Imatinib and pregnancy.

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excisionalonewillbeadequatetreatment.Theproblemremainshow-
ever,inselectingthepatientsforwhomradiationtherapycanbesafely
omitted.AsLagiosetalpointout,sparingpatientsunnecessarytreat-
ment and morbidity is a valid and important goal. However, we also
would mention that little or no difference in cardiac morbidity was
seen in a recent retrospective comparison of left- versus right-sided
breastcancerstreatedwithmodernradiationtechnique.8Inaddition,
arecentmeta-analysisshowedverylittlenonbreastcancermortalityin
recent trials of patients treated with breast-conserving surgery and
radiationtherapy.9Thepsychologicalimpactofalocalrecurrencealso
is worth mentioning. Although possibly not life-threatening, local
recurrence can be very distressing for some patients, who may elect
mastectomyforpsychologicalreasonsalone.
We agree that the best local therapy for various subgroups of
DCIS patients remains unclear. We believe that the best studies to
clarifythisareprospectivetrials.
Julia S. Wong
Department of Radiation Oncology, Dana-Farber Cancer Institute/Brigham and
Women’s Hospital, Harvard Medical School, Boston, MA
Susan C. Lester
Departments of Pathology, Brigham and Women’s Hospital, Harvard Medical
School, Boston, MA
Barbara L. Smith
Department of Surgery, Massachusetts General Hospital, Harvard Medical
School, Boston, MA
REFERENCES
1. Wong JS, Kaelin CM, Troyan SL, et al: Prospective study of wide excision
alone for ductal carcinoma in situ of the breast. J Clin Oncol 24:1031-1036, 2006
2. Anderson BO, Masetti R, Silverstein MJ: Oncoplastic approaches to partial
mastectomy: An overview of volume-displacement techniques. Lancet Oncol
6:145-157, 2005
3. Silverstein MJ, Recht A, Lagios MD (eds): Ductal Carcinoma in Situ of the
Breast (ed 2). Philadelphia, PA, Lippincott Williams and Wilkins, 2002, pp 185-204
4. Boland GP, Chan KC, Knox WF, et al: Value of the Van Nuys Prognostic
Index in prediction of recurrence of ductal carcinoma in situ after breast-
conserving surgery. Br J Surg 90:426-432, 2003
5. de Mascarel I, Bonichon F, MacGrogan G, et al: Application of the Van Nuys
Prognostic Index in a retrospective series of 367 ductal carcinomas in situ of the
breast examined by serial macroscopic sectioning: Practical considerations.
Breast Cancer Res Treat 61:151-159, 2000
6. Morrow M, Strom EA, Bassett LW, et al: Standard for the management of
ductal carcinoma in situ of the breast (DCIS). CA Cancer J Clin 52:256-276, 2002
7. Goldstein NS, Vicini FA, Hunter S, et al: Molecular clonality determination of
ipsilateral recurrence of invasive breast carcinomas after breast-conserving
therapy: Comparison with clinical and biologic factors. Am J Clin Pathol 123:679-
689, 2005
8. Patt DA, Goodwin JS, Kuo YF, et al: Cardiac morbidity of adjuvant radio-
therapy for breast cancer. J Clin Oncol 23:7475-7482, 2005
9. Clarke M, Collins R, Darby S, et al: Effects of radiotherapy and of differences
in the extent of surgery for early breast cancer on local recurrence and 15-year
survival: An overview of the randomised trials. Lancet 366:2087-2106, 2005
DOI: 10.1200/JCO.2006.07.0623
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Authors’ Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Imatinib and Pregnancy
TO THEEDITOR: WereadwithgreatinterestthearticlebyAult
etal1inarecentissueofJournalofClinicalOncology,describingthe
results of pregnancy among patients with chronic myeloid leuke-
mia (CML) treated with imatinib. We would like to add some
points and bring attention to some questions concerning imatinib
and pregnancy.
