To the Editor: With regard to the reports by Piccart-Gebhartand colleagues and Romond and colleagues (Oct. 20 issue)1,2on adjuvant trastuzumab, I have two concerns. The first is thatstatistics based on immature data are not necessarily significant.As an example, I cite the landmark 1976 report by Bonadonnaand colleagues,3 which established adjuvant chemotherapy withcyclophosphamide, methotrexate, and fluorouracil (CMF) for node-positivebreast cancer. They reported an extraordinary benefit in progression-freesurvival among postmenopausal patients at 27 months (P=0.001).However, at 36 months,4 there was less benefit (P=0.16), andat 20 years,5 there was no survival benefit from having receivedCMF. If Bonadonna et al. had terminated the study at 27 months,it would have been many years before a researcher would havedared to have a control group receiving no chemotherapy in astudy of postmenopausal breast cancer.
The second concern is the risk of long-term cardiac effects.The dire consequences of irradiating too much of the heart inpostoperative patients with breast cancer were not understooduntil more than 15 years after treatment. Since cardiac sideeffects of trastuzumab are not seen in laboratory animals, wehave no long-term data. This uncertainty should dampen our enthusiasmwhen prescribing adjuvant trastuzumab for patients with low-risk,HER2-positive breast cancer.
Stuart G. Gilbert, M.D. Maine Medical Center Portland, ME 04102 gilbes{at}spectrummg.com
References
Piccart-Gebhart MJ, Proctor M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in Her2-positive breast cancer. N Engl J Med 2005;353:1659-1672. [Free Full Text]
Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable Her2-positive breast cancer. N Engl J Med 2005;353:1673-1684. [Free Full Text]
Bonadonna G, Brusamolino E, Valagussa P, et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med 1976;294:405-410. [Abstract]
Bonadonna G, Rossi A, Valagussa P, Banfi A, Veronesi U. The CMF program for operable breast cancer with positive axillary nodes: updated analysis on the disease-free interval, site of relapse and drug tolerance. Cancer 1977;39:Suppl:2904-2915. [CrossRef][ISI][Medline]
Bonadonna G, Valagussa P, Moliterni A, Zambetti M, Brambilla C. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer. N Engl J Med 1995;332:901-906. [Free Full Text]
To the Editor: After preoperative chemotherapy, HER2 statusmay change from that detected in the core biopsy specimen tothat in a sample of the resected breast cancer in 4 to 35 percentof cases as assessed by immunohistochemistry and in 13 percentof cases as assessed by fluorescence in situ hybridization (FISH).1,2,3,4,5HER2-negative status may convert to a positive status in 2 to9 percent1,2,3 of patients, as assessed by immunohistochemistryor FISH, and from a positive status to a negative status in15 to 26 percent of patients, as assessed by immunohistochemistry1,4,5or in 4 percent, as assessed by FISH.1 In our limited experience,after neoadjuvant therapy with epirubicin and paclitaxel, intwo of eight patients (25 percent) the HER2 status shifted topositive, and in one patient (12.5 percent) it shifted to negative,as assessed by immunohistochemistry. The increasing use of neoadjuvantchemotherapy and the possible introduction of trastuzumab inthis setting or in adjuvant treatment raise the question ofwhether HER2 status should be better defined before treatmentwith trastuzumab is started. In the Herceptin Adjuvant (HERA)study reported by Piccart-Gebhart et al., 11 percent of thoseHER2-positive patients (approximately 560 patients) were treatedwith neoadjuvant chemotherapy; how did the authors manage thecare of patients whose HER2 status changed?
