Pathologic Response and Long-Term Follow-up

in Breast Cancer Patients Treated

With Neoadjuvant Chemotherapy
A Comparison Between Classifications and Their Practical Application
Adriana D. Corben, MD; Rita Abi-Raad, MD; Ion Popa, MD; Clarence H. Y. Teo, MD; Eric A. Macklin, PhD;
Frederick C. Koerner, MD; Alphonse G. Taghian, MD, PhD; Elena F. Brachtel, MD

 Context.—Breast cancer is increasingly treated with Results.—RDBN was associated with distant disease-free
neoadjuvant chemotherapy to improve surgical resectabil- survival by univariate and multivariate analysis (P ¼ .01
ity and evaluate tumor response, which is assessed and .004, respectively), as were lymph node metastases (P
histopathologically. Several histopathologic classification ¼ .02 and .01, respectively). Five patients (8%) had
systems have been previously described for assessment of complete pathologic response after neoadjuvant chemo-
treatment response. therapy, and none of them relapsed during the study
Objective.—To test performance in a side-by-side com- period. Survival was shorter among patients with higher
parison of several histopathologic classification systems Residual Cancer Burden scores, but the associations were
after neoadjuvant chemotherapy with clinical outcome. not significant. Miller-Payne grading and Sataloff tumor
Design.—Sixty-two patients were enrolled in a random- scores were not correlated with survival.
ized trial receiving sequential neoadjuvant chemotherapy
Conclusions.—Evaluation of breast specimens after neo-
with doxorubicin and paclitaxel. Histologic sections from
the patients’ tumors sampled before (core biopsy) and after adjuvant chemotherapy by the composite index RDBN
treatment (excision or mastectomy) were reviewed. correlates with long-term outcome. The residual disease in
Histologic response was assessed following National breast and nodes system is suitable for routinely processed
Surgical Adjuvant Breast and Bowel Project protocol pathology cases. This study confirms the importance of
B18, Miller-Payne grading, Sataloff tumor and nodes, lymph node status after neoadjuvant chemotherapy and
Residual Cancer Burden (RCB), and Residual Disease in favorable outcome in patients with pathologic complete
Breast and Nodes (RDBN). Pathologic classification results response.
were correlated with survival using Kaplan-Meier and Cox (Arch Pathol Lab Med. 2013;137:1074–1082; doi:
hazards regression with a median follow-up of 93 months. 10.5858/arpa.2012-0290-OA)

B reast cancer is increasingly treated with preoperative

neoadjuvant chemotherapy (NACT) to reduce local
Responses to NACT include a spectrum of morphologic
alterations in tumors and lymph nodes, ranging from
complete disappearance of invasive cancer cells (pathologic
disease and to directly evaluate treatment response, which
can provide additional prognostic information.1–5 complete response [pCR]) to partial tumor regression, no
response, or progressive tumor growth during treatment
(Figure 1, A through G).6,7 Pathologic complete response
has consistently been associated with good long-term
Accepted for publication September 18, 2012.
From the Departments of Pathology (Drs Corben, Popa, Teo, outcome but is achieved in only 10% to 20% of cases, and
Koerner, and Brachtel, Radiation Oncology (Drs Abi-Raad and certain subtypes such as lobular carcinoma show even lower
Taghian), and Biostatistics (Dr Macklin), Massachusetts General response rates.8,9 Higher rates of pCR can be achieved when
Hospital and Harvard Medical School, Boston. Dr Corben is now selecting for certain breast cancer subtypes and treatment
with Memorial Sloan-Kettering Cancer Center, New York, New York. regimens.5,10–12 The negative effect of residual tumor in
Dr Abi-Raad is now with Yale University, New Haven, Connecticut.
Dr Teo is now with Tan Tock Sen Hospital, Singapore. lymph nodes on long-term outcome has also been
The authors have no relevant financial interest in the products or established.6,13
companies described in this article. Clinical examination and imaging provide approximate
Presented at the 100th Annual Meeting of the United States and indicators of response to treatment, but careful gross and
Canadian Academy of Pathology; March 1, 2011; San Antonio, Texas histopathologic examination of the excision or mastectomy
(abstract 133).