Tyrosine kinases (TKs) are one of the most critical groups of
signaling molecules for the cellular regulation of proliferation,
differentiation, survival, function, and motility, and various tu-
mors overexpress TKs, leading to uncontrolled mitogenic signals
totheneoplasticcells.Imatinib(GleevecorGlivec;Novartis,Basel,
Switzerland) is a small-molecule tyrosine kinase inhibitor active
against BCR-ABL, c-ABL, ARG, PDGF-r, and c-KIT.2Although
imatinib has been used primarily for cancers such as CML, use of
imatinibhasdemonstratedthattyrosinekinaseinhibitorscanhave
a wide therapeutic window and heralds the era of targeted cancer
and noncancer disease therapy.
Informationabouttheeffectsofdrugsonthedevelopingembryo
is derived primarily from animal experiments and case reports de-
scribing the outcomes of pregnancies complicated with drug. Some
drugscanbeteratogenicinsomeanimalspecies,butnotinhumans.In
preclinicalstudiesimatinibwasfoundtobeteratogenicinrats,butnot
in rabbits, and impaired spermatogenesis was observed in rats, dogs,
and monkeys; however, there was no evidence that imatinib was
genotoxic.Theseobservationsleadtoconcernsthatmentreatedwith
imatinibmayhavereducedspermcounts.Clinicalexperiencehasnot
shownthistobetruebecausemalepatientswhowerereceivingtreat-
ment of imatinib were partners in 18 pregnancies and four healthy
infants. Owing to teratogenicity data in rats (causing exencephaly or
encephalocele, and absent or reduced frontal and absent parietal
bones),itisrecommendedthatwomentreatedwithimatinibbeaware
of the potential teratogenicity of imatinib, and effective contracep-
tion should be used during imatinib therapy to prevent pregnancy.2
HensleyandFord2reported26pregnancies(15inclinicaltrials,11in
nonclinicaltrials)amongwomentakingimatinib.Mostofthepatients
opted for elective therapeutic abortions, and only three patients car-
ried their pregnancies to term. Two infants were healthy, and one
infant had hypospadias. Recently, eight patients with CML who be-
came pregnant while receiving imatinib therapy were reported from
different areas of the world.3-7All of the fetuses had been exposed to
imatinib during the first trimester, and four fetuses have also been
exposedtoimatinibduringthesecondandthirdtrimesters.Sixofthe
reported eight pregnancies proceeded to term with healthy infants,
and two were terminated with unsatisfactory outcomes—one had
spontaneousabortion4andtheotherhadadeadfetuswithmeningo-
cele.7Morerecently,Aultetal1reportedtheirexperienceon19preg-
nanciesinvolving18patients(10femaleandeightmalepatients)who
conceived while receiving imatinib for the treatment of CML. Three
pregnancies (involving two female patients and one male patient)
endedinspontaneousabortion,andonepatienthadanelectiveabor-
tion. All other pregnancies were uneventful. Two of 16 infants had
minorabnormalitiesatorshortlyafterbirth(hypospadiasinoneand
rotationofsmallintestineinanother)thatweresurgicallyrepaired.
The reported outcomes of pregnancies under treatment of ima-
tinib are satisfactory, but do not indicate that imatinib can be safely
recommendedduringthefirsttrimesterofgestation.Whatcanwedo
ifapatientwithCMLafterhavingachievedamolecularremission,or
another patient receiving imatinib for a different disease wishes to
become involved in a pregnancy? Since we know the outcome of
Correspondence
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discontinuation of imatinib therapy after achieving a molecular re-
mission,shallweuseimatinibinthesecondorthirdtrimester?What
canwedointheeventofinadvertentconceptiononimatinibtherapy?
Although it is difficult to answer these questions, in light of reported
cases,weconcludethatpatientswhoareundertreatmentofimatinib
atthemomentofconceptionmayhavenormalpregnancies.Wethink
thateachcaseshouldbeexaminedindividuallyintermsoftheaggres-
siveness of the disease, and decisions should to be individualized. In
conclusion,inthefaceofcomplicatedpregnancywithimatinib,both
social and humanitarian factors should be considered, and the main
aimshouldbetoensuerahealthymotherandahealthyinfantinboth
theshort-andlong-term.
