Annals of Oncology Advance Access originally published online on June 1, 2006
Annals of Oncology 2006 17(8):1228-1233; doi:10.1093/annonc/mdl114
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© 2006 European Society for Medical Oncology
Response to neoadjuvant chemotherapy in lobular and ductal breast carcinomas: a retrospective study on 860 patients from one institution
From the departments of medical oncology, biostatistics, surgery, pathology, radiotherapy and radiology, Centre René Huguenin, Saint-Cloud, France
* Correspondence to: Dr M. Tubiana-Hulin, Centre René Huguenin, 35 rue Daily, 92210 Saint Cloud, France. Tel: +0-47-11-15-29; Fax: +01-47-11-15-83; E-mail: m.tubiana{at}stcloud-huguenin.org
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Abstract |
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 Top Abstract introductionpatients and methodsresultsdiscussionReferences |
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Background: We compared the impact of neoadjuvant chemotherapy on pathologic response and outcome in operable invasive lobular breast carcinoma (ILC) and invasive ductal breast carcinoma (IDC).
Patients and methods: We extracted from our database all patients with pure invasive lobular (n = 118, 14%) or pure invasive ductal carcinomas (n = 742, 86%). Their treatment included neoadjuvant chemotherapy, adapted surgery, radiotherapy and adjuvant hormonal treatment.
Results: Compared with IDC, ILC presented with larger tumors (T3: 38.1% versus 21.4%, P = 0.0007), more N0 nodes status (55.9% versus 43.3%, P = 0.01), less inflammatory tumors (5.9% versus 11.8%, P = 0.01), more hormone receptor positivity (65.5% versus 38.8%), lower histological grade (P < 0.0001). Final surgery was a mastectomy in 70% of patients with ILC (34% were reoperated after initial partial mastectomy) and in 52% of IDC after 8% of reoperation (P = 0.006). A pathological complete response (pCR) was achieved in 1% of ILC and 9% of IDC (P = 0.002). The outcome at 60 months was significantly better for ILC, but histologic type was not an independent factor for survival in multivariate analysis.
Conclusions: ILC appeared less responsive to chemotherapy but presented a better outcome than IDC. While new information on biological features of ILC is needed, we consider that neoadjuvant endocrine therapy in hormone receptor-positive ILC may be a more adapted approach than neoadjuvant chemotherapy.
Key words: invasive lobular breast carcinoma, neoadjuvant chemotherapy, pathological response, survival
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Invasive lobular carcinoma (ILC) accounts for only about 4%–15% of all breast carcinomas [1
–3]. ILC has a typical morphological aspect characterized by an infiltration of isolated or linear strands of round cells, triggering a low stromal reaction and surrounding unmodified anatomic structures. This particularity may explain why the tumor is rarely seen as a distinct mass, making the clinical and radiological diagnosis difficult, and often leading to the discovery of a large multifocal tumor mass. While the global evolution of ILC and IDC are quite similar [4–6], the prognosis seems to be more favorable for ILC [7, 8].
Primary chemotherapy is considered as a standard treatment for inoperable locally advanced breast cancer and in the earlier stages when conservative surgery is not feasible, the main objective is the downstaging of the tumor permitting a higher rate of breast conservation. Furthermore, pathological complete response in the breast and axillary node negativity after primary chemotherapy are strongly related to a better outcome [9–11] and are now usually considered as surrogates for survival. A few studies have shown that response to neoadjuvant chemotherapy is poorer in locally advanced ILC compared with IDC, with a greater need for mastectomy [3], whereas axillary involvement post chemotherapy is similar. Conversely, the long-term outcome of ILC appears to be better than for IDC [12, 13]. Consequently, in ILC, primary chemotherapy might not achieve the two main objectives of this strategy.
In order to further explore this observation, we conducted a retrospective study comparing the clinical and pathological characteristics as well as the long-term outcome of patients with ILC and IDC treated with neoadjuvant chemotherapy at the René Huguenin Anti-cancer Center, St-Cloud (France).
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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patients
In our center, between 1 January 1990 and 31 December 2002, 860 patients with pure ductal (n = 742 patients) or lobular breast (n = 118 patients) carcinomas were treated with neoadjuvant chemotherapy. The mean duration of follow-up was 65 months, range (10–177 months) and the data was last updated in August 2004. Clinical and pathological characteristics of the patients before treatment are presented in Table 1. Patients selected in this analysis had a histologically confirmed unilateral invasive stage II or III primary breast carcinoma (T2, T3, T4d, N0–2, M0), 12% had inflammatory symptoms. They had not received any prior treatment, had no history of any previous cancer and were considered as being eligible for neoadjuvant chemotherapy.