Giuseppe L. Banna, M.D. Armando Santoro, M.D. Istituto Clinico Humanitas 20089 Rozzano (Milan), Italy gbanna{at}yahoo.com
References
Varga Z, Caduff R, Pestalozzi B. Stability of the HER2 gene after primary chemotherapy in advanced breast cancer. Virchows Arch 2005;446:136-141. [CrossRef][ISI][Medline]
Arens N, Bleyl U, Hildenbrand R. HER2/neu, p53, Ki67, and hormone receptors do not change during neoadjuvant chemotherapy in breast cancer. Virchows Arch 2005;446:489-496. [CrossRef][ISI][Medline]
Taucher S, Rudas M, Mader RM, et al. Influence of neoadjuvant therapy with epirubicin and docetaxel on the expression of HER2/neu in patients with breast cancer. Breast Cancer Res Treat 2003;82:207-213. [CrossRef][ISI][Medline]
Burstein HJ, Harris LN, Gelman R, et al. Preoperative therapy with trastuzumab and paclitaxel followed by sequential adjuvant doxorubicin/cyclophosphamide for HER2 overexpressing stage II or III breast cancer: a pilot study. J Clin Oncol 2003;21:46-53. [Free Full Text]
Vincent-Salomon A, Jouve M, Genin P, et al. HER2 status in patients with breast carcinoma is not modified selectively by preoperative chemotherapy and is stable during the metastatic process. Cancer 2002;94:2169-2173. [CrossRef][ISI][Medline]
To the Editor: In his editorial1 accompanying the reports ofthe results of the HERA trial and of the combined results reportedby Romond et al. of the National Surgical Adjuvant Breast andBowel Project (NSABP) trial B-31 and the North Central CancerTreatment Group (NCCTG) trial N9831, Hortobagyi suggests thatthe difference in disease-free survival between the two trialscan be explained by the difference in the schedule of trastuzumabadministration (concurrent vs. sequential) and by the use oftaxanes in only a minority of patients in the HERA trial. However,another consideration would be lead-time bias, because owingto the design of the trials, day 0 in the HERA trial was definedas after completion of adjuvant chemotherapy and a median of8.4 months after the diagnosis of breast cancer, whereas day0 in the North American NSABP B-31 and NCCTG N9831 trials wasthe day of the initiation of adjuvant chemotherapy with trastuzumab.Although the authors do not provide the relevant data, day 0in the NSABP B-31 and NCCTG N9831 trials would probably be onlyabout four months after diagnosis. I believe that this four-monthdifference is enough to explain the moderate difference observed.Reanalysis of the data with a common zero point (e.g., the dayof diagnosis or the day of surgery) would help to resolve thisissue.
Ioannis G. Gounaris, M.D. Derriford Hospital Plymouth PL6 8DH, United Kingdom johngounaris{at}hotmail.com
References
Hortobagyi G. Trastuzumab in the treatment of breast cancer. N Engl J Med 2005;353:1734-1736. [Free Full Text]
To the Editor: We were surprised by Hortobagyi's suggestionthat the findings of Sato et al.1 in their study of monoclonalantibodies against the epidermal growth factor receptor "encouragedscientists at Genentech to develop a mouse monoclonal antibodywith high affinity for the extracellular domain of the HER2transmembrane protein," since Genentech knew of more directevidence of the therapeutic potential of antibody against Her2/neu.Beginning in the early 1980s, we collaborated with Weinberg'slaboratory to develop a monoclonal antibody against Her2/neuand reported our findings in 1985 and 1988.2,3 Treatment ofHer2/neu-transformed cancer cells with the antibody reversedthe malignant phenotype in vitro, and the antibody inhibitedthe growth of rodent tumors expressing Her2/neu in vivo. Theseobservations stimulated the development by Genentech of an antibodyagainst human Her2/neu. Genentech scientists used an immunizationprotocol similar to ours, and the resultant antibodies weretested similarly.
Our comments on the history of the development of Her2/neu-targetedtherapeutics are in no way meant to minimize the work of thescientists at Genentech and collaborators in the developmentof trastuzumab (Herceptin). However, the etiquette of sciencedictates that the guiding published studies be recognized ina manner that maintains an accurate historical record.
Makoto Katsumata, Ph.D. Jeffrey A. Drebin, M.D., Ph.D. Mark I. Greene, M.D., Ph.D. University of Pennsylvania School of Medicine Philadelphia, PA 19104-6082 mkatsuma{at}mail.med.upenn.edu
Drs. Drebin and Greene are inventors of a patent and disclosurelicensed by Genentech dealing with monoclonal antibodies top185Her2/neu.
