Characterizing Response to Neoadjuvant Chemotherapy in Invasive Lobular Breast Carcinoma

Characterizing Response to Neoadjuvant Chemotherapy in Invasive Lobular Breast Carcinoma

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Characterizing response to neoadjuvant chemotherapy in invasive lobular breast carcinoma Luis A. Riba, MD,a Teresa Russell, BS,a Amulya Alapati, MD,a Roger B. Davis, ScD,b and Ted A. James, MDa,* a

Department of Surgery/BreastCare Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts b Division of General Medicine and Primary Care, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts

article info

abstract

Article history:

Background: Pathological complete response (pCR) after neoadjuvant chemotherapy (NCT)

Received 3 February 2018

for breast cancer is associated with improved survival and facilitates conservative surgical

Received in revised form

strategies. Invasive lobular carcinoma (ILC) has been observed to have decreased response

8 July 2018

to NCT compared with invasive ductal carcinoma (IDC). This study seeks to evaluate na-

Accepted 2 August 2018

tional trends in the use of NCT for ILC compared with IDC, and determine if there is a

Available online xxx

subset of ILC patients who demonstrate favorable response rates. Methods: This is a study using the National Cancer Database. The cohort consisted of pa-

Keywords:

tients with stage 1-3 ILC treated between 2010 and 2014, and a reference cohort of patient

Neoadjuvant chemotherapy

with IDC. For patients receiving NCT, pCR was assessed and clinically relevant variables

Breast cancer

were used in multivariable logistic regression models for each histologic subtype, modeling

Lobular carcinoma

for pCR achievement. Survival analysis was performed for each histologic group to evaluate potential survival benefits of achieving pCR. Results: Our study cohort consisted of 384,887 women, of which 9.7% had ILC. A significantly lower rate of pCR after NCT was found in the cases of ILC compared with those of IDC (8.7% versus 23.2%). Increased response was seen in ILC patients with HER2-positive and TNBC subtypes. A survival benefit was demonstrated in patients with ILC who achieved pCR. Conclusions: While response to NCT in patients with ILC is uncommon, our findings demonstrate a selective benefit for patients with HER2-positive tumors and TNBC. In addition, pCR is correlated with a clear survival advantage in ILC. ª 2018 Elsevier Inc. All rights reserved.

* Corresponding author. Beth Israel Deaconess Medical Center, Linsey BreastCare Center, 330 Brookline Avenue, Boston, MA 02215. Tel.: þ1 617 667 5509; fax: þ1 617 667 9711. E-mail address: [email protected] (T.A. James). 0022-4804/$ e see front matter ª 2018 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jss.2018.08.011

riba et al  neoadjuvant chemotherapy in lobular carcinomass

Background Along with the implementation of screening policies leading to earlier detection of breast cancer, improvements in systemic therapy have been vitally important as a determinant of increased patient survival. The use of neoadjuvant chemotherapy (NCT) has proven useful in facilitating breast conserving therapy and reducing the burden of axillary disease.1-10 As a result, NCT has become more widely accepted as an option in the management of breast cancer.1-6 Achievement of pathological complete response (pCR), defined by the U.S. Food and Drug Administration as noninvasive or in situ cancer residuals in the breast and all sampled lymph nodes, after NCT has been correlated with improved outcomes.6 pCR can be used as a surrogate indicator of overall survival, allowing for the assessment of tumor response to NCT and the discrimination between favorable and unfavorable outcomes in certain subsets of patients.11,12 However, response to NCT varies significantly between different breast cancer subtypes. Patients with invasive lobular carcinoma (ILC), accounting for approximately 15% of all cases of breast cancers in the United States, have been shown to have lower response rates to NCT when compared with patients with invasive ductal carcinoma (IDC), the most frequent histologic subtype.13 Studies have reported pCR rates ranging from 3% to 11% in ILC patients treated with NCT, compared with 16.7%-25% in IDC patients.5,6,14-16 As a result of the tendency for lower pCR rates in patients with ILC, NCT is used less frequently in these patients on a national level, which could impact their ability to derive the benefits of NCT.1618 However, our understanding of the importance of molecular subtypes in predicting the behavior of breast cancer suggests that intrinsic subtype classification, rather than histology, may be the primary driver influencing response to NCT. Consequently, there is a need to determine if a subset of patients with ILC demonstrating greater response to NCT can be identified based on distinctive tumor-specific characteristics.19-23 The purpose of this study is to characterize the overall utilization of NCT for ILC, determine the response to NCT in ILC, and identify characteristics that potentially predict improved pCR rates in ILC patients. As a secondary aim, we seek to determine if there is a 5-y survival benefit for patients with ILC who achieve pCR. Determining characteristics that differentiate patients with ILC who may benefit from NCT will help to inform clinical practice, leading to increased options and more effective treatment regimens for ILC.

