Outcomes of breast-conservation therapy for invasive lobular carcinoma are equivalent to those for invasive ductal carcinoma

The American Journal of Surgery 192 (2006) 552–555

Presentation

Outcomes of breast-conservation therapy for invasive lobular carcinoma are equivalent to those for invasive ductal carcinoma Thao N. Vo, M.D.a, Funda Meric-Bernstam, M.D.a, Min Yi, M.D., M.S.a, Thomas A. Buchholz, M.D.b, Frederick C. Ames, M.D.a, Henry M. Kuerer, M.D.a, Isabelle Bedrosian, M.D.a, Kelly K. Hunt, M.D.a,* a

Department of Surgical Oncology, Unit 444, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA b Department of Radiation Oncology, Unit 1202, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA Manuscript received April 6, 2006; revised manuscript June 9, 2006 Presented at the 7th Annual Meeting of the American Society of Breast Surgeons, Baltimore, Maryland, April 5–9, 2006

Abstract Background: Breast-conservation therapy (BCT), including wide local excision and postoperative irradiation, is considered standard treatment for early-stage invasive ductal carcinoma (IDC). The use of BCT in patients with invasive lobular carcinoma (ILC) has been questioned because of concerns regarding ipsilateral breast recurrence and risk of bilateral breast cancer. We evaluated our institutional experience with BCT and compared treatment outcomes for ILC with those for IDC. Methods: A review of our BCT database revealed 84 patients with ILC and 1,126 with IDC with stage I or II disease treated with BCT and radiation between 1976 and 1999. We evaluated local-regional recurrence, disease-specific survival, and contralateral breast cancer rates in both groups. Results: The 5- and 10-year local-regional recurrence rates for the ILC group were 1% and 7%, respectively, and 4% and 9%, respectively, for the IDC group (P ⫽ .70). There were no significant differences in the 5- and 10-year disease-specific survival rates between the groups. Contralateral breast cancer occurred in 11.3% of patients with IDC and 11.9% of patients with ILC. Conclusions: BCT achieves similar local-regional control and survival outcomes in selected patients with ILC or IDC. Breast-conservation therapy is an appropriate treatment strategy for patients with early-stage invasive lobular carcinoma. © 2006 Excerpta Medica Inc. All rights reserved. Keywords: Invasive lobular carcinoma; Invasive ductal carcinoma; Breast-conservation therapy; Radiation therapy

Invasive lobular carcinoma (ILC) accounts for 8% to 14% of all breast cancers [1,2] and has been increasing in incidence, especially among postmenopausal women [1]. Arising in the terminal ductules of the breast lobule, ILC is pathologically and clinically quite distinct from invasive ductal carcinoma (IDC). By virtue of their distinct growth pattern and biology, lobular carcinomas often fail to form distinct masses that can be easily diagnosed by palpation or mammography [1– 4]. Although ultrasonography has been shown to be more sensitive than mammography in detecting ILC, it may also significantly underestimate the size of ILC lesions [2,4]. This, along with reports of an increased propensity for multifocal, multicentric, and bilateral distribu* Corresponding author. Tel.: ⫹1-713-792-7216; fax: ⫹1-713-792-4689. E-mail address: [email protected]

tion of ILC, makes early diagnosis challenging and breastconservation therapy (BCT) more difficult. BCT, including wide local excision and postoperative irradiation, is considered standard of care for early IDC. However, its use in treating patients with ILC has been questioned because of concerns regarding increased rates of recurrence in the ipsilateral breast and bilateral breast cancer [1–3]. Despite this, as the use of BCT has gained in popularity, so too has its use in treating patients with earlystage ILC [2]. Our objective was to review our experience with BCT for patients with ILC and to compare the localregional recurrence, disease-specific survival, and contralateral breast cancer rates with those in patients given the same treatment for IDC. We identified 1210 patients with stage I or II ILC or IDC who had undergone BCT at The University of Texas M.D.

