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Breast-Conservation Therapy in Early-Stage Breast Cancer Patients With a Positive Family History

From the Department of Obstetrics and Gynecology (GV), Senology Geneva University, Geneva, Switzerland; Departments of Surgical Oncology (NQM, FM, KKH, ANM, FCA, HMK, MIR, BF, GB, SES), Radiation Oncology (TAB), and Breast Medical Oncology (GNH), The University of Texas M.D. Anderson Cancer Center, Houston, Texas; and Karmanos Cancer Center (LAN), Detroit, Michigan.

Correspondence: Address correspondence and reprints requests to: S. Eva Singletary, MD, FACS, Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 444, Houston, TX 77030-4095; Fax: 713-792-2225; E-mail: esinglet{at}mdanderson.org

	ABSTRACT

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Background: Our goal was to evaluate the role of breast-conservation therapy in early-stage breast cancer patients with a family history (FH) of breast cancer.

Methods: Between 1970 and 1994, 1324 female patients with breast cancer were treated with breast-conservation therapy at our institution. From these, we identified 985 patients with stage 0-II breast cancer and who had available information on FH status. FH was considered positive in any patient who had a relative who had been previously diagnosed with breast cancer. Disease-specific survival was calculated from the date of initial diagnosis using the Kaplan-Meier method.

Results: The stage distribution for the 985 patients was as follows: 0 in 65 (7%), I in 500 (51%), and II in 420 (43%). The median age was 50 years (range, 21–88), with a median follow-up time of 8.8 years (range, .25–29). The median tumor size was 1.5 cm. FH was positive in 31%. There were no significant differences in locoregional recurrence, distant recurrence, disease-specific survival, or incidence of contralateral breast cancer in patients with a positive FH versus patients with a negative FH.

Conclusions: Breast-conservation therapy is not contraindicated in early-stage breast cancer patients with a positive FH.

	INTRODUCTION

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Over the past 10 years, much attention has been given to germline mutations that are associated with the development of breast cancer. The BRCA1 and BRCA2 genes, the gene for ataxia telangiectasia, and the p53 gene have all been implicated in increased susceptibility to breast cancer.^1–3 Still controversial, however, is whether such genes also contribute to a poor prognosis in affected patients. Although it seems intuitively appealing that this might be the case, a definitive answer to this question has been elusive, in part because of the difficulty in obtaining information about specific genetic alterations in a retrospective series of patients.

This question can be approached in another way by using family history (FH) as a surrogate for specific genetic information. A FH of breast or ovarian cancer in a close relative increases a woman’s lifetime risk of developing breast cancer⁴ and may also place her at increased risk for early-onset or bilateral disease.^5,6 Approximately 20% of breast cancer patients report a positive FH and, of these, an estimated 25% represent germline mutations.⁷

Although using FH as a surrogate for genetic information has the potential disadvantage of confounding genetic background with clustering due to environmental factors, it has the advantage of casting a wider net when compared with studies that examine a single genetic mutation. Patients with many types of genetic susceptibilities, including some not yet described, might be ascertained through a positive FH. In addition, this type of information is more widely available from clinical records, allowing the identification of a much larger patient group.

Breast-conservation therapy (BCT), consisting of lumpectomy and postoperative radiation treatment, has largely replaced mastectomy as the treatment standard for patients with early-stage breast cancer. Long-term prospective trials have indicated that the survival rates after the two surgical procedures are similar,^8,9 and the improved cosmetic outcome after BCT has made breast cancer surgery a more acceptable prospect for many.

There have been conflicting reports about whether a positive FH is associated with poor outcome in patients receiving BCT and would therefore be a contraindication for this treatment option.^10–12 For this study, we reviewed the records of 1324 patients at the M. D. Anderson Cancer Center who underwent segmental mastectomy followed by adjuvant radiotherapy with or without axillary lymph node dissection. Our aim was to evaluate the effect of FH on treatment outcomes in early-stage breast cancer patients receiving BCT.