Methods Data source The data used in this study were derived from deidentified National Cancer Database (NCDB) participant user files.24,25 The NCDB is a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society. The NCDB compiles more than 34 million historical records from more than 1500 Commission on Cancereaccredited facilities and contains information from over 70% of newly

437

diagnosed cancer cases in the United States. The study was submitted for IRB approval and received an exemption.

Cohort selection The cohort for this study consisted of female patients in the NCDB with clinical stage 1-3 primary ILC diagnosed and treated between 2010 and 2014 at NCDB reporting facilities (n ¼ 600,573). A comparison group of patients with stage 1-3 IDC was used as a reference cohort. We included patients treated in any NCDB facility type across all geographical regions of the United States. The analysis included patients who received only NCT. Patients were assessed for eligibility based on our exclusion criteria, which included multiple cancer sites, use of neoadjuvant endocrine therapy, and unavailability of key variables such as timing of systemic therapy, tumor marker testing, tumor grade, or surgical intervention description (See Fig. 1).

Statistical analysis Statistical analysis was performed with SAS Version 9.4 (SAS Institute Inc, Cary, North Carolina). Descriptive statistics were used to describe the study cohort. Age was used as a continuous variable for initial cohort description, using t-tests for comparisons between groups; furthermore, age groups were created for categorical analyses. c2 tests were used to compare categorical demographic data, tumor characteristics, and systemic therapy regimens. Patients who received only NCT were then identified and similar descriptive statistics were used to analyze their characteristics. These patients were also assessed for their rates of pCR according to distinct demographic and tumor characteristics. Unadjusted logistic regression analyses were performed, modeling for independent association with the occurrence of pCR. Variables including age, ethnicity, comorbidity index, clinical TNM stage, tumor grade, and molecular subtype were selected for their clinical significance. These variables were then evaluated using multivariable logistic regression models, modeling for the occurrence of pCR. From these multivariable regression models, we obtained odds ratios and 95% confidence intervals (CIs) for each variable as a correlate of pCR. The KaplaneMeier method was used to estimate survival distributions, and logrank tests were used to assess the differences in overall 5-y survival, comparing between patients who achieved pCR and those who did not. The landmark method was applied using the time of the first surgical procedure as the time origin for the survival analysis, this being the point at which pCR can be determined based on surgical pathology reports. Cox proportional hazards regression models were fit to obtain adjusted hazard ratios for pCR, age group, ethnicity, comorbidity index, clinical stage, tumor grade, and molecular subtypes. The use of adjuvant hormonal therapy or postmastectomy radiation therapy was also included in the adjusted survival model.