Reprints: Elena F. Brachtel, MD, Department of Pathology, specimen after chemotherapy is necessary to assess the
Massachusetts General Hospital, 55 Fruit St, WRN2, Boston, MA breast and lymph nodes for residual carcinoma.14,15 A tumor
02114 (e-mail: ebrachtel@partners.org). that shows complete clinical response still can show residual
1074 Arch Pathol Lab Med—Vol 137, August 2013 Breast Cancer Patients Treated With Neoadjuvant Chemotherapy––Corben et al
Figure 1. Histopathologic examples of treatment effect after neoadjuvant chemotherapy (NACT). Invasive ductal carcinoma in a pretreatment
breast core biopsy (A). Residual breast carcinoma post-NACT (B). Residual high-grade ductal carcinoma post-NACT (C). Complete pathologic
response in the breast with scar tissue but no tumor cells (D). Lymph node post-NACT with residual micrometastasis (’) adjacent to scar tissue (E).
Macrometastasis with viable tumor cells in post-NACT lymph node (F). Lymph node partly replaced by fibrous scar tissue with no residual carcinoma
after NACT (G) (hematoxylin-eosin, original magnifications 320 [A], 312 [B], 3400 [C and F], 340 [D and G], and 3100 [E]).

carcinoma on microscopic examination; conversely, a of 4 groups of complete and partial response.23,24 Residual
palpable residual mass may show only fibrosis.7,16 The Disease in Breast and Nodes (RDBN) uses the formula
majority of breast carcinomas treated with NACT produce a RDBN ¼ 0.2 3 tumor size (cm) þ lymph node stage (0–3) þ
pathologic partial response, and this area with its broad and histologic grade (1–3), which takes into account tumor size,
often morphologically challenging spectrum of residual lymph node stage, and histologic grade to determine the
carcinoma is less well defined.17–20 levels of response.25–27 Residual ductal carcinoma in situ is
Several histopathologic classifications are available to compatible with complete pathologic response in the
categorize the tumor response to NACT. The original NSABP-B18, RDBN, and RCB classifications, and Miller-
National Surgical Adjuvant Breast and Bowel Project Payne grade 5.3,21,23,26,28
(NSABP) B18 trial recognized 2 categories: pCR, defined We chose the classifications for their basis in histopa-
as no histologic evidence of invasive tumor cells in the thology and because they provide a spectrum ranging from
breast, and pINV, indicating histologic evidence of residual simple dichotomy (NSABP-B18) and linear histologic
invasive carcinoma cells.3,6 Miller-Payne grading provides a response in breast only (Miller-Payne) or breast and lymph
5-step scale based on tumor cellularity in the excision/ nodes (Sataloff) to more complex algorithms, including a
mastectomy specimen as compared with the pretreatment formula (RDBN) or Web calculator (RCB). We then tried out
core biopsy.21 Sataloff et al22 proposed a dual 4-tier system, how they performed in our hands with an archival cohort.
separately assessing residual tumor and treatment in Several other classifications are not included at this point:
primary tumor site and lymph nodes. Residual Cancer for example, American Joint Committee on Cancer (AJCC)29
Burden (RCB) uses size and cellularity of the tumor bed ‘‘y’’ staging uses standard clinicopathologic staging param-
including the percentage of residual ductal carcinoma in situ eters posttreatment. Chevallier et al30 devised a 4-step
and tumor burden in lymph nodes with a statistically algorithm to grade response in breast and lymph nodes. The
complex algorithm. The result is a continuous score Rouzier nomogram integrates clinical stage, estrogen
obtained by Web calculator, which is then assigned into 1 receptor status, histologic grade, and number of chemo-
Arch Pathol Lab Med—Vol 137, August 2013 Breast Cancer Patients Treated With Neoadjuvant Chemotherapy––Corben et al 1075
therapy cycles to predict complete response and survival.31 Statistical Analysis and Endpoint Definitions
Prior comparative studies have included NSABP-B18, Distant relapse was defined as histopathologic and/or radio-
Chevallier, and Sataloff classifications.32,33 logic documentation of distant metastasis. Distant disease-free
Because of the variety and complexity of classification survival (DDFS) was defined as the time interval between surgery
schemes, clinicians and pathologists alike may question if and the first documented distant relapse, death, or last follow-up.
any classification should be used when reporting the Overall survival (OS) was defined as the time between surgery
findings in breast cancer specimens after NACT. This study and death or last follow-up, whichever occurred first. The T and N
attempts to resolve this situation by performing a side-by- categories were assigned according to the American Joint
side comparison of some of the available histopathologic Committee on Cancer.29 Survival curves were estimated by
Kaplan-Meier product-limit estimates. Log-rank tests were used
classifications using pre- and post-NACT tissue specimens
for unadjusted, univariate analysis of each classification scheme as
in relation to clinical outcome. a predictor of DDFS and OS, stratified by treatment randomiza-
tion. Linear trend tests were used for ordinal classifications. Cox
MATERIALS AND METHODS proportional-hazards regression, adjusting for age and stratified
Patients by treatment randomization, was used for age-adjusted univariate
and multiple regression models. Number of positive lymph nodes
Sixty-two patients were enrolled between 2000 and 2004 in and maximum tumor diameter were Winsorized at their 90th
randomized clinical trial 99-278 (ClinicalTrials.gov identifier percentiles to avoid undue influence by a few highly leveraged
NCT00096291) for sequential NACT with doxorubicin (A) and points. P values were increased by Winsorizing in all cases. P
paclitaxel (T).34 Patient consent and approval by the institutional values , .05 were considered statistically significant. Hazard
review board had been obtained. Patients were randomized to ratios (HRs) were given when trends were tested across groups.