References
Sato JD, Kawamoto T, Le AD, Mendelsohn J, Polikoff J, Sato GH. Biological effects in vitro of monoclonal antibodies to human epidermal growth factor receptors. Mol Biol Med 1983;1:511-529. [Medline]
Drebin JA, Link VC, Stern DF, Weinberg RA, Greene MI. Down-modulation of an oncogene protein product and reversion of the transformed phenotype by monoclonal antibodies. Cell 1985;41:697-706. [CrossRef][Medline]
Drebin JA, Link VC, Greene MI. Monoclonal antibodies reactive with distinct domains of the neu oncogene-encoded p185 molecule exert synergistic anti-tumor effects in vivo. Oncogene 1988;2:273-277. [ISI][Medline]
To the Editor: Remarkable advances in the treatment of breastcancer with trastuzumab were recently reported, but the useof this drug can result in substantial financial losses forthe providers of the medication. Trastuzumab is sold by Genentechin 440-mg multidose vials. When a dose is prepared accordingto the package insert with the use of the supplied diluent,only 420 mg of trastuzumab per vial can be removed. The Centersfor Medicare and Medicaid Services (CMS) sets the payment fortrastuzumab on the basis of information supplied to the providerby Genentech, and the CMS assumes, on the basis of its calculations,that 440 mg can be obtained from each vial.
This difference of 5 percent is important because of the tremendouscost of trastuzumab. Each vial provides treatment for one tothree patients, and each vial costs about $2,300. The loss tothe provider is about $100 per vial. The total sales of trastuzumabin 2004 were $483 million. The loss incurred by providers wastherefore more than $20 million. These losses will increasewith expanded use of trastuzumab. The compelling nature of theresults reported challenges Genentech to provide this valuablemedication in a preparation that does not penalize providers.
David M. Mastrianni, M.D. 1 West Ave. Saratoga Springs, NY 12866 dmmastrianni{at}saratogahemonc.com
Dr. Gelber and colleagues reply: Dr. Gilbert expresses concernthat the statistical significance observed in the trials evaluatingadjuvant trastuzumab therapy for patients with HER2-positivebreast cancer could be lost with additional follow-up. He citesthe initial study of CMF by Bonadonna et al. as an example.The total sample size in the trial by Bonadonna et al. was 386patients, approximately 1/10 the size of the sample in eachof the reported trastuzumab trials. The magnitude of the treatmentdifference observed in the HERA trial after one year of medianfollow-up was substantial and highly significant. Even in theunlikely case that the observation and trastuzumab groups haveequivalent hazard rates beyond one year, the chance that thestatistical significance would be lost after four additionalyears of follow-up is less than 20 percent. Nevertheless, weacknowledge that the current results reflect a reduction inthe number of relapses among patients at high risk for earlyrecurrence and that determining the ultimate magnitude of thetreatment benefit for patients at risk for later recurrence,such as those with node-negative, hormone-receptor–positivedisease, requires further follow-up.
We agree that the lack of information about the long-term cardiaceffects of trastuzumab must be taken into account but are comfortedby increasing evidence suggesting that trastuzumab-induced cardiotoxicitymay be reversible.1 The risk can also be minimized by optimalpatient selection; in NSABP trial B-31, for instance, olderpatients and those who had preexisting cardiac dysfunction wereat highest risk for cardiac toxic effects.2 These issues shouldbe discussed with patients, who can then make an informed decision.
Drs. Banna and Santoro cite several studies reporting that theHER2 status may change after preoperative chemotherapy. Thenumber of patients included in these studies was small (usuallyfewer than 30), and all authors concluded that the observedchanges in the HER2 status should be considered nonsignificant.Understandably, there is currently more concern about potentialchanges in the HER2 status in patients receiving preoperativetrastuzumab in addition to chemotherapy. In the HERA trial,the treatment effect of trastuzumab was exactly the same forpatients who received neoadjuvant chemotherapy as for thosewho received only postoperative chemotherapy.