Results Based on the pre-established inclusion and exclusion criteria, our study cohort consisted of 36,785 (9.6%) women diagnosed

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Fig. 1 e Flow chart of patients who met inclusion/exclusion criteria for the study cohort and general description of histologic subtypes and delivery of neoadjuvant chemotherapy.

with stage 1-3 ILC, and 344,360 (90.4%) reference patients with IDC, receiving NCT between the years 2010 and 2014 (see Fig. 1). Patients with ILC were more likely to present with lowto intermediate-grade tumors, and hormone receptor (HR)e positive and HER2-negative subtypes, compared to patients with IDC. NCT was used in 6.6% of the cases of ILC (n ¼ 2417) compared with 13.9% of the IDC cases (n ¼ 47,697). General characteristics of the cohort in association with the histologic variant are depicted in Table 1. Rates of pCR after NCT were found to be significantly lower for ILC compared with IDC (8.7% compared with 23.3%). General characteristics of the cohort that received NCT, in association with the histologic variant, are depicted in Table 2. We observe that patients in the ILC group are older and more commonly non-Hispanic whites. These patients were also more frequently diagnosed at a more advanced stage of disease, and tended to have lower grade tumors. Patients in the ILC group were HR-positive in the vast majority of cases, with less than 10% presenting with HR-negative disease. Regarding HER2 status, 85.6% of patients in the ILC group were HER2-negative. An analysis was performed for direct associations between clinical variables and the occurrence of pCR, encountering varying rates of pCR depending on patients’ characteristics (see Supplement 1). Unadjusted regression analysis for patient characteristics confirmed significant associations between the achievement of pCR and younger age, higher tumor grade, and HER2positive and TNBC molecular subtypes in patients with ILC (see Supplement 2). Multivariable logistic regression analysis found several persistent associations with pCR. Age was still observed to have a significant association, with higher pCR occurrence in patients <40 y of age, compared with patients in the 40-54 y age group. Lower pCR occurrence was seen in patients >65 y of age. Compared with clinical stage 3 disease, stage 2

presentation was seen to be associated with increased rates of pCR. Compared to patients with HR-positive/HER2-negative tumors, those with HER2-positive or TNBC subtypes had significantly higher response rates. No association between tumor grade and pCR was observed with ILC (Table 3). Survival analysis demonstrated a 5-y survival benefit of achieving pCR in ILC patients undergoing NCT (Figs. 2 and 3). The unadjusted hazard ratios of pCR were 0.89 (95% CI, 0.511.57) for the ILC group, compared with 0.37 (95% CI, 0.34-0.41) for the IDC group. After covariable adjustment, the mortality hazard ratio for patients achieving pCR was 0.46 (95% CI, 0.250.84; P ¼ 0.012) in the ILC group and 0.33 (95% CI, 0.30-0.37; P < 0.001) in the IDC group. Covariable adjustment of the KaplaneMeier survival plots were performed, adjusting for variables which included age, ethnicity, CDCC, clinical stage, tumor grade, tumor markers, administration of adjuvant hormonal therapy, and use of postmastectomy radiation therapy. See Table 4 for further detail.

Discussion The role of NCT in the treatment of ILC has long been a topic of debate. Taken collectively, our study and others have observed a lower rate of pCR after NCT in cases of ILC6,14-16 The apparent lack of response in these patients has traditionally discouraged the widespread use of NCT for the treatment of ILC.16-18,26,27 However, our results identify a subset of ILC patients with comparable pCR rates to that of IDC patients, who appear to benefit from this therapy. Molecular subtypes, particularly HER2-positive and TNBC, were identified as primary predictors of response to NCT in patients with ILC. In fact, the response rates in patients with triple negative and HR-negative/HER2-positive ILC were 20.5% and 37.9%, compared with 27.6% and 38.1% for equivalent IDC molecular

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riba et al  neoadjuvant chemotherapy in lobular carcinomass

Table 1 e Study cohort characteristics according to histologic group.

Table 2 e General characteristics of patients who received neoadjuvant chemotherapy.