receive both chemotherapeutic agents doxorubicin (A) and Statistical analyses were performed using SAS (version 9.2, SAS
paclitaxel (T) in either the sequence A . T or T . A. At interim Institute, Cary, North Carolina). Graphs were generated with
analysis for the pathology evaluation, the survival in both groups MedCalc Software (version 11.2.1, MedCalc Software, Maria-
was not significantly different, and statistical analysis included kerke, Belgium).
stratification for treatment randomization. Patients underwent
diagnostic core biopsies before NACT, followed by excision or RESULTS
mastectomy after NACT. Mean (median) patient age at diagnosis
was 49 (48) years, ranging from 30 to 68 years. For patients Clinicopathologic Factors and Clinical Outcome
without recurrence, the mean and median follow-up time was 93 The findings are summarized in Table 1. Mean (median)
months. tumor size was 4.3 (3.5) cm pre-NACT and 1.8 (1.4) cm
Histologic Samples post-NACT. The majority of tumors were invasive ductal
carcinomas (n ¼ 54), with positive estrogen receptor and
Tissue samples were fixed in 10% neutrally buffered formalin and negative human epidermal growth factor receptor 2 status.
paraffin embedded following standard protocols of the histology
Lymph node involvement was associated with survival. No
laboratory. Five-micrometer sections were stained with hematox-
ylin-eosin for histologic review. If original slides were unavailable correlations with DDFS or OS were detected between pre-
at the time of this study, recuts from archival paraffin blocks were NACT tumor size measured by magnetic resonance imaging
prepared. Immunohistochemical stains for E-cadherin, myoepithe- and post-NACT tumor size established by pathologic
lial cells (p63, calponin, and smooth muscle myosin), lymphatic evaluation. Pre-NACT median tumor size in the 5 breast
endothelial cells (D2-40 and CD31), and estrogen and progester- tumors with pCR was 6.5 cm, and was therefore larger than
one receptor proteins were prepared following standard immuno- the median tumor size in the overall study population of 3.5
peroxidase protocols. Human epidermal growth factor receptor 2 cm. Also, in our study, histologic type (invasive ductal
evaluation was primarily done by immunohistochemistry with versus invasive lobular carcinoma), histologic grade, pres-
scoring as described followed by fluorescence in situ hybridization ence of lymphovascular invasion, estrogen receptor or Her2
in cases with equivocal (2þ) Human Epidermal Growth Factor
status, and some patient characteristics, such as age or
Receptor 2 (HER2) immunohistochemical staining.35 Most immu-
nohistochemical and fluorescence in situ hybridization tests were
menopausal status, did not correlate with prognosis.
