PII S0360-3016(00)00761-6

CLINICAL INVESTIGATION Breast

LOCAL-REGIONAL CONTROL IN BREAST CANCER PATIENTS WITH APOSSIBLE GENETIC PREDISPOSITION

LAURA M. FREEDMAN, M.D.,* THOMAS A. BUCHHOLZ, M.D.,* HOWARD D. THAMES, PH.D.,†

ERIC A. STROM, M.D.,* MARSHA D. MCNEESE, M.D.,* GABRIEL N. HORTOBAGYI, M.D.,‡

S. EVA SINGLETARY, M.D.,§ KEITH M. HEATON, M.D.,§\ KELLY K. HUNT, M.D.\

Departments of *Radiation Oncology,†Biomathematics,‡Breast Medical Oncology,§Surgical Oncology, The University of TexasM.D. Anderson Cancer Center, Houston, TX;\Department of Surgical Oncology, University of Arkansas for Medical Sciences,

Little Rock, Arkansas

Purpose: Local control rates for breast cancer in genetically predisposed women are poorly defined. Because sucha small percentage of breast cancer patients have proven germline mutations, surrogates, such as a family historyfor breast cancer, have been used to examine this issue. The purpose of this study was to evaluate local-regionalcontrol following breast conservation therapy (BCT) in patients with bilateral breast cancer and a breast cancerfamily history.Methods and Materials: We retrospectively reviewed records of all 58 patients with bilateral breast cancer anda breast cancer family history treated in our institution between 1959 and 1998. The primary surgical treatmentwas a breast-conserving procedure in 55 of the 116 breast cancer cases and a mastectomy in 61. The medianfollow-up was 68 months for the BCT patients and 57 months for the mastectomy-treated patients.Results: Eight local-regional recurrences occurred in the 55 cases treated with BCT, resulting in 5- and 10-yearactuarial local-regional control rates of 86% and 76%, respectively. In the nine cases that did not receiveradiation as a component of their BCT, four developed local-regional recurrences (5- and 10-year local-regionalcontrol rates of BCT without radiation: 49% and 49%). The 5- and 10-year actuarial local-regional control ratesfor the 46 cases treated with BCT and radiation were 94% and 83%, respectively. In these cases, there were twolate local recurrences, developing at 8 years and 9 years, respectively. A log rank comparison of radiation versusno radiation actuarial data was significant at p 5 0.009. In the cases treated with BCT, a multivariate analysisof radiation use, patient age, degree of family history, margin status, and stage revealed that only the use ofradiation was associated with improved local control (Cox regression analysisp 5 0.021). The 10-year actuarialrates of local-regional control following mastectomy with and without radiation were 91% and 89%, respectively.Conclusions: Patients with a possible genetic predisposition to breast cancer had low 5-year rates of localrecurrence when treated with breast conserving surgery and radiation, but the local failure rate exceeded 50%when radiation was omitted. Our data are consistent with the hypothesis that patients with an underlying geneticpredisposition develop cancers with radiosensitive phenotypes. © 2000 Elsevier Science Inc.

Breast cancer, Breast conservation therapy, Genetic predisposition, Radiation.

INTRODUCTION

The discovery of tumor suppressor genes including BRCA1and BRCA2 has resulted in an increased interest in whethergermline mutations affect tumor biology. The majority ofindividuals with a predisposing germline mutation in atumor suppressor gene inherit one normal gene allele andone abnormal allele (a heterozygous mutation). Breast can-cers that arise in these individuals have a loss of heterozy-gosity in the normal locus, with a resulting loss in thenormal function of the tumor suppressor gene (1, 2). It is

conceivable that this loss of function may influence thetreatment outcome of cancers arising in genetically predis-posed individuals. Unfortunately, there currently are insuf-ficient clinical data to determine the optimal treatment strat-egy for breast cancers occurring in patients with a geneticpredisposition. This deficiency in data has led to a contro-versy surrounding whether these patients can be safelytreated with breast conserving therapy (BCT) or ratherrequire mastectomy.

It is presumed that a variety of germline mutations in

Reprint requests to: Thomas A. Buchholz, Department of Ra-diation Oncology, Box 97, The University of Texas M.D. Ander-son Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030.Tel.: (713) 792-3400; Fax: (713) 794-5573; E-mail: tbuchhol@notes.mdacc.tmc.edu

Presented at the 1999 ASTRO meeting, San Antonio, Texas,October 1999.

