993;85:714–7.[Medline]
  27. Quesada JR, Reuben J, Manning JT, Hersh EM, Gutterman JU. {alpha}-Interferon for induction of remission in hairy-cell leukemia. N Engl J Med 1984;310:15–8.[Abstract]
  28. Carson DA, Piro LD, Wasson DB, Carrera CJ, Beutler E. Activity of 2-chloro-2'-deoxyadenosine in chronic lymphocytic leukemia, hairy cell leukemia, and autoimmune hemolytic anemia. Adv Exp Med Biol 1989;253A:427–31.
  29. Lill MC, Golde DW. Treatment of hairy-cell leukemia. Blood Rev 1990;4:238–44.[CrossRef][Medline]
  30. Estey EH, Kurzrock R, Kantarjian HM, et al. Treatment of hairy cell leukemia with 2-chlorodeoxyadenosine (2CdA). Blood 1992;79:882–7.[Abstract/Free Full Text]
  31. Seymour JF, Kurzrock R, Freireich EJ, Estey EH. 2-Chlorodeoxyadenosine induces durable remissions and prolonged suppression of CD4+ lymphocyte counts in patients with hairy cell leukemia. Blood 1994;83:2906–11.[Abstract/Free Full Text]
  32. Spiers AS, Parekh SJ, Bishop MB. Hairy-cell leukemia: induction of complete remission with pentostatin (2'-deoxycoformycin). J Clin Oncol 1984;2:1336–42.[Medline]
  33. Seymour JF, Talpaz M, Kurzrock R. Response duration and recovery of CD4+ lymphocytes following deoxycoformycin in interferon-{alpha}-resistant hairy cell leukemia: 7-year follow-up. Leukemia 1997;11:42–7.[CrossRef][Medline]
  34. Haffner ME. Adopting orphan drugs-two dozen years of treating rare diseases. N Engl J Med 2006;354:445–7.[Free Full Text]
  35. Kris MG, Natale RB, Herbst RS, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 2003;290:2149–58.[Abstract/Free Full Text]
  36. Shepherd FA, Rodrigues PJ, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123–32.[Abstract/Free Full Text]
  37. Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005;366:1527–37.[CrossRef][Medline]
  38. Han SW, Kim TY, Hwang PG, et al. Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol 2005;23:2493–501.[Abstract/Free Full Text]
  39. Tsao MS, Sakurada A, Cutz JC, et al. Erlotinib in lung cancer—molecular and clinical predictors of outcome. N Engl J Med 2005;353:133–44.[Abstract/Free Full Text]
  40. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129–39.[Abstract/Free Full Text]
  41. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497–500.[Abstract/Free Full Text]
  42. Cappuzzo F, Hirsch FR, Rossi E, et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst 2005;97:643–55.[Abstract/Free Full Text]
  43. Pao W, Miller VA. Epidermal growth factor receptor mutations, small-molecule kinase inhibitors, and non-small-cell lung cancer: current knowledge and future directions. J Clin Oncol 2005;23:2556–68.[Abstract/Free Full Text]
  44. Yang SH, Mechanic LE, Yang P, et al. Mutations in the tyrosine kinase domain of the epidermal growth factor receptor in non-small cell lung cancer. Clin Cancer Res 2005;116:2106–10.



This article has been cited by other articles:


Home page
 Molecular Cancer TherapeuticsHome page
J. Rodon, V. DeSantos, R. J. Ferry Jr., and R. Kurzrock
Early drug development of inhibitors of the insulin-like growth factor-I receptor pathway: Lessons from the first clinical trials
Mol. Cancer Ther., September 1, 2008; 7(9): 2575 - 2588.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
Y. C. Ip, S. T. Cheung, Y. T. Lee, J. C. Ho, and S. T. Fan
Inhibition of hepatocellular carcinoma invasion by suppression of claudin-10 in HLE cells
Mol. Cancer Ther., November 1, 2007; 6(11): 2858 - 2867.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Braiteh, F.
Right arrow Articles by Kurzrock, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Braiteh, F.
Right arrow Articles by Kurzrock, R.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online