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Clinical tumor response to neoadjuvant chemotherapy was not measured since the information on presurgical tumor size was not automatically recorded in the database.
Pretreatment diagnosis was established by our pathologists on a core needle biopsy. The histological type was defined according to the World Health Organization classification [1]. We excluded non-classical subtypes of ILC, especially mixed IDC and ILC and undifferentiated subtypes [14].
The histologic grade was defined according to the Scarff-Bloom and Richardson (SBR) grading system [15]. After 1999, the Elston and Ellis rules to improve the reproducibility of the SBR grading system were routinely applied [16]. In our center, a modified SBR scoring system (mSBR) that takes into account only the two nuclear components of SBR grade was shown to improve the SBR prognostic value [17, 18]. Consequently, two histoprognostic subgroups were defined: a low-risk group mSBR 1 (or nuclear grade 1: additional score 2, 3, 4) and a high-risk group mSBR 2 (or nuclear grade 2: additional score 5 and 6).
From 1990 to 1997, estrogen (ER) and progesterone receptors (PR) were assayed using an ELISA method on frozen tumor samples [ER-EIA monoclonal, PgR monoclonal (Abbott Laboratories, Abbott Park IL 60064, USA)]. The cut-off value for positivity was 15 fmol/mg protein, 24.5% of ILC and 36.5% of IDC (P < 0.01) were measured by biochemical methods. This discrepancy simply reflects a lower proportion of ILC diagnosed before 1997 compared with the latter period. After 1997, ER and PR were measured by immunochemistry (IHC) with standard procedures using monoclonal antibodies (1D5) against ER (DAKO-SA Trappes, France) and (1A6) against PR (Novocastra laboratories, Newcastle, UK). IHC results were expressed quantitatively with a cut-off set at 10% of stained cells and semiquantitative IHC hormone receptor results were well correlated with enzyme immunoassay status [19].
treatment
All neoadjuvant chemotherapy was anthracycline-based. Patients were either participating in a randomized or non-randomized clinical trial (nine different chemotherapy protocols were conducted during this 12-year period) or treated according to the standard treatment of the center. The various chemotherapy regimens included a combined strategy (37 patients) with three cycles of preoperative AVCMF, adapted surgery and three cycles of postoperative AVCMF (doxorubicin 40 mg/m2, vincristine 1 mg/m2, cyclophosphamide 600 mg/m2, methotrexate 30 mg/m2 and 5-fluorouracil 900 mg/m2, intravenously), or preoperative chemotherapy only: four cycles of AC (doxorubicin 60 mg/m2, cyclophosphamide 600 mg/m2), or four cycles of FAC (5-fluorouracil 500 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2), or four cycles of FEC 60 or six cycles of FEC 100 (epirubicin 60 or 100 mg/m2, cyclophosphamide 500 mg/m2, 5-fluorouracil 500 mg/m2), or four cycles of anthracyclines plus taxanes (doxorubicin 50 mg/m2, plus docetaxel 75 mg/m2 or doxorubicin 60 mg/m2 plus paclitaxel 200 mg/m2). Moreover, four patients were treated with two lines of neoadjuvant chemotherapy AC followed by 5-FU-cisplatyl or FEC 100 followed by taxotere.
surgery
Breast surgery was either a lumpectomy or a total mastectomy. Patients underwent an axillary nodal dissection except one patient with ILC and six patients with IDC who refused nodal dissection. Two patients with IDC had axillary dissection without tumorectomy because of patient refusal, as no breast tumor persisted after chemotherapy at clinical and radiological examination.
All patients with ILC underwent surgery following chemotherapy (see Table 2), 47% of patients had initial conservative surgery. However, 34% required reoperation as they had compromised margins on pathological examination. Consequently, only 30% of ILC patients had conservative surgery, including one patient with ILC who had to undergo an extended lumpectomy following the initial lumpectomy. In comparison, initial breast conservative surgery was performed in 52% with IDC and a further mastectomy was required significantly less frequently than for patients with ILC. Finally, conservative surgery was significantly more frequent for IDC than for ILC (Table 2). Local recurrences were observed in 2.5% of ILC and 7.3% of IDC (P = 0.054).