	METHODS

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Patients
From 1970 to 1994, 1324 female patients were treated with BCT at the M. D. Anderson Cancer Center. Patients with a previous history of breast cancer (n = 45) or other primary malignancies (other than basal cell carcinoma or carcinoma in situ of the cervix; n = 56) were excluded from this study. From the remaining group, we identified 985 patients with early-stage breast cancer (stages 0-II) for whom information was available on FH status. FH was considered positive if at least one relative had a prior diagnosis of breast cancer. Medical records for these 985 patients were obtained, and data were extracted on clinical and pathological variables and on disease outcomes. Original pathology reports were used to obtain details about tumor histology.

Treatment
Patients were treated with wide excision of the tumor, with or without a level I-II axillary lymph node dissection. All patients had complete excision of the primary tumor by gross examination. When pathological examination indicated positive or unknown margins, patients underwent re-excision in an attempt to obtain negative microscopic margins.

All patients were treated with postsurgical radiotherapy. The ipsilateral breast was treated to a median dose of 45 to 50 Gy, delivered in 25 fractions over a 5-week period. Radiation was delivered in medial and lateral tangential fields of cobalt 60, 6 MV photons, or 18 MV photons. A 10 to 20 Gy boost was typically delivered to the primary tumor site.

Doxorubicin-based adjuvant chemotherapy (usually 5-fluorouracil, doxorubicin, and cyclophosphamide) was recommended for patients with histologically proven lymph node involvement. Tamoxifen was recommended for postmenopausal patients with estrogen-receptor positive tumors after the completion of chemotherapy or after surgery in those patients who did not receive chemotherapy.

Statistical Analysis
Descriptive statistics were calculated to assess differences between groups. Frequency distributions for discreet variables were compared between groups using ² analysis. The medians of continuous variables were compared between groups using the Mann-Whitney U-test. Disease-specific interval probabilities were calculated by the product limit method of Kaplan and Meier,¹³ and differences in survival were assessed using the log-rank test. P values less than or equal to .05 were considered to be statistically significant. Statistical analysis was performed using the SPSS 10.1 software package (SPSS Inc., Chicago, IL).

	RESULTS

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Patient and Tumor Characteristics
Of 985 patients with early-stage breast cancer treated with BCT, 308 (31%) had a positive FH of breast cancer (FH+). Of these, 149 (48%) had one or more first-degree relatives (mother, sister, daughter) with breast cancer (FH+/1st), and 159 (52%) had second-degree or other relatives with breast cancer (FH+/other). Of the FH+/other patients, 72% had second-degree relatives (aunt, grandmother, niece) with breast cancer, and 28% had other relatives (great-aunt, great-grandmother, cousin, and so on) with breast cancer.

Table 1 presents demographic and treatment characteristics for patients with and without a positive FH. In comparing all FH+ patients versus FH- patients, there were no significant differences in median age, ethnicity, tumor stage, or treatment. The median age in the patient sample was 50 years (range, 21–88). Most patients (>80%) were white, and most had stage I or II cancer. The majority of patients (>82%) received a level I-II axillary lymph node dissection. Adjuvant chemotherapy was given to 25% of patients, whereas 20% of patients received tamoxifen. There were also no significant differences in ethnicity, cancer stage, or treatment when FH+/1st patients were compared with FH+/other patients. For this comparison, however, there was a significant difference in median patient age (54 vs. 47; P < .001).

View larger version (21K): [in this window] [in a new window]   FIG. 1. Disease-specific survival as a function of family history in early-stage breast cancer patients treated with breast-conservation treatment. 1st degree, previous occurrence of breast cancer in a first-degree family member; Others, previous occurrence of breast cancer in any other family member; No FH, no family history of breast cancer in any relative.