Acknowledgments—This work was supported by GrantT32CA77050, awarded by the National Cancer Institute, U.S.Department of Health and Human Services. T.A.B. is supported bya Career Development Award (BC980154), Department of De-fense Breast Cancer Research Program.

Accepted for publication 21 June 2000.

Int. J. Radiation Oncology Biol. Phys., Vol. 48, No. 4, pp. 951–957, 2000Copyright © 2000 Elsevier Science Inc.Printed in the USA. All rights reserved

0360-3016/00/$–see front matter

951

tumor suppressor genes contribute to the fivefold increasedrisk of breast cancer development noted in individuals witha family history of cancer. Germline mutations in eitherBRCA1 or BRCA2 contribute to 7–10% of all newly diag-nosed breast cancer cases. The 15–20% of breast cancerpatients with a positive family history for breast cancer whodo not have a germline mutation in a BRCA gene may haveother yet undiscovered predisposing mutations. How thesemutations affect the natural history and treatment responseof a tumor is unknown.

In this paper, we studied the outcome of women with apossible genetic predisposition using clinical parameters asa surrogate for genetically predisposed disease. This strat-egy captures a broader population than studying only indi-viduals with a BRCA1 or BRCA2 mutation. While otherauthors have used positive family history as a surrogate forgenetically predisposed disease, we elected to study theoutcome of women with a history of bilateral breast canceras well as a positive family history. The rationale for se-lecting this surrogate group was that these patients had ahigher likelihood of having disease influenced by a germlinemutation in a tumor suppressor gene. The clinically relevantfinding we hoped to demonstrate was that BCT is appropri-ate for breast cancer patients who may be genetically pre-disposed to the development of the disease.

METHODS AND MATERIALS

Between 1959 and 1998, 58 women with bilateral breast can-cer and a family history of breast cancer were treated at TheUniversity of Texas M.D. Anderson Cancer Center. The med-ical records of these patients were reviewed for clinical andpathologic characteristics of each breast cancer. Parametersstudied included family history, age and stage at diagnosis,pathologic information, type of treatment, and outcome.

For the 58 women, the mean age at diagnosis of first andsecond breast cancer was 48 (range 24–94) and 53 (range29–94), respectively. Sixty-seven percent of the patientswere Caucasian, 19% were African American, and the re-

maining 14% were members of other ethnic populations.The majority (72%) of patients presented with cancer inonly one breast, with only 16 women (28%) being diag-nosed with synchronous disease. More than half of thetumors (56%) were self-detected, 26% were mammographi-cally detected, and 18% were detected following a clinicalexamination.

Each case was staged individually according to 1997American Joint Committee on Cancer (AJCC) stagingguidelines (3). The stage at presentation was defined as thepathological stage except in the 17 cases treated with neo-adjuvant chemotherapy. Due to possible downstaging, theclinical stage at diagnosis was used for analysis of thesetumors. As for location within the breast, 45% of the can-cers were in the upper outer quadrant, 14% in the upperinner quadrant, 9% in the lower outer quadrant, 8% in thelower inner quadrant, and 5% in the central breast. Fifteenbreasts (13%) had disease involving multiple quadrants.The exact location of 8 tumors (7%) could not be verified.Patient and tumor characteristics as well as stage at presen-tation are seen in Table 1.

Family history was considered positive if at least onefirst- or second-degree relative had a diagnosis of breastcancer. The number of relatives with a family history ofbreast cancer as well as the relationship to the patient isshown in Table 2. Sixty-nine percent of the patients had atleast one first-degree relative with a history of breast cancer.The remaining 31% had one or more second-degree rela-tives with a history of breast cancer. Twenty-two percent of

Table 1. Patient and tumor characteristics

BCT 1 XRT BCT no XRT Mastectomy1 XRT Mastectomy no XRT

Number of breasts 46 9 37 24Average age at diagnosis 49 56 44.7 48.7Histology:

IDC 37 (80%) 7 (78%) 32 (86%) 17 (71%)ILC 2 (4%) 1 (11%) 4 (11%) 3 (13%)Other 7 (15%) 1 (11%) 1 (3%) 4 (17%)

Family history:At least one first degree relative 30 (65%) 7 (78%) 27 (73%) 17 (71%)One or more second degree relatives 13 (35%) 2 (22%) 10 (27%) 7 (29%)

Stage at diagnosis:0 1 (2%) 1 (11%) 0 2 (8%)I 27 (54%) 4 (44%) 4 (11%) 11 (46%)II 18 (39%) 2 (22%) 18 (49%) 5 (21%)III 2 (4%) 2 (22%) 13 (35%) 3 (13%)Unknown 0 0 2 (5%) 3 (13%)

Table 2. Family history

One first degree relative 18Multiple first degree relatives 6One second degree relative 9Multiple second degree relatives 9One first degree and one second degree relative 7Multiple first and second degree relatives 6One first degree and multiple second degree relatives 3

952 I. J. Radiation Oncology● Biology ● Physics Volume 48, Number 4, 2000

the women had a total of 3 or more relatives with breastcancer. Five women had a female relative with a history ofbilateral breast cancer, and one patient had a male relativewith breast cancer.

