|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2005.04.6672 on February 27 2006 © 2006 American Society of Clinical Oncology.
Tales From a Targeted TherapyBaylor College of Medicine, Houston, TX
Here a star, and there a star, A well-worn password in clinical oncology today is targeted therapy. It opens the door not only to important therapeutic advances, but also to funding, career advancement, and attention to individuals and institutions that use them. Tamoxifen is one of the oldest and perhaps the best characterized targeted therapy in oncology. In examining the newly published trial by Colleoni et al1 of tamoxifen after chemotherapy in premenopausal breast cancer patients, we can learn not only about breast oncology, but also more broadly about developing future targeted therapies and perhaps even a little bit about human nature. Learning from past travails can enhance future progress. Ultimately, as the results of International Breast Cancer Study Group Trial 13-93 clearly demonstrate, tamoxifen is powerfully therapeutic in premenopausal women after chemotherapy, reducing the risk of recurrence in these women with estrogen receptor (ER) –positive disease by nearly half.1 Given that 60% of breast cancers in premenopausal women are ER positive, tamoxifen's ability to reduce the total burden of breast cancer is two to three times that of trastuzumab. However, this achievement has been spoken more quietly compared with trastuzumab, without the rock star status afforded in recent American Society of Clinical Oncology sessions. I checked, and I have no albums by Dr Colleoni or his colleagues in my collection. Nevertheless, since tamoxifen first appeared in adjuvant trials in the mid-1970s (and it is now 2006), the developmental road proving this profound effect has been surprisingly long, winding, and filled with experiential insight that, in theory, should make us wise. In the 1980s and into the early 1990s, when this trial was initiated, it seemed that tamoxifen might not be effective in younger women with early-stage breast cancer.2 How did it happen that we lost our way, at least for a while? How did the phenomenon of reducing the risk of recurrence of breast cancer by nearly one half in premenopausal women, one of the largest effects in all of clinical oncology, remain hidden from plain view for so long? Here, the tale yields several illuminating possibilities. One may be that chemotherapy-induced amenorrhea, which occurs in more than half of patients, lowers systemic estrogen levels by 80% to 90%, reducing ligand-stimulated activation of ER and, in effect, becoming the primary targeted therapeutic intervention. The addition of tamoxifen may not be further effective in these patients, or its effect is attenuated or masked. We know that ovarian ablation alone is highly effective adjuvant therapy in ER-positive premenopausal breast cancer.3 Indeed, in the present study,1 chemotherapy-induced amenorrhea, which was loosely defined with a low bar of missing only one menstrual period, was associated with a 40% reduction in risk of recurrence in ER-positive patients, regardless of whether they received tamoxifen. The authors do not tell us whether amenorrhea in the ER-positive tamoxifen-treated patients was associated with a further reduction in recurrence compared with no amenorrhea in that group.
For patients who retain ovarian function, tamoxifen, as a competitive binder of ER, might be predicted to be less effective in a relative sea of ligand excess, as found in premenopausal women compared with postmenopausal women. Competition with estrogen for the receptor would be expected to reduce tamoxifen binding, lowering its efficacy. However, there is consistent evidence from small trials that tamoxifen is quite effective in premenopausal women with metastatic disease, with efficacy similar to ovarian ablation4-6; up to now, the activity of most therapies in metastatic disease has been closely mirrored in the adjuvant setting. Also, in one study of ER-positive early-stage breast cancer patients, 5 years of tamoxifen alone was as effective in women younger than 50 years as in women In theory, tamoxifen-sensitive cells might all be killed by the initial chemotherapy, so that following up with tamoxifen would not be effective. However, tamoxifen is already known to remain effective after chemotherapy, both in the metastatic setting8 and in the adjuvant treatment of postmenopausal women.2 In the adjuvant setting, the proportional reduction in risk achieved by tamoxifen is unchanged, whether chemotherapy is administered or not, as long as the tamoxifen duration is 5 years.9 Finally, for whatever reason, evidence suggests that ER-positive cells are relatively less sensitive to chemotherapy10 and, thus, may be more likely to remain after chemotherapy treatment. Some previous adjuvant trials in premenopausal women did seem to indicate that adding tamoxifen to chemotherapy was not effective.2,9,11-13 However, these trials were substantially underpowered and, therefore, may have yielded false-negative results. Underpowering or prolonged accrual periods, such as the period seen in the present study, can usually be remedied by greater cooperativity and sharing of credit. Nearly all important advances in clinical care in breast oncology have been accomplished through cooperative effort. In the rarefied arena where practice standards are overturned and established anew, the words "my research" can echo and break chillingly over progress. Compounding the issue of underpowering