Characteristic

Characteristic

Invasive lobular carcinoma

Invasive ductal carcinoma

n ¼ 36,785 (9.6%) n (%)

P value

Invasive lobular carcinoma

Invasive ductal carcinoma

n ¼ 344,360 (90.4%)

n ¼ 2417 (4.8%)

n ¼ 47,697 (95.2%)

n (%)

n (%)

n (%)

Age (y) Mean (SD)

Age (y) 63 (12)

59 (13)

<0.001

Age group (y) <40 40-54

<0.001

<40

504 (1.4)

20,452 (5.9)

9147 (24.9)

104,895 (30.5)

40-54

10,028 (27.2)

93,577 (27.2)

65

17,106 (46.5)

125,436 (36.4)

Ethnicity

55 (10)

51 (12)

<0.001

129 (5.3)

7803 (16.3)

<0.001

1044 (43.2)

21,408 (44.9)

55-64

765 (31.7)

12,013 (25.2)

65

479 (19.8)

6473 (13.6)

Non-Hispanic white

1905 (78.8)

32,167 (67.4)

Non-Hispanic black

265 (11.0)

8871 (18.6)

Other

247 (10.2)

6659 (14.0)

2123 (87.8)

42,076 (88.2)

294 (12.2)

5,621 (11.8)

Ethnicity

Non-Hispanic white

30,932 (84.1)

268,456 (78.0)

Non-Hispanic black

3140 (8.5)

40,070 (11.6)

Other

2713 (7.4)

35,834 (10.4)

<0.001

CDCC 1

Mean (SD) Age group (y)

55-64

0

30,790 (83.7)

287,251 (83.4)

5,995 (16.3)

57,109 (16.6)

0.160

0 1

<0.001

1

21,078 (57.3)

211,425 (61.4)

1

175 (7.3)

13,054 (35.5)

108,828 (31.6)

2

1243 (51.4)

27,644 (58.0)

3

2653 (7.2)

24,107 (7.0)

3

999 (41.3)

15,298 (32.0)

Low grade

10,354 (28.2)

72,750 (21.1)

Intermediate grade

23,542 (64.0)

142,845 (41.5)

2889 (7.8)

128,765 (37.4)

HR-positive/ HER2-positive

1,583 (4.3)

37,677 (10.9)

HR-positive/ HER2-negative

34,569 (94.0)

Tumor grade

500 (20.7)

1630 (3.4)

1552 (64.2)

14,198 (29.8)

Low grade

365 (15.1)

31,869 (66.8)

HR-positive/ HER2-positive

289 (12.0)

9540 (20.0)

HR-positive/ HER2-negative

1943 (80.4)

16,787 (35.2)

239,177 (69.5)

HR-negative/ HER2-positive

58 (2.4)

6199 (13.0)

Triple-negative

127 (5.2)

15,171 (31.8)

Yes

211 (8.7)

11,067 (23.2)

No

2206 (91.3)

36,630 (76.8)

Intermediate grade High grade

HR-negative/ HER2-positive

141 (0.4)

17,226 (5.0)

Triple-negative

492 (1.3)

50,280 (14.6)

<0.0001

4,098 (11.1)

44,309 (12.9)

NCT

407 (1.1)

25,366 (7.4)

NHT

867 (2.4)

3652 (1.0)

NCT þ AHT

2,010 (5.5)

22,331 (6.5)

NHT þ ACT

210 (0.6)

685 (0.2)

ACT

974 (2.6)

<0.001

132,957 (38.6)

8,521 (23.2)

71,675 (20.8)

<0.0001

Pathologic complete response <0.001

43,385 (12.6)

19,698 (53.5)

<0.0001

Hormonal receptors

Systemic therapy

Adjuvant combined

4755 (10.0)

Tumor grade <0.001

Hormonal receptors

AHT

0.573

Clinical stage

2

No systemic therapy

<0.001

CDCC

Clinical stage

High grade

P value

CDCC ¼ Charlson-Deyo comorbidity score; NHT ¼ neoadjuvant hormonal therapy; AHT ¼ adjuvant hormonal therapy; ACT ¼ adjuvant chemotherapy.

<0.0001

CDCC ¼ Charlson-Deyo comorbidity score.

subtypes. These findings should be taken into consideration when planning multimodality treatment decisions. Patients with ILC presenting with favorable predictive features (e.g., HER2-positive, triple-negative) should be considered suitable candidates for NCT. Alternatively, cases of ILC without these favorable predictive features may be better suited for alternative approaches including neoadjuvant endocrine therapy. Further studies will evaluate the comparative effectiveness of both of these neoadjuvant approaches in subsets of ILC.