0002-9610/06/$ – see front matter © 2006 Excerpta Medica Inc. All rights reserved. doi:10.1016/j.amjsurg.2006.06.020

T.N. Vo et al. / The American Journal of Surgery 192 (2006) 552–555

902 (80.1) 224 (19.9)

15 (17.9) 69 (82.1) 0

164 (14.6) 957 (85.0) 5 (.4)

64 (76.2) 16 (19.0) 4 (4.8)

789 (70.1) 332 (29.5) 5 (.4)

20 (23.8) 55 (65.5) 9 (10.7)

207 (18.4) 821 (72.9) 98 (8.7)

54 (64.3) 24 (28.6) 6 (7.1)

724 (64.3) 314 (27.9) 88 (7.8)

55 (65.5) 12 (14.3) 17 (20.2)

587 (52.1) 309 (27.4) 230 (20.4)

40 (47.6) 18 (21.4) 26 (31)

485 (43.1) 319 (28.3) 322 (28.6)

8 (9.5) 74 (88.1) 2 (2.4)

78 (6.9) 950 (84.4) 98 (8.7)

21 (25) 63 (75) 0

345 (30.6) 779 (69.2) 2 (.2)

35 (41.7) 48 (57.1) 1 (1.2)

312 (27.7) 795 (70.6) 19 (1.7)

10 (11.9) 74 (88.1)

127 (11.3) 999 (88.7)

ILC ⫽ invasive lobular carcinoma; IDC ⫽ invasive ductal carcinoma.

Anderson Cancer Center between January 1976 and December 1999. All clinical and pathologic information had been entered into a relational computer database (Microsoft Access; Microsoft Corp, Redmond, WA) that was exclusively designed for patients undergoing BCT. Patients who had received neoadjuvant chemotherapy or hormonal therapy and patients who had tumors of mixed lobular and ductal type histology were excluded from this review. Included in our study were all patients who had undergone complete macroscopic excision of the primary

Local-regional recurrence-free survival

1.00

78 (92.9) 6 (7.1)

0.80

24–88 52

0.60

34–78 60

P = 0.69 0.40

Age, yrs Range Median Race White Not white Family history of breast cancer in mother or sister Yes No Unknown Tumor size T1 T2 T3 Positive lymph nodes Yes No Not dissected Pathology stage I IIA IIB Estrogen receptor positive Yes No Not done Progesterone receptor positive Yes No Not done Margin positive or close (ⱕ2 mm) Yes No Unknown Adjuvant chemotherapy Yes No Unknown Adjuvant hormone therapy Yes No Unknown Contralateral breast cancer Yes No

0.20

ILC, n ⫽ 84 (%) IDC, n ⫽ 1126 (%)

Invasive ductal carcinoma (N=1126) Invasive lobular carcinoma (N=84)

0.00

Patients

tumor and received postoperative radiation treatment with or without a boost to the primary tumor bed. Margins were reported as negative, close (ⱕ2 mm), or positive. The primary tumor was also assessed for lymphovascular invasion. Specimens were examined grossly, mammographically, and in some cases, microscopically with frozen sections to obtain tumor-free margins during surgery. In general, a level I or II axillary lymph node dissection was performed through a separate incision. Chemotherapy was usually administered to patients with histologically proven lymph node involvement and to nodenegative patients with a high risk for recurrence [5]. Adjuvant hormone therapy was usually offered to women whose tumors were positive for hormone receptors, regardless of age, menopausal status, axillary lymph node status, or tumor size [6]. Disease was staged according to the American Joint Committee on Cancer [7]. Staging was based on the pathologic findings when possible or on clinical and pathologic factors when an axillary node dissection had not been performed or when the microscopic tumor size was not reported. The pathologic features of the primary tumors were obtained by reviewing the original pathology reports. Estrogen and progesterone receptor status was determined by biochemical or immunohistochemical analysis. The primary focus of this study was to evaluate local-regional recurrence, which was defined as invasive cancer detected in the ipsilateral breast or regional nodes at any time after initial BCT. We compared the 2 patient groups (IDC or ILC) with regard to age, race, clinical and pathologic characteristics, and treatment outcome. Differences in categorical characteristics between the patient groups were analyzed by a Fisher exact test. The log-rank test was used to compare times to recurrence and survival rates between the groups. Actuarial local-regional recurrence and overall survival curves were calculated according to the Kaplan-Meier method. Potential risk factors associated with local-regional recurrence and survival rates were identified by a univariate log-rank test. Statistical analyses were performed by using Stata 8.0 software (StaCorp, College Station, TX); P values less than .05 were considered statistically significant.

Proportion free of local-regional recurrence

Table 1 Patient, tumor, and treatment characteristics

553

0

20

40

60

80 100 120 140 160 180 200 220 240 Time (months)

Fig. 1. Local-regional recurrence-free survival.