Ridvan Ali, Fahir Ozkalemkas, Tulay Ozcelik,
Vildan Ozkocaman, and Atilla Ozkan
Division of Hematology, Department of Internal Medicine, Uludag University
School of Medicine, Bursa, Turkey
REFERENCES
1. Ault P, Kantarjian H, O’Brien S, et al: Pregnancy among patients with chronic
myeloid leukemia treated with imatinib. J Clin Oncol 24:1204-1208, 2006
2. Hensley ML, Ford JM: Imatinib treatment: Specific issues related to safety,
fertility, and pregnancy. Semin Hematol 40:21-25, 2003
3. Heartin E, Walkinshaw S, Clark RE: Successful outcome of pregnancy in
chronic myeloid leukemia treated with imatinib. Leukemia Lymphoma 45:1307-
1308, 2004
4. AlKindi S, Dennison D, Pathare A: Imatinib in pregnancy. Eur J Haematol
74:535-537, 2005
5. Ali R, Ozkalemkas F, Ozcelik T, et al: Pregnancy under treatment of imatinib
and successful labor in a patient with chronic myelogenous leukemia (CML):
Outcome of discontinuation of imatinib therapy after achieving a molecular
remission. Leuk Res 29:971-973, 2005
6. Prabhash K, Sastry PSRK, Biswas G, et al: Pregnancy outcome of two
patients with imatinib. Ann Oncol 16:1983-1984, 2005
7. Choudhary DR, Mishra P, Kumar R, et al: Pregnancy on imatinib: Fatal
outcome with meningocele. Ann Oncol 17:178-179, 2006
DOI: 10.1200/JCO.2006.06.9310
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Authors’ Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
INREPLY: WeappreciatethethoughtfulcommentsfromDrAli
et al. What to do about the therapy with imatinib is frequently an
important dilemma for a young patient with chronic myeloid leuke-
miawhowantstobecomepregnant.Thisisparticularlyimportantfor
femalepatients,althoughthepotentialconsequencesthatexposureto
imatinibmayhaveonthequantityandqualityofthesperm,andhow
these could affect the fetus also have to be considered. It is true that
patients who receive imatinib at the time of conception may have
normal pregnancies, but this is not always the case, and the data are
still limited. Open discussion with the patient, as proposed by Dr Ali
and colleagues, is very important, as is educating patients on these
issues at the start of therapy, just as one educates patients about the
goals of therapy and potential adverse events. Most important, as we
haveanincreasingnumberofcancerpatientslivinglongerandreceiv-
ing chronic therapy with agents such as imatinib, it is becoming
increasingly important to develop adequate models and trials to pre-
dict and understand the teratogenicity of these compounds. As
pointed out by Dr Ali et al, the currently available animal models are
notalwaysgoodpredictorsofwhatmaybeexpectedinotherspecies.
Inaddition,prospectiveinvestigationoftheseaspectsinpatients,with
designeduniformstrategies(forexample,plannedinterruptionsafter
cytogenetic or molecular remissions, use of alternative interventions
during pregnancy) will help us design better strategies to address this
importantissue.
Jorge E. Cortes and Hagop Kantarjian
Department of Leukemia, The University of Texas M.D. Anderson Cancer
Center, Houston, TX
DOI: 10.1200/JCO.2006.07.0151
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Authors’ Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following authors or their 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.
Authors Employment Leadership Consultant StockHonorariaResearch FundsTestimony Other
Jorge E. Cortes Novartis
Pharmaceuticals (C)
Hagop KantarjianNovartis
Pharmaceuticals (C)
Dollar Amount Codes
(A) ? $10,000 (B) $10,000-99,999(C) ? $100,000 (N/R) Not Required
Correspondence
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