	DISCUSSION

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A similar conclusion is reached when the comparison is restricted to studies dealing with BCT patients. A study by Haas et al.¹⁴ defined FH+ patients as those with a first- or second-degree relative with breast cancer. At a median follow-up time of 6.1 years, they found no significant difference in overall survival at either 5 years or 10 years in FH+ versus FH- patients. Chabner et al.¹⁵ examined the effects of FH on survival in patients younger than 36 years. They defined FH+ as breast cancer occurring in a first-degree relative under the age of 50 or ovarian cancer in a first-degree relative occurring at any age. They reported a trend toward higher rates of overall survival in FH+ patients versus FH- patients at both 5 and 10 years, but the differences were not significant (92% vs. 80% and 78% vs. 67%, respectively). Similarly, Brekelmans et al.¹⁶ showed a tendency (nonsignificant) toward increased postrelapse survival after LRs in FH+ cases (defined as first- or second-degree relative with breast cancer) at 2 and 5 years after relapse. These studies are consistent with the results of the current study. In contrast, the study by Chen et al.¹⁷ showed lower rates of 5-year overall survival in FH+ patients compared with FH- patients. This difference was significant for patients older than 50 years (84% vs. 92%, respectively; P = .017) but not in patients younger than 50 years (84% vs. 90%, respectively; P = .590). In the study by Haas et al.,¹⁴ there was also a trend toward decreased survival in FH+ patients over the age of 50, but in that case, the difference was not significant.

Family History and Local Recurrence
Although long-term studies have demonstrated acceptable survival outcomes in patients treated with BCT compared with mastectomy, those same studies have also shown a lifelong risk for LR in the treated breast. This increased risk ranges between 10% and 15% at 10 to 15 years.^18–20 Most such recurrences can be salvaged by additional surgery, with a median overall survival rate of 69% at a 5-year follow-up time.²¹ However, these events are psychologically traumatic for the patient, and considerable effort has been made to screen potential BCT patients for risk factors that significantly affect LR.

Concern about FH as a risk factor for LR after BCT stemmed from an early study conducted at the Memorial Sloan-Kettering Cancer Center.¹¹ This study showed an increased rate of LR in FH+ patients treated with BCT for ductal carcinoma in situ. Subsequent studies have not supported this finding. Three retrospective studies that compared FH+ versus FH- patients after BCT reported no difference in LR in either older or younger patients groups.^14,15,17 In addition, two case control studies in which BCT patients who had experienced LR were analyzed for FH showed no association between LR and FH.^16,22 These results are consistent with the findings in the current study.

Family History and the Risk of Contralateral Breast Cancer
Whereas most studies have shown that a positive FH is associated with an increased incidence of contralateral breast cancer (CBC), the magnitude of the increase has varied among studies. Anderson and Badzioch²³ reported the development of CBC in 556 breast cancer patients with a FH of breast cancer in a mother, sister, or second-degree relative. For all FH+ patients, the risk was 28% compared with 13% in a control series of patients. The risk was especially high in premenopausal patients (35% to 38%) compared with postmenopausal patients (11% to 26%). In the National Surgical Adjuvant Breast Project B-04 study, Fisher et al.²⁴ found that patients with bilateral disease were 1.5 to 2 times more likely to have a positive FH, although in this case the difference was not significant. Bernstein et al.²⁵ reported an increased risk of CBC associated with a first-degree FH (relative risk = 1.91); the risk was increased up to 2-fold in patients less than 46 years of age. A study by Israeli et al.²⁶ found CBC in 11% of FH+ patients versus 9% of FH- patients at a follow-up time of 5 years.