554

T.N. Vo et al. / The American Journal of Surgery 192 (2006) 552–555 Table 2 Actuarial outcomes

0.80

Outcome

ILC*

IDC

0.60

5-year 10-year 5-year 10-year rate, % rate, % rate, % rate, %

0.20

0.40

P = 0.95

Invasive ductal carcinoma (N=1126) Invasive lobular carcinoma (N=84)

0.00

Proportion free of recurrence

1.00

Disease-free survival

0

20

40

60

80 100 120 140 160 180 200 220 240 Time (months)

Survival 96.3 Local failure 1.4 Local-regional failure 1.4 Overall failure (local-regional ⫹ distant) 8.8

P value†

81 3.5 6.8

96 4.1 4.4

85.3 8.3 8.6

.65 .28 .69

20

12

21.7

.95

ILC ⫽ invasive lobular carcinoma; IDC ⫽ invasive ductal carcinoma. * 95% confidence intervals for both groups. † Log-rank test.

Fig. 2. Disease-free survival.

Patient and Tumor Characteristics We identified a total of 1,210 patients with stage I or II breast cancer who were treated with BCT: 84 with ILC and 1126 with IDC (Table 1). Compared with IDC, ILC was significantly more common in older patients and was more common in whites than nonwhites. Patients diagnosed with ILC were also associated with a higher proportion of estrogen receptor–positive tumors, and they were more likely to receive adjuvant hormone therapy. There was no significant difference between the 2 groups with respect to length of follow-up, family history of breast cancer, tumor stage, nodal status, final margin status, use of adjuvant chemotherapy, and radiation boost (all P ⱖ .1). Local-Regional Recurrence and Survival The local-regional recurrence, overall recurrence, and survival rates are shown in Figures 1 through 3. There was no significant difference in the rates of local and distant failure between the 2 groups (Table 2). The 5-year and 10-year local failure rates were not significantly different between the groups. Among the 5 patients who experienced local-regional recurrence in the ILC group, 2 were alive with no evidence of disease at the time of our analysis, 2 had died of the disease after having received salvage treatment for recurrence, and 1 had died of an unknown cause after having received salvage treatment for recurrence. Among

Contralateral Breast Carcinoma Contralateral breast cancer occurred in 127 (11.3%) of the 1126 patients with IDC and in 10 (11.9%) of the 84 patients with ILC (P ⫽ .86) during the follow-up time.

0.80 0.60 0.20

0.40

P = 0.65

Invasive ductal carcinoma (N=1126) Invasive lobular carcinoma (N=84)

0.00

Proportion still surviving

1.00

Overall survival

0

20

40

60

80 100 120 140 160 180 200 220 240 Time (months)

Fig. 3. Overall survival.

85 patients who had experienced local-regional recurrence in the IDC group, 59 were alive free of disease, 2 were alive with the disease and being treated for recurrent disease, 18 had died of the disease, and 6 had died of unknown causes at the time of our analysis. There was also no statistically significant difference in the survival rates between the groups at the mean follow-up times of 10.5 years and 11.0 years in the ILC and IDC groups, respectively. Also, the 5-year and 10-year overall survival rates were not significantly different between the groups. A univariate log-rank test was used to identify potential risk factors associated with local-regional recurrence (based on time to recurrence). The variables were age, pathologic tumor size, margin status, receptor status, stage, and histology (ILC or IDC). We did not find any difference in localregional recurrence rates between the groups with respect to these variables (hazards ratio ⫽ 1.27, P ⫽ .76) (data are not shown). A similar analysis by stepwise multiple-variables Cox regression analysis was performed to identify factors associated with overall recurrence and death. There was insufficient evidence to prove a difference in disease-free and overall survival rates between the groups (Table 3). The younger patients, patients with more advanced disease stage, and those who did not receive hormone treatment were at increased risk for death according to the Cox regression analysis (P ⬍ .0001, P ⫽ .003, and P ⫽ .002, respectively).

Summary Although ILC has been shown to have clinical and biologic characteristics distinct from IDC [1–3], we found no statistically meaningful differences in rates of local-regional or distant recurrence or survival in stage I or II patients treated with BCT. Our univariate analysis of the multiple clinical and pathologic features associated with local-regional and overall recurrence and survival also showed that the diagnosis of ILC was not a risk factor. However, some investigators have reported higher local failure rates in patients with ILC treated with BCT. Du Toit et al [8] reported

T.N. Vo et al. / The American Journal of Surgery 192 (2006) 552–555

555

Table 3 Multivariate Cox regression analysis for disease-free and overall survival in patients with invasive ductal carcinoma (IDC) or invasive lobular carcinoma (ILC) Disease-free survival HR Age, y* Family history of breast cancer No vs yes Pathologic stage IIA vs I IIB vsy I Estrogen receptor status Negative vs positive Margin positive or close (ⱕ2 mm) No vs yes Adjuvant chemotherapy No vs yes Adjuvant hormone therapy No vs yes Histology IDC vs ILC