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Fig. 2 e KaplaneMeier curve for overall survival according to achievement of pCR in patients with ILC. (Color version of figure is available online.) ILC has been widely and historically differentiated from IDC by its immunohistochemical profiling, tendency to present with lower histologic grade and low mitotic index, and its greater likelihood of being HR-positive, and HER2- and p53negative.28,29 It is these intrinsic immunohistochemical/molecular factors that have been closely related to the substandard chemosensitivity of this morphological subtype of breast cancer, and not the histologic type itself,14,27 as evidenced by our findings of greater response rates to NCT in ILC subtypes demonstrating triple-negative or HER2-positive features.

Our results also demonstrate a clear 5-y survival benefit on achievement of pCR in patients with ILC, even after adjusting for clinically relevant variables such as age, ethnicity, comorbidity index, clinical stage, tumor grade, tumor molecular subtypes, and the use of adjuvant hormonal therapy or postmastectomy radiation therapy. Although previous studies have not found a direct survival benefit in achieving pCR in ILC cases, the low frequency of ILC and uncommon use of NCT in ILC results in prior studies having much smaller sample sizes that may limit their ability to detect an effect.5,27

Fig. 3 e KaplaneMeier curve for overall survival according to achievement of pCR in patients with IDC. (Color version of figure is available online.)

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riba et al  neoadjuvant chemotherapy in lobular carcinomass

Table 3 e Multivariable analysis for the achievement of pCR in each histologic group. Invasive lobular carcinoma Characteristic

Invasive ductal carcinoma OR

95% CI

1.34

0.75-2.39

Age group (y) <40

Characteristic

OR

95% CI

<40

1.08

1.01-1.15

40-54

1 (Ref)

Age group (y)

40-54

1 (Ref)

55-64

1.07

0.76-1.50

55-64

0.93

0.88-0.98

65

0.56

0.36-0.88

65

0.85

0.80-0.92

Non-hispanic white

1 (Ref)

Ethnicity Non-Hispanic white

Ethnicity 1 (Ref)

Non-Hispanic black

0.74

0.44-1.24

Non-hispanic black

0.84

0.80-0.92

Other

0.94

0.58-1.53

Other

0.92

0.86-0.98

0

1 (Ref)

1

0.91

0.85-0.98

0.81-0.94

CDCC 0 1

CDCC 1 (Ref) 1.02

0.65-1.62

Stage 1

0.56

0.29-1.08

Stage 2

1 (Ref)

Stage 3

0.91

0.67-1.23

1.37

0.94-2.01

Clinical stage

Clinical stage

Tumor grade Low grade Intermediate grade High grade

Stage 1

0.87

Stage 2

1 (Ref)

Stage 3

0.75

0.72-0.79

0.54-0.77

Tumor grade

1 (Ref) 1.19

0.80-1.75

Tumor markers

Low grade

0.64

Intermediate grade

1 (Ref)

High grade

1.52

1.44-1.61

Tumor markers

HR-positive/HER2-negative

1 (Ref)

HR-positive/HER2-negative

1 (Ref)

HR-positive/HER2-positive

4.83

3.38-6.91

HR-positive/HER2-positive

2.64

HR-negative/HER2-positive

11.16

6.16-20.21

HR-negative/HER2-positive

4.23

3.94-4.54

4.92

2.98-8.12

Triple-negative

2.47

2.32-2.62

Triple-negative C statistic ¼ 0.718

2.48-2.83

C statistic ¼ 0.662

CDCC ¼ Charlson-Deyo comorbidity score.