In addition to breast cancer family history, 27 patientshad at least one other family member with a history ofcancer other than breast. Two of these patients had familyhistories of ovarian cancer.

Eight of the women in this study were diagnosed withanother type of cancer prior to or following their breastcancer diagnoses. Specifically, three had ovarian cancer,two had thyroid cancer, one had lung cancer, one hadstomach cancer, and one patient developed a malignantfibrous histiocytoma of the chest wall after treatment in anirradiated field.

Pathological analysisDetails of pathology were obtained from review of pa-

thology reports. Breast cancer histology was infiltratingductal carcinoma in 78%, invasive lobular carcinoma in 9%,and other or not specified in 13%. Table 3 shows otherpathological features of the 116 breast cancers studied inthis report. Information regarding nuclear grade was avail-able in 73 cases.

TreatmentBCT was performed in at least one breast in 36 of the 58

patients. In terms of the 116 breast tumors treated, theprimary surgical management was a breast conserving pro-cedure in 55 cases and a mastectomy in 61 cases. For

patients undergoing BCT, a segmental mastectomy wasperformed. Axillary lymph node dissection was performedin 38/55 (70%) of the conservatively treated breasts. Rea-sons for lack of dissection were noninvasive disease, ad-vanced age, and patient preference. The majority of thepatients without axillary lymph node dissections had StageI disease.

Radiation therapy was routinely recommended followingbreast conserving operative procedures. Average dose to theintact breast with initial fields was 4888 cGy (4500 cGy–5040 cGy). During the early years of the study, 30 breastswere irradiated with cobalt-60 gamma rays, but in the mid-1980s, photons (median energy 6 MV) were used. Thirty-two breasts received an additional 5–20 Gy (average dose1193 cGy) to the tumor bed as a boost. Four patientsunderwent iridium implant as boost therapy. Treatmentfields were designed to cover areas at risk for each case. Allbreasts were treated with medial and lateral tangent fields.Additionally, 28 breasts received at least one other field,with 10 patients receiving treatment using five fields. Five-field therapy included the breast tangents, an internal mam-mary chain treatment, supraclavicular and axillary apexcoverage, and a posterior axillary boost field.

For the 61 cases treated with mastectomy, the surgicalprocedure was a simple mastectomy in 5 cases, a radicalmastectomy in 6 cases, and a modified radical mastectomyin 50 cases. Sixty-one percent (37/61) of these cases alsoreceived radiation as a component of care.

Various chemotherapy regimens were used in 36 patients,12 of whom were treated with BCT. Three of the 12 womenreceived their chemotherapy as neoadjuvant therapy. Twen-ty-eight of the 36 patients given chemotherapy received it astreatment of their first cancer; and an additional 8 womenwere treated with chemotherapy at the diagnosis of thesecond cancer. Twenty-three of the patients receiving che-motherapy had lymph node-positive disease. Numerous reg-imens were utilized over the time course of this study, butdoxorubicin was a component of the regimen in 33 of the 36women, including all but one woman treated with chemo-therapy and BCT. Hormonal medications were a componentof care in 19 women, 13 of whom had received priorchemotherapy. Only six women treated with BCT under-went hormonal therapy as a component of care.

Statistical analysisActuarial statistics using methods of Kaplan-Meier were

used to estimate local control (4). Patients were censored atthe time of last follow-up or at the time of death. Time zerowas the date of pathologic diagnosis for each breast cancer.Local-regional recurrences were defined as an ipsilateralbreast, chest wall, or lymph node recurrence occurring asthe first evidence of recurrent disease without simultaneousdistant metastases. Local-regional recurrences following thedevelopment of metastatic disease were often not reliablyrecorded in medical records and therefore were not felt to beappropriate for this retrospective analysis. Actuarial datawere compared with two-sided log rank tests. Multivariate

Table 3. Tumor characteristics

Characteristic Number BCTNumber

mastectomy

Degree of differentiationWell 3 4Moderate 20 15Poor 15 16Unknown 17 26

Hormone statusER2 17 17ER1 18 19ER Unknown 20 25PR2 15 11PR1 17 13PR Unknown 23 37

MarginsPositive 4* 3,2 mm 4 5Negative 40 36Unknown 7 17

DCIS componentYes 13 10

Lymph vascular invasionYes 8 14No 26 16Unknown 21 31

* Two of four positive for in situ disease at margin.