In the present study, which was restricted to patients treated with BCT, the incidence of contralateral breast cancer was only slightly higher in FH+ patients (8% to 9%) compared with FH- patients (6%) at median follow-up times ranging from 8.2 to 8.8 years. This difference was not significant. This is in contrast to two earlier studies of patients treated with BCT that showed significantly increased rates of CBC in FH+ patients. Chabner et al.¹⁵ reported a significant difference in the rate of CBC in FH+ patients versus FH- patients (14% vs. 3%, respectively, at 5-year follow-up), and Brekelmans et al.¹⁶ found a more than 2-fold increase in the incidence of CBC in FH+ patients versus FH- patients (10.3% vs. 4.8%, respectively.) Differing results in these three studies may stem from several causes. First, the latter two studies used a more restricted definition of FH+ (first-degree relatives only, as compared with first- and second-degree relatives in our study). Although we were unable to identify any significant differences between the two FH groups in our study, the incidence of CBC was marginally higher in FH+/1st patients compared with FH+/other patients. Age is also a potential confounding factor. The study by Chabner et al.¹⁵ involved patients less than 36 years of age, reflecting the influence of younger age reported in earlier studies by Anderson and Badzioch²³ and by Bernstein et al.²⁵ It should be noted, however, that Brekelmans et al.¹⁶ found significantly increased rates of CBC in both young and old FH+ patients. Finally, there may be different risk factors involved for synchronous versus metachronous CBCs. Israeli et al.²⁶ found that the increase in CBCs with FH+ was caused by an excess of synchronous CBCs in the FH+ patients, with no increase in metachronous CBCs. In the current study, 20 of 23 cases of CBC were metachronous. No information was available about the timing of second primary tumors for the other two studies.

Family History as a Surrogate for Germline Mutations
Although FH is, at best, an imperfect surrogate for germline mutations, the results of two recent studies analyzing outcomes in patients heterozygous for BRCA1/BRCA2 mutations are surprisingly similar to the results of this study at follow-up times of less than 10 years. Pierce et al. examined outcomes in 71 women with a BRCA1/BRCA2 mutation and early-stage breast cancer treated with BCT compared with 213 matched controls.²⁷ They found no significant differences between groups in rates of LR, cause-specific survival, or overall survival, but did find a significant difference in the incidence of CBC (22% vs. 2%; P < .001.) Robson et al. studied 305 women of Ashkenazi descent who had been treated with BCT.²⁸ Of these, 28 women were found to have BRCA1/BRCA2 mutations. LR was slightly more common in the mutation group, but the difference was not significant. They found that distant disease-free survival and breast cancer-specific survival were both reduced in the women with genetic mutations, but on multivariate analysis, these reductions were associated with tumor stage and nodal status rather than mutation status.

At longer follow-up times, patients heterozygous for BRCA1/BRCA2 mutations may be at increased risk for the occurrence of ipsilateral breast tumors. A recent study by Haffty et al.²⁹ analyzed rates of relapse in women with documented BRCA1/BRCA2 mutations compared with women with no documented genetic predisposition. Relapse rates in the two groups were similar through year 7. At a median follow-up time of 12 years, however, the rate of ipsilateral relapse was 49% in the BRCA1/BRCA2 group versus 21% in the sporadic group. The location, histologic appearance, and extended time to occurrence indicate that these relapses are in fact second primary tumors. This is supported by the observation that similar rates of tumor occurrence are seen in the contralateral breast in these patients.

The clinical implications of these findings are that, although patients with BRCA1/BRCA2 mutations may be acceptable candidates for BCT, long-term monitoring and follow-up is necessary, and prophylactic treatment with tamoxifen or other antiestrogens may be useful. Because up to 25% of FH+ patients may carry germline mutations,⁷ these same cautions may be indicated.

	CONCLUSIONS

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This study analyzed the effect of FH on outcomes in a large series of patients treated with BCT at a single institution. The results support earlier findings indicating that FH+ is not a contraindication for BCT in early-stage breast cancer patients. In fact, FH+ patients tend to show slightly more favorable rates of survival than FH- patients, although this may be true only in younger patients. It is noteworthy that all studies show an increased incidence of CBC associated with positive FH, regardless of variations in treatment or patient characteristics. This consistency warrants special care in ensuring that FH+ patients receive appropriate counseling about this risk. In addition, because up to 25% of FH+ patients may carry a germline mutation, careful long-term follow-up is indicated.

	Footnotes

 
There have been conflicting reports about whether a positive family history is associated with poor outcomes in patients receiving breast-conservation therapy. We reviewed the records of 1324 patients who received segmental mastectomy followed by adjuvant radiotherapy to evaluate the effect of family history on treatment outcomes.

Received for publication June 5, 2002. Accepted for publication July 24, 2002.

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