The following limitations were recognized in our study. The size discrepancy between the numbers of patients with ILC compared with IDC resulted in wider CIs affecting the statistical significance of certain regression analyses in which the odds ratio was in fact larger than in the IDC group. However, the aims of this study were primarily focused on analysis of the ILC group. The IDC group was included in the analysis to serve as a reference point being the most common histologic subtype, and through our methods we were not attempting to do a direct comparison of these two evidently different groups. Although our data set allowed us to confirm significant associations between treatment response in the ILC group and their respective receptor status, fixed granularity of the NCDB prevented the inclusion of known significant factors into our models and analyses, including p53 and Ki67 testing, tumor multifocality, extracapsular extension, and location of positive nodes. Another limitation of our study is the lack of detail about the specific chemotherapy regimen used in each case, information that could be of importance for analyzing the varying response to different treatment regimens. In addition, the NCDB contains only a single variable providing the time of initiation of chemotherapy;

therefore, we are not able to assess whether a patient received NCT and then had additional chemotherapy after surgery. This would not be a limitation for the pCR analysis because this is determined at the time of surgery, but it could affect the survival analysis. Owing to particularities in the reporting of immunotherapy in the NCDB, we acknowledge that our survival models do not incorporate the use of anti-HER2 therapy as a factor influencing mortality rates. However, it may be reasonable to assume that most patients with HER2-positive cancer received immunotherapy, while those patients with HER2-negative cancers did not.

Conclusions While complete response to NCT in patients with ILC is uncommon, our findings demonstrate selective benefit from NCT in the treatment of patients with HER2-positive and triple-negative ILC. These specific cases of ILC demonstrate pCR rates comparable with those found in cases of IDC. This selective benefit is, in addition, correlated with a clear survival benefit.

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Table 4 e Proportional hazard regression models for mortality. Invasive lobular carcinoma Characteristic Response to NCT

Invasive ductal carcinoma P value

95% CI

0.46

0.25-0.84

0.012

pCR No pCR Age group (y)

HR

1 (Ref)

1.46

0.71-2.99

1 (Ref)

55-64

1.69

1.17-2.44

1.37

0.89-2.13

65

Response to NCT

<0.001

pCR

Age group (y)

40-54

Ethnicity

P value

No pCR

0.049

<40

Characteristic

0.505

HR

95% CI

0.33

0.30-0.37

1 (Ref) <0.001

<40

1

0.90-1.11

40-54

1 (Ref)

55-64

1.11

1.03-1.20

1.42

1.30-1.55

65 Ethnicity

<0.001

Non-hispanic white

1 (Ref)

Non-hispanic black

1.21

0.78-1.86

Non-hispanic black

1.25

1.16-1.34

Other

0.79

0.41-1.51

Other

0.84

0.76-0.94

CDCC

0.012

0

CDCC 1 (Ref)

1 Clinical stage

1.68

0.39 1 (Ref)

Stage 3

2.17

0.14-1.09

1.56-3.02

0.492

Low grade

0.60-1.44

1 (Ref)

High grade

1.23

0.84-1.80

0.005 1 (Ref)

HR-negative/HER2-positive

1.76

1 (Ref) 1.29

1.18-1.41

Stage 1

0.43

0.36-0.51

Stage 2

1 (Ref)

<0.001

Stage 3

2.33

2.19-2.49

Low grade

0.59

0.44-0.79

Intermediate grade

1 (Ref)

<0.001

High grade Tumor markers

HR-positive/HER2-negative

<0.001

1

Tumor grade 0.93

Intermediate grade

Tumor markers

1.12-2.52

Clinical stage

Stage 2

1 (Ref)

0

<0.001

Stage 1

Tumor grade

Non-hispanic white

1.59

1.46-1.73

<0.001

HR-positive/HER2-negative

1 (Ref)

0.74-4.18

HR-negative/HER2-positive

0.49

0.42-0.56

HR-positive/HER2-positive

1.12

0.65-1.94

HR-positive/HER2-positive

0.54

0.48-0.61

Triple-negative

2.80

1.60-4.91

Triple-negative

1.08

0.97-1.21

Adjuvant hormonal therapy

0.009

Yes No Postmastectomy radiation

Adjuvant hormonal therapy 1 (Ref) 2.68

1.66-4.33

<0.001 1 (Ref)

No

1.07

0.73-1.57

1 (Ref)

No Postmastectomy radiation

Yes

<0.001

Yes

2.08

1.86-2.33

<0.001

Yes

1 (Ref)

No

1.19

1.11-1.29

CDCC ¼ Charlson-Deyo Comorbidity Score.