953Breast conservation therapy for genetically predisposed patients● L. M. FREEDMAN et al.

analysis was performed using the Cox proportional hazardmodel (5).

RESULTS

Treatment resultsThe median follow-up for the index breast cancers treated

with BCT was 68 months (3–245). The median follow-up ofpatients from the date of the pathological diagnosis of theirfirst breast cancer was 98 months (range 9–461 months).There were 8 local-regional recurrences in the 55 breaststreated with BCT, including those patients who did notreceive radiation as a component of care. The 5- and 10-yearactuarial local-regional control rates for the BCT cases were86% and 76%. Nine of the 55 BCT cases did not haveradiation therapy as part of treatment, and 4 of these 9 casesdeveloped local recurrences (crude recurrence rate of44.4%). The 5- and 10-year actuarial local regional controlrates for the BCT cases treated without radiation were 49%and 49% (618.73% standard error (S.E.)). Only 4 localrecurrences occurred in the 46 BCT cases treated withbreast conservation surgery followed by radiation therapy(crude recurrence rate of 8.7%). The 5- and 10-year actu-arial local regional control rates for these cases were 94%(64.0% S.E.) and 83% (68.2% S.E.), respectively. Figure1 displays the actuarial local-regional control curves for theBCT cases divided according to the use of radiation. Thedifference in loco-regional control for these two groups wasstatistically significant atp 5 0.009. This difference re-mained significant (p 5 0.021) in amultivariate analysis

that incorporated radiation use, age (under or over 40 at firstdiagnosis), degree of family history (primary vs. second-ary), margin status (negative vs. positive or close), andstage.

All four of the recurrences that occurred in the patientswho did not receive radiation as a component of care weredetected within five years of diagnosis. However, in thepatients treated with BCT and radiation, two of the fourrecurrences occurred at a time greater than eight years fromthe original diagnosis. Table 4 shows treatment and out-come details for the eight cases of local recurrence thatfollowed BCT. Two recurrences involved both the breastand lymph nodes while the other six involved only thebreast. The two late recurrences were both only within theirradiated breast, and one of these recurred in a separatebreast quadrant.

Complications possibly related to radiation were noted in16 cases, eight in cases treated with BCT and eight in casestreated with mastectomy. The most common complication,seen in eight patients, was arm edema. Each of these pa-tients received treatment in the early era with cobalt-60.Other complications included seven cases of Grade III skintoxicity and two cases of radiation pneumonitis. Only onepatient treated with photons developed a Grade III toxicity.In this case, treatment was stopped at 46 Gy because of anacute skin reaction. One patient developed a malignantfibrous histiocytoma of the chest wall 20 years followingcobalt-60 radiation of an intact breast. This patient alsosuffered a Grade III skin complication and radiation pneu-monitis (noted above).

Fig. 1. Figure 1 displays actuarial local control for the BCT patients divided according to the use of radiation. Log rankcomparison of the data noted a statistically significant difference for the subgroups (p5 0.009).

954 I. J. Radiation Oncology● Biology ● Physics Volume 48, Number 4, 2000

In the 61 breasts treated with mastectomy, there werefive local recurrences, three occurring in patients who didnot receive radiation. The 10-year actuarial rates of local-regional control following mastectomy with and withoutradiation were 91% and 89%, respectively. All localrecurrences involved the chest wall with three of thesecases also failing in a draining lymph node region. Of thepatients with stage I–II disease, local recurrences devel-oped in 3/16 cases treated with mastectomy alone and1/22 of the cases treated with mastectomy and radiation.Median follow-up was 57 months for the mastectomy-treated cases.

DISCUSSION

Data from this study support the use of breast conserva-tion surgery and radiation for women with personal andfamily histories suggestive of an underlying genetic predis-position to breast cancer. In this paper, we reported a 5-year94% local control rate for women with a personal history ofbilateral breast cancer and a family history of breast cancerfollowing treatment with breast-conserving surgery and ra-diation. This local control rate is identical to our overallinstitutional experience for BCT, which is predominantlydetermined by treatment of sporadic breast cancer. For the1,406 cases treated with BCT in our institution between1955–1995, the local-regional recurrence rate followingBCT in 1,406 cases was also 94% (median follow-up of 6.5years) (6).