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Post-operative treatment consisted mainly of external radiotherapy, adjuvant endocrine therapy (in the case of hormone receptor-positivity) and complementary non-predetermined adjuvant chemotherapy (68 patients).
response
Pathological complete response (pCR) was evaluated after surgery and defined as the absence of invasive carcinoma in the breast and the axillary nodes (ILC, 117 evaluable patients; IDC, 734 evaluable patients).
statistical analysis
Overall survival was defined as the time from diagnosis to death by any cause. Relapse-free survival was defined as the time from diagnosis until the first occurrence of disease recurrence (local, regional, distant or controlateral breast cancer). Non-breast primary malignancies were excluded (ILC, 4; IDC, 14). Differences between groups were analyzed by the chi-square test (or Fisher's exact test) for categorical variables and non-parametric tests for continuous variables. Actuarial curves were calculated using the Kaplan–Meier method and were compared with the log-rank test. A logistic regression model was performed to analyze independent factors associated with breast-conserving treatments. Multivariate analysis was carried out to assess the relative influence of prognostic factors on overall and event-free survival, using the Cox proportional hazards model in a backward stepwise procedure.
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results |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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patients
A total of 860 patients with either ILC (n = 118 patients) or IDC (n = 742 patients), treated with neoadjuvant chemotherapy and surgery, were followed in our center for a mean period of greater than 5 years. Overall, patients with ILC tended to be slightly older, with a larger tumor, lower SBR grade, higher N0 and HR+, and with less frequent inflammatory signs (see Table 1).
surgery
Breast surgery was either a lumpectomy or a total mastectomy. Conservative surgery was significantly more frequent for IDC than for ILC (see Table 2). Local recurrences were observed in 2.5% of ILC and 7.3% of IDC (P = 0.054).
Since the type of surgery partially reflected the effect of treatment on tumor size, we performed a logistic regression analysis assessing the relationship between the type of surgery and pretreatment characteristics (tumor size, HRs, mSBR, age less than or greater than 50, histological subtype). It showed that tumor size, HR positivity and histological type are independent factors for lumpectomy (not shown).
pathological response and survival
Histology following neoadjuvant chemotherapy showed persisting invasive lesions in 99% of the patients with ILC: only 1% of the patients had a pathological complete response (pCR) in breast and axillary samples, whereas 9% of patients with IDC had a pCR. Breast complete response was similar to pCR, 1% versus 9% in favor of IDC. Residual invaded lymph nodes were more frequent in patients with ILC and the rate of patients with positive lymph nodes greater than three was higher in patients with ILC (Table 2).
The relationship of pCR to hormone receptor status showed that in patients with IDC there was a higher frequency of pCR in HR- than in HR+ patients. Results cannot be interpreted in patients with ILC as only one patient had a pCR.
Despite the fact that the response to neoadjuvant chemotherapy and surgical outcome was globally better in patients with IDC, the follow-up at 60 months showed a better relapse-free survival in patients with ILC (76.5% versus 60.8%; see Figure 1). Results were similarly in favor of ILC for overall survival (91.7% versus 79.3%; see Figure 2).
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Differences in relapse-free survival and overall survival were still significant when only non-inflammatory tumors were considered.
In the univariate analysis, age (<50/
50), initial tumor size (T1T2/T3T4), histological type (IDC/ILC), ER status (ER+/ER–), PR status (PR+/PR–), SBR grading (1, 2, 3), mSBR grading (1/2), surgical treatment (conservative/mastectomy) and pathological response (pCR/no pCR) were all highly significant for 5-year disease-free survival (results not shown).
A multivariate analysis on the whole population, assessing the relationship between overall and event-free survival and various characteristics such as age, pathological type, tumor size, mSBR (nuclear) grade, hormone receptor status and lymph node status, was performed as shown in Table 3.