95% CI

Overall survival P value

HR

95% CI

P value

.97

.95–.99

.003

1.04

1.02–1.05

⬍.0001

1.07

.63–1.83

.79

1.08

.64–1.8

.78

1.67 2.15

1.09–2.58 1.17–4.00

.02 .01

1.49 1.34

.95–2.34 .61–3.00

.08 .45

1.00

.66–1.54

1.00

1.59

.99–2.57

.06

.82

.22–3.11

.77

.99

.22–4.30

.71

1.08

.68–1.70

.75

1.13

.68–1.88

.88

1.83

1.12–3.01

.016

1.73

1.06–2.85

⬍.0001

.92

.31–2.71

.88

.90

.37–2.15

.60

HR ⫽ hazards ratio; CI ⫽ confidence interval. * Continuous variant.

a local recurrence rate of 42% after BCT in patients with ILC, 2 and a half times higher than that seen in patients with IDC (17%). There was no difference in local recurrence rates after mastectomy between the 2 groups [8]. Hussien et al [9] also concluded that patients with ILC treated with BCT have a greater risk of local recurrence than patients treated by mastectomy because there was a significant difference in the mean time to local recurrence between the BCT group and the total mastectomy group. Our study confirms the results of Arpino et al [1] who recently reported that there were no statistically significant differences in disease-free survival and recurrence rates between patients with ILC or IDC. Santiago and colleagues [10] also found that patients with ILC or IDC had similar outcomes when treated with BCT. The differences in sample size and length of follow-up likely account for the differences between studies. These differences may account for the discrepancies in overall recurrence and survival rates. Singletary et al [2] reviewed the National Cancer Database for the outcome of patients treated for ILC. They found that patients who underwent BCT or mastectomy had similar rates of local-regional and distant recurrence and 5-year diseasefree survival. They also noted that the percentage of patients with ILC who had undergone BCT had almost tripled over the study period (1989 –2001) [2]. In conclusion, lobular and ductal breast cancers can be managed similarly, and the histologic subtype (lobular or ductal) should not be a factor in the therapeutic decisionmaking process. ILC is not a prognostic factor for localregional or distant recurrence or for overall survival. BCT is

equally safe for patients with invasive lobular carcinoma and invasive ductal carcinoma of the breast. References [1] Arpino G, Bardou JV, Clark MG, Elledge MR. Infiltrating lobular carcinoma of the breast: tumor characteristics and clinical outcome. Breast Cancer Res 2004;6:R149 –56. [2] Singletary SE, Patel-Parekh L, Bland KI. Treatment trends in earlystage invasive lobular carcinoma: a report from the National Cancer Data Base. Ann Surg 2005;242:281–9. [3] Yeatman TJ, Cantor AB, Smith TJ, et al. Tumor biology of infiltrating lobular carcinoma: implications for management. Ann Surg 1995; 222:549 – 61. [4] Gill KH, Berg AW. Case 39: invasive lobular carcinoma. Radiology 2001;221:132– 6. [5] Mansour EG, Gray R, Shatila AH, et al. Case: survival advantage of adjuvant chemotherapy in high-risk node-negative breast cancer: tenyear analysis. J Clin Oncol 1998;16:3486–92. [6] National Institutes of Health, Consensus Development Conference Statement. Adjuvant Therapy for Breast Cancer. National Institutes of Health, Consensus Development Conference Statement, November 1–3, 2000. [7] Greene LF, Page LD, Flaming DI, et al. Breast. In: Greene LF, Page LD, Flaming DI, et al, eds. AJCC Cancer Staging Manual. 6th ed. Chicago, IL: Springer; 2002:223– 40. [8] Du Toit RS, Locker AP, Ellis IO, et al. An evaluation of differences in prognosis, recurrence patterns and receptor status between invasive lobular and other invasive carcinomas of the breast. Eur J Surg Oncol 1991;17:251–257. [9] Hussien M, Lioe TF, Finnegan J, Spence RAJ. Surgical treatment for invasive lobular carcinoma of the breast. Breast 2003;12:23–35. [10] Santiago JR, Harris EER, Qin L, et al. Similar long-term results of breast-conservation treatment for stage I and II invasive lobular carcinoma compared with invasive ductal carcinoma of the breast. Cancer 2005;103:2447–54.