in the earlier studies, tamoxifen was also administered for what turned out to be a suboptimal period (1 to 2 years rather than 5 years). This is especially true for women younger than 50 years; the 1998 meta-analysis9 demonstrated that the effect of tamoxifen was particularly dependent on duration for this age group and that only with a treatment duration of 5 years was a beneficial effect clearly seen. Shorter durations of tamoxifen may overlap with temporary, chemotherapy-induced amenorrhea. In the portion of patients in whom ovarian function returns, longer duration tamoxifen, which could block the effect of resurging estrogen levels, becomes clearly more advantageous. Furthermore, to be effective, a targeted therapy must arrive at the target. Noncompliance or nonpersistence rates in trials of chronic oral therapy regularly approach at least 30% or more, as they did in this trial. It is probably higher in day-to-day practice. It is a significant problem of which many oncologists are unaware. Thus, the effect of the therapy can be significantly underestimated because, unbeknownst to the investigators and biostatisticians, noncompliance surreptitiously underpowers the study. It may be that younger patients are more likely to be noncompliant than older patients for a variety of reasons, making the effect of tamoxifen more difficult to detect in this particular age group. Perhaps hormonal therapy should be packaged and presented like oral contraceptives are packaged and presented so they can be scrutinized with like precision. Lastly, and possibly most importantly, the target for tamoxifen is found less frequently in tumors diagnosed in premenopausal women. ER is the only known therapeutic target for tamoxifen. Because of issues of poor methodology both in the United States and Europe, ER has been inaccurately measured at least 20% of the time, predominantly involving not only false-negative assays,14,15 but also false-positive assays. This lack of attention to standardization of methodology and to linking assay results and cutoffs to clinical trial outcomes gave rise to the notion that either it was not important to measure ER16 or ER-negative tumors responded to tamoxifen.2,16 In reality, this latter phenomenon was simply a result of false-negative assays. These reasons and the speculative possibility that tamoxifen might have clinically important alternative targets probably led the investigators to include ER-negative tumors in this study. The small subset of patients with undetectable ER seemed to have a worse outcome in this study when they received tamoxifen. Although it could be postulated that this is a result of the deleterious effects of tamoxifen acting on extra-ER targets or a result of agonistic effects on sequestered ER or other molecules, a more likely scenario is the play of chance alone. This latter explanation is reinforced by the findings of National Surgical Adjuvant Breast and Bowel Project (NSABP) B-23, in which 2,008 ER-negative patients (< 10 fmol/mg protein) were randomly assigned to receive or not receive tamoxifen for 5 years.17 There was no difference in outcome in terms of breast cancer recurrence in the two groups. In the NSABP study, patients having tumors with ER levels as high as 9 fmol or progesterone receptor–positive tumors were considered negative as opposed to the current study subset, which limited tumors to having an ER level or progesterone receptor level of essentially 0 fmol/mg. Whether this difference in cut points could obscure a deleterious effect of tamoxifen in this particular subset is unclear, although it remains a testable hypothesis in a reanalysis of this NSABP database. The problem of not measuring or inaccurately measuring the target when evaluating targeted therapy is destructive on a number of planes. It can lead researchers in the wrong direction, sometimes even for decades, as we see here for ER. It wastes large numbers of extremely valuable and vulnerable resources, the clinical trial participants, and exposes them to treatments from which they are unlikely to benefit but will experience all the toxicities. Not effectively measuring the presence of a defined therapeutic target substantially increases the risk of discarding a therapy that could be effective in specific subsets because the signal is drowned out against the noise created by the whole unmeasured population, most of whom might not have the target. Finally, mismeasurement of ER is a lethal medical error. In the United States, 190,000 patients are diagnosed with breast cancer annually, and approximately 50,000 are classified as ER negative. If 20% of these patients are actually ER positive, this would be some 10,000 patients. In this group, 3,000 deaths will occur. Conservatively, tamoxifen, when administered appropriately, could have prevented 1,000 to 1,500 of these deaths. Advocates of advancements in breast oncology should be up in arms. One wonders what the threshold of the fallen must be. It is time to accurately identify targets of targeted therapy and give this as high or higher priority than the drug development itself. Not to do so is anti-intellectual and a throwback to a lot of bad habits. Investigators who designate their approaches as therapeutically targeted should prospectively measure, with standardized methodology, the target (and/or its functionality) and make it an entry criterion, especially in phase III studies or studies that test proof of concept. Hopefully, current and future targeted therapies will not take 30 years