The majority of clinical data concerning how germlinemutations may affect tumor biology have come from studiesof BRCA1. Our strategy of studying women with bilateralbreast cancer and a positive family history captured a muchbroader population than studies specifically focused on in-dividuals with BRCA1 or BRCA2 mutations. Indeed, thepatient population analyzed in this study may have a varietyof predisposing genetic mutations and would be predicted tohave a low overall rate of having a germline BRCA1 mu-

tation. Shattuck-Eidens et al. published data on the proba-bility of having a germline mutation of BRCA1 given anindividual’s personal cancer history, age at diagnosis, fam-ily history, and whether the individual is of AshkenaziJewish descent (7). From these data, we estimated theprobability of having a BRCA1 mutation for each patient inour population. The average of these probabilities for thepatients in our series was 15%. This estimation does notaccount for the impact of having multiple relatives withbreast cancer or the impact of having family members withbilateral breast cancer history. As 60% of our study popu-lation had at least one of these factors, 15% is likely anunderestimation. Additionally, these graphs account onlyfor possibility of BRCA1 mutations and do not predict forother genetic mutations.

It is possible that a number of patients in this studydeveloped bilateral breast cancers independent of an under-lying genetic condition. Unfortunately, the percentage ofwomen in our study population for whom a genetic factorcontributed to their disease development cannot be deter-mined.

A number of other institutions have also investigatedlocal recurrence rates following BCT using clinical surro-gates for genetic predisposition. Chabneret al. studied localcontrol rates following BCT in young breast cancer patientswith a positive family history treated at the Joint Center forRadiation Therapy (JCRT) (8). These authors compared 29women age 36 or less who had a first-degree relative with ahistory of breast cancer before age 50 or a family history ofovarian cancer to 172 women age 36 or less who did notmeet these family history criteria. This study found nostatistically significant differences in the rates of local re-currence, distant failure, or second non-breast cancer in thetwo groups. The 5-year crude local recurrence rate was 3%in those with positive family history versus 14% who didnot have a family history.

Haas et al. reported the University of Pennsylvaniaexperience with BCT for young age patients with positive

Table 4. Information on patients with recurrences

Patient Family historyTime to

recurrence Status Stage XRT* Chemo* Margins

1 Multiple secondary 18 months DOD T2N0 Yes No Negative2 Single primary 8 years Alive after salvage T2N0 Yes No Negative3 Single primary 25 months DOD T2N0 No† No Unknown4 Multiple primary 22 months DOD T1N1 Yes No Negative5 Single secondary 1 month DOD T1N0 No‡ No Negative6 Single primary 9 months Dead, other cause T1N0 No§ No Negative7 Multiple primary and multiple

secondary 58 months Alive after salvage T2N0 Noi Yes Negative8 Multiple secondary 9 years Alive after salvage T2N0 Yes No Unknown

Abbreviations: Chemo5 chemotherapy; DOD5 dead of disease; XRT5 radiation.*Radiation and chemotherapy specified at the time of initial treatment.†Refused radiation.‡Developed recurrence at the start of radiation, 7.4 Gy delivered.§Radiation not offered (patients 94 years old).iRefused radiation.

955Breast conservation therapy for genetically predisposed patients● L. M. FREEDMAN et al.

family histories (9). In 1,021 patients, there was nodifference in local control when the patients were dividedaccording to family history of breast cancer. In patientsless than or equal to 40 years old, the 5-year local failurerate was 8% for those with a first-degree relative withbreast cancer, 2% for those with a non-first-degree rela-tive with breast cancer, and 12%with a negative familyhistory (p $ 0.18). Of note, the previously mentioned Shat-tuck-Eidens graphs estimate that the rate of a BRCA1 mutationin young women with one breast cancer and a positive familyhistory is only about 8–10%.

Finally, a study published by Harroldet al. from YaleUniversity investigated the relationships between youngage, family history, and local relapse in 984 women treatedwith BCT (10). The 10-year actuarial local recurrence ratefor the entire group was 15%. In the 52 women withrecurrent disease and in a matched control set of 52 caseswith local control, there was no difference in the familyhistory pedigrees.