In view of these results, the decision to administer chemotherapy in the neoadjuvant setting to patients with ILC in an effort to achieve significant cytoreduction and improve outcomes should be determined carefully on a case by case basis, taking into consideration the complex biological characteristics of these tumors.

Acknowledgment The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytic or statistical methodology employed, or the conclusions drawn from these data by the investigator.

This work was conducted with support from Harvard Catalyst,The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR001102 and financial contributions from Harvard University and its affiliated academic health care centers). The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers, or the National Institutes of Health. Authors’ contributions: L.A.R. and T.A.J. helped in conception or design of the work. Data collection was carried out by L.A.R. Data analysis and interpretation was carried out by L.A.R., R.B.D., and T.A.J. Drafting the article was done by L.A.R.,

riba et al  neoadjuvant chemotherapy in lobular carcinomass

T.R., and T.A.J. Critical revision of the article was performed by L.A.R., T.R., R.B.D., and T.A.J. Final approval of the version to be published was done by L.A.R., T.R., R.B.D., and T.A.J.

13.

Disclosure

14.

The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article.

15.

Supplementary data

16.

Supplementary data related to this article can be found at https://doi.org/10.1016/j.jss.2018.08.011. 17.

references 18. 1. Bear HD, Anderson S, Brown A, et al. The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from national surgical adjuvant breast and bowel project protocol B-27. J Clin Oncol. 2003;21:4165e4174. 2. Fisher BB, Bryant J, Wolmark N, et al. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol. 1998;16:2672e2685. 3. Rastogi P, Anderson SJ, Bear HD, et al. Preoperative chemotherapy: updates of national surgical adjuvant breast and bowel project protocols B-18 and B-27. J Clin Oncol. 2008;26:778e785. 4. Van Nes JGH, Putter H, Julien JP, et al. Preoperative chemotherapy is safe in early breast cancer, even after 10 years of follow-up; clinical and translational results from the EORTC trial 10902. Breast Cancer Res Treat. 2009;115:101e113. 5. Wenzel C, Bartsch R, Hussian D, et al. Invasive ductal carcinoma and invasive lobular carcinoma of breast differ in response following neoadjuvant therapy with epidoxorubicin and docetaxel þ G-CSF. Breast Cancer Res Treat. 2007;104:109e114. 6. Truin W, Vugts G, Roumen RMH, et al. Differences in response and surgical management with neoadjuvant chemotherapy in invasive lobular versus ductal breast cancer. Ann Surg Oncol. 2016;23:51e57. 7. Onitilo AA, Onesti JK, Single RM, et al. Utilization of neoadjuvant chemotherapy varies in the treatment of women with invasive breast cancer. PLoS One. 2013;8:7e9. 8. James T, McCahill L, Ratliff J, et al. Quality assessment of neoadjuvant therapy use in breast conservation: barriers to implementation. Breast J. 2009;15:524e526. 9. Kantor O, Sipsy LM, Yao K, James TA. A predictive model for axillary node pathologic complete response after neoadjuvant chemotherapy for breast cancer. Ann Surg Oncol. 2018;25:1304e1311. 10. Ajmani GS, James TA, Kantor O, Wang CH, Yao KA. The impact of facility volume on rates of pathologic complete response to neoadjuvant chemotherapy used in breast cancer. Ann Surg Oncol. 2017;24:3157e3166. 11. Vasudevan D, Jayalakshmy PS, Kumar S, Mathew S. Assessment of pathological response of breast carcinoma in modified radical mastectomy specimens after neoadjuvant chemotherapy. Int J Breast Cancer. 2015;2015:536145. 12. Von Minckwitz G, Untch M, Blohmer JU, et al. Definition and Impact of pathologic complete response on prognosis after

19.