to determine who may and may not benefit from a profoundly effective treatment, such as tamoxifen. The present study, in part because of the persistence of the investigators, did at last arrive into "day"; tamoxifen, indeed, is effective therapy after chemotherapy in premenopausal women with ER-positive tumors. Hopefully, the results of this trial will also further drive a stake through the heart of the idea that tamoxifen is effective in accurately measured ER-negative tumors. Importantly, perhaps, it demonstrates that the approach of testing a targeted therapy when the putative target is not known to be present is a low-yield clinical research strategy. The next steps on the remarkable journey of adjuvant hormonal therapy for breast cancer are to determine whether the combination of either tamoxifen or aromatase inhibitors with ovarian ablation is better than tamoxifen alone in premenopausal women, which is currently being tested in the Suppression of Ovarian Function Trial. Technology will also continue to sharpen the knife of molecular dissection, more deeply exposing and sharply defining the cellular structures that determine endocrine responsiveness and, thus, who will benefit or not. Additionally, further future therapeutic steps may be to block components of growth factor pathways that are intertwined with ER using small molecules that inhibit growth factor kinases, ras, or mTOR. Thus, there are many stars left in the molecular heavens, and now we have past tales to, hopefully, better speed the way. Author's Disclosures of Potential Conflicts of Interest The author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Author Contributions
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
REFERENCES
1. International Breast Cancer Study Group: Tamoxifen after adjuvant chemotherapy for premenopausal women with lymph node–positive breast cancer: International Breast Cancer Study Group Trial 13-93. J Clin Oncol 24:1332-1341, 2006 2. Early Breast Cancer Trialists' Collaborative Group: Systemic treatment of early breast cancer by hormonal, cytotoxic or immune therapy: 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet 339:71-85, 1992[Medline] 3. Jonat W, Kaufmann M, Sauerbrei W, et al: Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: The Zoladex Early Breast Cancer Res Association Study. J Clin Oncol 20:4628-4635, 2002 4. Klijn JGM, Beex LV, Mauriac L, et al: Combined treatment with buserelin and tamoxifen in premenopausal metastatic breast cancer: A randomized study. J Natl Cancer Inst 92:903-911, 2000 5. Ingle JN, Krook JE, Green SJ, et al: Randomized trial of bilateral oophorectomy versus tamoxifen in premenopausal women with metastatic breast cancer. J Clin Oncol. 4:178-185, 1986[Abstract] 6. Buchanan RB, Blamey RW, Durrant KR, et al: A randomized comparison of tamoxifen with surgical oophorectomy in premenopausal patients with advanced breast cancer. J Clin Oncol 4:1326-1330, 1986 7. Fisher B, Constantino J, Redmond C, et al: A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med 320:479-484, 1989[Abstract] 8. The Australian and New Zealand Breast Cancer Trials Group, Clinical Oncological Society of Australia: A randomized trial in postmenopausal patients with advanced breast cancer comparing endocrine and cytotoxic therapy given sequentially or in combination. J Clin Oncol 4:186-193, 1986[Abstract] 9. The Early Breast Cancer Trialists' Collaborative Group: Tamoxifen for early breast cancer: An overview of the randomised trials. Lancet 351:1451-1467, 1998[CrossRef][Medline] 10. Paik S, Shak S, Tang G, et al: A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351:2817-2826, 2005 11. Ingle J, Everson LK, Wieand HS, et al: Randomized trial to evaluate the addition of tamoxifen to cyclophosphamide, 5-fluorouracil, prednisone adjuvant therapy in premenopausal women with node-positive breast cancer. Cancer 63:1257-1264, 1989[CrossRef][Medline] 12. Andersson M, Kamby C, Jensen MB, et al: Tamoxifen in high-risk premenopausal women with primary breast cancer receiving adjuvant chemotherapy: Report from the Danish Breast Cancer Co-Operative Group DBCG 82B Trial. Eur J Cancer 35:1659-1666, 1999[CrossRef][Medline] 13. Tormey DC, Gray R, Gilchrist K, et al: Adjuvant chemohormonal therapy with cyclophosphamide, methotrexate, 5-fluorouracil, and prednisone (CMFP) or CMFP plus tamoxifen compared with CMF for premenopausal breast cancer patients: An Eastern Cooperative Oncology Group trial. Cancer 65:200-206, 1990[CrossRef][Medline] 14. Rhodes A, Jasani B, Balaton AJ, et al: Immunohistochemical demonstration of oestrogen and progesterone receptors: Correlation of standards achieved on in house tumours with that achieved on external quality assessment material in over 150 laboratories from 26 countries. J Clin Pathol 53:292-301, 2000 15. Allred DC, Land B, Paik S: Estrogen receptor expression as a predictive marker of the effectiveness of tamoxifen in the treatment of DCIS: Findings from NSAP Protocol B-24. Breast Cancer Res Treat 76:S36, 2002 (suppl 1) 16. Barnes D, Fentiman IS, Millis RR, et al: Who needs steroid receptor assays? Lancet 1:1126-1127, 1989[Medline] 17. Fisher B, Anderson S, Tan-Chiu E, et al: Tamoxifen and chemotherapy for axillary node-negative estrogen receptor-negative breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol 19:931-942, 2001
Related Article
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
50 years old (presumed to be pre- and postmenopausal, respectively), although no improvement in survival was noted at that time.