Taken together, these three series and our data suggestthat contributing genetic factors for breast cancer devel-opment do not increase the risk of developing a localrecurrence with BCT. However, because the number ofpatients with BRCA mutations in these series was likelysmall, these data do not adequately address the risk ofrecurrence for individuals with known mutations. Re-cently, three series have evaluated the relationship oflocal control rate following BCT for individuals withknown BRCA1 or BRCA2 mutations. In 52 patients withipsilateral breast recurrences following BCT, Turneretal. reported a 15% rate of BRCA1 germline mutations(11). However, this study did not provide data specifi-cally addressing whether the local recurrence rate follow-ing BCT is increased for women with a BRCA1 or aBRCA2 mutation. In a multi-institutional study compar-ing 73 women with proven BRCA1 or BRCA2 mutationsto 219 matched controls with presumed sporadic breastcancer, Pierceet al. reported local failure-free survivalrates of 99% in the genetic cohort and 96% in thesporadic cohort (median follow-up of 5.3 and 4.6 years,respectively) (12). Finally, Robsonet al. reported thatAshkenazi women with a BRCA founder mutation had arate of ipsilateral breast recurrence of 22% (n 5 28)versus 6.9% (n 5 277) who did nothave a BRCA muta-tion (p 5 0.25) (13). Interestingly, in the patients with amutation, the rate of contralateral breast cancers was27%, which raises the question as to whether the ipsilat-eral breast events were true recurrences or new primarytumors.

Despite developing cancers with aggressive biologicalphenotypes (more common to have high nuclear grade,ER 2, PR 2 disease, and p53 mutations (14–16)), breastcancer patients with a BRCA1 or BRCA2 germline muta-tion do not have a worse prognosis (15, 17, 18). Thisdisparity may be attributable to an increased sensitivity to

DNA-damaging therapies in BRCA-related cancers. As pre-viously indicated, loss of BRCA1, BRCA2, or ATM func-tion results in a cellular deficiency in double-strand DNAbreak repair (19–23). Therefore, tumor cells with a ho-mozygous mutation in any of these genes would be pre-dicted to have a marked sensitivity to DNA-damaging ther-apies, such as ionizing radiation. Our clinical data supportthe hypothesis that breast cancers developing in geneticallypredisposed individuals have biologically aggressive phe-notypes that are sensitive to ionizing radiation. In the smallnumber of women who were treated with BCT withoutradiation, the crude local recurrence rate was 44%, and allof these recurrences developed within five years. Whenradiation was used as a component of breast conservationtherapy, the 5-year local control rate was 94%.

The exquisite radiosensitivity associated with homozy-gous tumor suppressor gene mutations has not been dem-onstrated with heterozygous BRCA mutations (19, 20).This suggests that women with BRCA germline muta-tions can be safely treated with radiation therapy.Gaffney et al. reported no increase in radiation compli-cations in 21 breast cancer patients with a known BRCA1or BRCA2 mutation (24). Similarly, Pierceet al. foundno deleterious effect of radiotherapy in women with aheterozygote mutation in BRCA1 or BRCA2 (12). In ourstudy, only one minor complication occurred in the pa-tients treated with photon radiation. The complicationrate for our population was similar to the overall BCTexperience at our institution (10% complication rate,most of which were mild and self-limited).

Patients with a genetic predisposition for breast cancerare likely to have an increased risk for developing newbreast cancer primaries. In the JCRT study, the youngpatients with a positive family history had a 5.7-fold in-creased risk of developing contralateral breast cancer com-pared with those with a negative family history (6). In ourstudy, 2 of the 4 patients who developed a breast recurrencefollowing BCT with radiation treatment had a recurrenceafter eight years. It is quite possible that these recurrencesrepresented new primaries. In the Yale case-control studyrelating local-regional control to BRCA mutation status, themedian interval of ipsilateral tumor recurrence for individ-uals with a germline BRCA1 or BRCA2 mutation was 7.8years, compared to a median interval of 4.7 years forwomen without one of these mutations (11). These authorsalso speculate whether a number of these late local-regionalrecurrences are new primary tumors within the ipsilateralbreast.

In conclusion, our results further support that BCT, in-cluding both surgery and radiation therapy, is appropriatetreatment for women with a possible genetic predispositionto breast cancer. We hypothesize that these tumors aresensitive to DNA-damaging therapies. These patients needto be carefully followed for the development of new pri-mary breast cancers.

956 I. J. Radiation Oncology● Biology ● Physics Volume 48, Number 4, 2000

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957Breast conservation therapy for genetically predisposed patients● L. M. FREEDMAN et al.