20.

21.

22.

23.

24. 25.

26.

27.

28.

29.

443

neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol. 2012;30:1796e1804. Li CI, Anderson BO, Daling JR, Moe RE. Trends in incidence rates of invasive lobular and ductal breast carcinoma. JAMA. 2003;289:1421e1424. Lips EH, Mukhtar RA, Yau C, et al. Lobular histology and response to neoadjuvant chemotherapy in invasive breast cancer. Breast Cancer Res Treat. 2012;136:35e43. Loibl S, Volz C, Mau C, et al. Response and prognosis after neoadjuvant chemotherapy in 1,051 patients with infiltrating lobular breast carcinoma. Breast Cancer Res Treat. 2014;144:153e162. Petrelli F, Barni S. Response to neoadjuvant chemotherapy in ductal compared to lobular carcinoma of the breast: a metaanalysis of published trials including 1,764 lobular breast cancer. Breast Cancer Res Treat. 2013;142:227e235. Katz A, Saad ED, Porter P, Pusztai L. Primary systemic chemotherapy of invasive lobular carcinoma of the breast. Lancet Oncol. 2007;8:55e62. Tubiana-Hulin M, Stevens D, Lasry S, et al. Response to neoadjuvant chemotherapy in lobular and ductal breast carcinomas: a retrospective study on 860 patients from one institution. Ann Oncol. 2006;17:1228e1233. Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. the value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology. 1991;19:403e410. Petruolo OA, Pilewskie M, Patil S, et al. Standard pathologic features can be used to identify a subset of estrogen receptorpositive, HER2 negative patients likely to benefit from neoadjuvant chemotherapy. Ann Surg Oncol. 2017;24:2556e2562. Boughey JC, McCall LMM, Ballman KV, et al. Tumor biology correlates with rates of breast-conserving surgery and pathologic complete response after neoadjuvant chemotherapy for breast cancer: findings from the ACOSOG Z1071 (Alliance) prospective multicenter clinical trial. Ann Surg. 2014;260:608e616. Houssami N, MacAskill P, Von Minckwitz G, Marinovich ML, Mamounas E. Meta-analysis of the association of breast cancer subtype and pathologic complete response to neoadjuvant chemotherapy. Eur J Cancer. 2012;48:3342e3354. Straver ME, Rutgers EJT, Rodenhuis S, et al. The relevance of breast cancer subtypes in the outcome of neoadjuvant chemotherapy. Ann Surg Oncol. 2010;17:2411e2418. National Cancer Database. Available at: https://www.facs. org/quality-programs/cancer/ncdb. Accessed April 6, 2018. Boffa DJ, Rosen JE, Mallin K, et al. Using the national cancer database for outcomes research. JAMA Oncol. 2017;3:1722e1728. Cristofanilli M, Gonzalez-Angulo A, Sneige N, et al. Invasive lobular carcinoma classic type: response to primary chemotherapy and survival outcomes. J Clin Oncol. 2005;23:41e48. Mathieu MC, Rouzier R, Llombart-Cussac A, et al. The poor responsiveness of infiltrating lobular breast carcinomas to neoadjuvant chemotherapy can be explained by their biological profile. Eur J Cancer. 2004;40:342e351. Reed AEM, Kutasovic JR, Lakhani SR, Simpson PT. Invasive lobular carcinoma of the breast: morphology, biomarkers and ’omics. Breast Cancer Res. 2015;17:12. Domagala W, Markiewski M, Kubiak R, Bartkowiak J, Osborn M. Immunohistochemical profile of invasive lobular carcinoma of the breast: predominantly vimentin and p53 protein negative, cathepsin d and oestrogen receptor positive. Virchows Arch A Pathol Anat Histopathol. 1993;423:497e502.