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The results showed that event-free survival and overall survival were related to tumor size, mSBR (nuclear) grade, receptor status and nodal involvement, but not related to age and pathological type.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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In accordance with various international publications, we observed that the incidence of ILC increased in our center from 3.6% in 1985 to 9% in 1999 and to 12% by the end of 2002. In published retrospective studies, various different methodologies have been used to select and define pure ILC. They were either extracted from a data base [4
, 8, 20] as in our study, or based on a systematic pathological review of all lobular specimens [8, 13, 21]. The same heterogeneity applied for the control groups, which were either defined as classical IDC [5, 8] or ‘carcinomas other than lobular’ or mixed ductal and lobular carcinomas [4]. Also, regarding the collection of parameters such as grade or receptors, they were either extracted from a database and reflected the evolution of procedures over time in a stable pathologists team, or were specially reviewed for the study [12, 13]. Previously, strategies for treating primary breast cancer did not differ due to histological breast carcinoma subtype (lobular or ductal): neoadjuvant chemotherapy was largely used when breast conservation appeared compromised due to large tumor size and the patient was suitable for chemotherapy [22]. In our study, we observed that differences in surgery between ILC and IDC were not erased by neoadjuvant chemotherapy: less patients with ILC had an initial lumpectomy (47% versus 52%) and reoperation was significantly more frequent (34% versus 8%). Finally, conservative surgery was performed in 30% of patients with ILC and 48% with IDC.
In terms of survival, neoadjuvant strategy, mostly based on anthracyclines, appeared to be similar to a standard surgery followed by adjuvant chemotherapy [9, 23] the main advantage being more breast-conserving surgery. Moreover, the rates of clinical response and, more specifically, pathological response are closely related to survival and may be used as substitutes for treatment effect on survival. Several studies have shown that chemotherapy, with or without taxanes, is less effective in patients with positive hormone receptors, a low proliferation and a lobular histologic type [24]. Our group of 860 patients under 70 years old and free of any other major disease treated with anthracycline-based chemotherapies used in our center since 1990, gave results that are similar to those published by the MD Anderson Center [12] or the Gustave Roussy Institute (IGR) [13]. The MD Anderson study, which was based on 1034 patients including 122 (12%) patients with ILC, reported older patient age, a higher percentage of positive receptors (92% versus 62%), a lower nuclear grade (16% versus 56% of nuclear grade 3) and a higher rate of stages IIIB and C. Pathological complete response was significantly lower (3% versus 15%, P < 0.001) and a higher number of greater than three positive nodes was found on axillary dissection. However, survival curves at 70 months showed a survival rate without recurrence and a global survival rate higher than in IDC.
In the IGR study [13], which included 457 patients with T2 > 3 cm to T4 tumors treated between 1987 and 1995, 34 (8.3%) were ILC. Grade I and II tumors with positive hormone receptors were more frequent. None of them presented a pCR, while it was observed in 9% of the patients overall. A multivariate study showed that lobular type is an independent predictor of poor clinical response to chemotherapy, associated with lesser chances of conservative breast surgery, while the estrogen receptor status is not an independent factor. However, no survival disadvantage for ILC was observed. Multivariate analysis showed that lobular histological type was not an independent factor for disease-free survival, in contrast to ER status, age, pathological response and nodal status. In our series, lobular histologic type determined significantly fewer complete pathological responses than IDC, and histologic type was an independent factor for type of surgery. However, it was not an independent factor for survival conversely to nodal status, hormone receptor status and mSBR (nuclear grade). The strong expression of ER (and consequently the treatment by tamoxifen) and low cell proliferation are two factors associated with a better survival rate [30–32]. The importance of these two factors, which partly constitute the phenotype of lobular carcinomas, probably explains the model's absence of selection for histologic type.
Moreover in ILC, poor response to neoadjuvant chemotherapy is not linked to worse survival, so chemotherapy response does not seem to have an impact on survival in ILC in the same way as it does for patients with IDC [12].
Being retrospective, this study has certain limitations. However, the results were substantially similar to those already reported from other large series. In conclusion, these convergent results appear to show that neoadjuvant chemotherapy is not a suitable strategy in most invasive lobular breast carcinomas: it fails to fulfill the two main objectives, which are a high rate of breast conservation and pathological response as a surrogate marker of survival (at present no survival benefit has been demonstrated). Furthermore, it exposes the patient to the toxicities of chemotherapy and the incurred additional cost may be unnecessary. The use of neoadjuvant endocrine therapy should be extended to this indication, while awaiting the results of genomics and proteomics, which will allow the use of targeted therapies.
Received for publication February 6, 2006. Revision received April 6, 2006. Accepted for publication April 10, 2006.
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