Max Mano, M.D. Jules Bordet Institute 1000 Brussels, Belgium
David Cameron, M.D. Western General Hospital Edinburgh EH4 2XU, Scotland
Richard D. Gelber, Ph.D. Dana–Farber Cancer Institute Boston, MA 02115
for the HERA Trial Study Team
References
Ewer MS, Vooletich MT, Durand J-B, et al. Reversibility of trastuzumab-related cardiotoxicity: new insights based on clinical course and response to medical treatment. J Clin Oncol 2005;23:7820-7826. [Free Full Text]
Tan-Chiu E, Yothers G, Romond E, et al. Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31. J Clin Oncol 2005;23:7811-7819. [Free Full Text]
Dr. Bryant and colleagues reply: Dr. Gilbert expresses concernthat the reports on NSABP trial B-31 and NCCTG trial N9831 andthe HERA trial are based on immature data. He cites as an exampleof the need for caution the early report by Bonadonna et al.of the statistical significance after 27 months of follow-upbut not in subsequent reports. We believe that the analogy isnot convincing, for several reasons. First, the preliminaryreport by Bonadonna et al. was based on 29 events in 209 postmenopausalpatients. The results of trial B-31 and trial N9831 are basedon 394 events in 3351 patients, and the HERA results are basedon 347 events in 3387 patients. Both studies were reported perprotocol, only after crossing prespecified reporting boundariesdesigned to prevent the release of premature data. The 1976Bonadonna study was not reported in this way. The analyses inthe NSABP B-31 and NCCTG N9831 trials and in the HERA trialindicated relative risk reductions for disease-free–survivalevents of 52 and 46 percent, respectively, with confidence intervalsruling out reductions of less than 41 to 33 percent, respectively.Data from these trials document a strong and statistically significantsubsequent benefit in patients who were alive and disease-freeentering their fourth year of follow-up. Bonadonna's data didnot.
Although short-term cardiotoxicity data have been published,we agree with Dr. Gilbert that the long-term cardiac effectsbeyond three years are not yet documented and must be closelyfollowed in the future. In this regard, continued follow-upof cardiotoxicity data is of critical importance.
John Bryant, Ph.D. National Surgical Adjuvant Breast and Bowel Project Pittsburgh, PA 1521
Edward Romond, M.D. University of Kentucky Lexington, KY 40536
Edith A. Perez, M.D. Mayo Clinic Jacksonville, FL 32224
Dr. Hortobagyi replies: Dr. Gounaris postulates that the delay in instituting trastuzumab therapy until after the completionof chemotherapy created a lead-time bias, which could explainthe differences in outcomes between the HERA trial and the combinedNorth American trials. However, starting the disease-free survivalcurves four months after the initiation of adjuvant therapyin the HERA trial would have the opposite effect, leading toan artificial improvement in disease-free survival as a resultof excluding patients in whom treatment failed during that interval.The remaining patients should have a better prognosis afterpatients with relapse are removed from the analysis.
We appreciate the perspective of Dr. Katsumata et al. on thesequence of events in the conceptual development of antibodytherapy to growth factors. Their contribution to the developmentof monoclonal antibody therapy for HER2 was clearly important,although the concept that monoclonal antibodies have antitumoractivity was already in the literature at the time of the firstpublication mentioned in their letter. Progress often resultsfrom consolidating knowledge from several sources; which aspect"encouraged scientists at Genentech" the most to develop trastuzumabcan be determined only by those scientists.
Gabriel N. Hortobagyi, M.D. University of Texas M.D. Anderson Cancer Center Houston, TX 77030
Dr. Mastrianni's letter was referred to Genentech, the manufacturerof trastuzumab, which offers the following reply: The problemwith reconstituting trastuzumab (Herceptin) is not uncommonamong products packaged in multidose vials. It results fromcompliance with the packaging regulations of the Food and DrugAdministration (FDA) and government price-reporting requirements.In accordance with FDA requirements for labeling multidose vials,the vials contain 440 mg of Herceptin. The actual amount physiciansobtain may differ because of variation in the technique usedto reconstitute the product with the supplied diluent and thenumber of withdrawals per vial.
As required by statute, the reimbursement of physicians forproducts administered to Medicare beneficiaries is set at 106percent of the average sale price. Accordingly, Genentech reportsits product price, which is based upon vial unit sales to wholesalers,to the CMS on a quarterly basis. Genentech is in full compliancewith all applicable FDA labeling and price-reporting requirementsfor Herceptin.
Hal Barron, M.D. Genentech South San Francisco, CA 94080
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