done at time of primary diagnosis. RDBN Predicts Survival After NACT
Histopathologic Review Among the classification schemes evaluated, the age-
Study pathologists reviewed hematoxylin and eosin and immu- adjusted trend for the 4 levels of RDBN predicted DDFS but
nohistochemically stained sections from patients’ tumors sampled not OS in our cohort (Figure 2, A and B; Table 2). The age-
before (core biopsy) and after treatment (excision or mastectomy). unadjusted trend for the 4 levels of RDBN predicted both
The findings reported at time of initial histopathologic evaluation DDFS (P ¼ .01; HR, 2.54; 95% confidence interval [CI], 1.36–
were updated when necessary. Histologic grading was performed 5.08) and OS (P ¼ .04; HR, 2.25; 95% CI, 1.06–5.16). The
as previously described.36,37 The macroscopic measurements of continuous RDBN score was also associated with DDFS (P ¼
tumor bed area and residual tumor mass were supplemented by .01; HR, 1.55; 95% CI, 1.11–2.25) but not OS (P ¼ .08; HR,
microscopic measurements. Proportion of ductal carcinoma in situ 1.44; 95% CI, 0.98–2.20) when analyzed by Cox propor-
and overall tumor cellularity was estimated following the instruc- tional-hazards regression with adjustment for age. The
tions of the authors or using the Web-based calculator as
applicable.23,24 The number of positive lymph nodes was grouped
RDBN score remained a significant independent predictor of
for American Joint Committee on Cancer staging and individual DDFS even in multiple Cox regression models that adjusted
classification schemes.22,26,29 for age and each of the pathologic predictors Sataloff tumor
(P ¼ .002; HR, 1.88; 95% CI, 1.29–2.91), Sataloff nodes (P ¼
Radiologic Imaging .02; HR, 2.13; 95% CI, 1.22–4.25), RCB (P ¼ .01; HR, 2.07;
All patients had magnetic resonance imaging of the breast before 95% CI, 1.23–3.56), pretreatment tumor size (P ¼ .003; HR,
NACT. The maximum diameter of the largest nodule evaluated by 1.79; 95% CI, 1.24–2.71), posttreatment tumor size (P ¼ .001;
magnetic resonance imaging served as tumor size pre-NACT, and HR, 2.1; 95% CI, 1.37 to 3.34), NSABP-B18 (P ¼ .01; HR,
the gross or histologic evaluations defined tumor size post-NACT. 1.88; 95% CI, 1.22–3.05), and number of involved lymph
1076 Arch Pathol Lab Med—Vol 137, August 2013 Breast Cancer Patients Treated With Neoadjuvant Chemotherapy––Corben et al
 Table 1. Clinicopathologic Parameters
Distant Died of Survival,
Total Relapse Disease mo DDFS OS
No. % No. % No. % DDFS OS P HR 95% CI P HR 95% CI
Patient age, y (N ¼ 62)
,50 36 58 13 72 8 62 84 89 .09 1.85 0.98–4.25 .10 2.37 0.99–8.12
50 26 42 5 28 5 38 89 90
Menopause status (N ¼ 61)
Pre 37 61 11 65 7 58 84 89 .66 0.74 0.18–2.86 .46 0.51 0.08–2.89
Post 24 39 6 35 5 42 89 90
Diagnosis core biopsy (N ¼ 61)
IDC 54 89 14 78 11 85 89 90 .24 2.01 0.55–5.95 .87 1.14 0.17–4.42
ILC 7 11 4 22 2 15 65 83
Lymph vessel invasion (N ¼ 60)
Absent 41 68 9 56 7 58 87 92 .15 2.15 0.73–6.11 .09 3.07 0.81–11.56
Present 19 32 7 44 5 42 85 89
Lymph nodes post-NACT (N ¼ 60)
N0 28 47 4 25 3 25 89 90 ,.01 2.25 1.31–3.99 .04 1.85 1.01–3.40
N1 18 30 5 31 5 42 81 92
N2 11 18 4 25 2 17 85 93
N3 3 5 3 19 2 17 19 38
ER status (N ¼ 62)
þ 45 73 13 72 9 69 85 92 .92 0.94 0.32–3.42 .60 0.69 0.19–3.25
 17 27 5 28 4 31 88 89
HER2 status (N ¼ 62)
3þ/amplified 16 26 3 17 3 23 89 90 .70 0.77 0.17–2.49 .85 0.86 0.13–3.53
Not amplified 46 74 15 83 10 77 84 90
Size of IC pre-NACT (MRI), cm (N ¼ 62)
.2 0 0 0 0 0 0 NA NA .53 0.70 0.19–1.99 .51 0.60 0.09–2.29
.2–5 46 74 14 78 11 85 83 89
.5 16 26 4 22 2 15 89 98
Size of IC post-NACT (pathologic evaluation), cm (N ¼ 60)
Absent 5 8 0 0 1 8 103 103 .26 1.42 0.77–2.59 .88 0.94 0.43–1.95
,2 33 55 9 56 9 69 84 90
.2–5 17 29 4 25 2 15 85 89
.5 5 8 3 19 1 8 64 93
Grade of IC pre-NACT (N ¼ 62)
1 2 3 0 0 0 0 115 115 .96 0.98 0.47–2.16 .45 1.50 0.55–4.78
2 25 40 9 50 5 38 84 94
3 32 52 8 44 7 54 84 89
Cannot grade 3 5 1 6 1 8 87 87
Grade of IC post-NACT (N ¼ 62)
1 6 10 0 0 0 0 114 114 .09 2.04 0.94–5.16 .06 2.95 1.08–10.57
2 21 34 6 33 4 31 83 92
3 25 40 10 56 8 61 83 89
Cannot grade 10 16 2 11 1 8 88 88
Abbreviations: CI, confidence interval; DDFS, distant disease-free survival; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2;
HR, hazard ratio; IC, invasive carcinoma; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; MRI, magnetic resonance imaging; NA,
not available; NACT, neoadjuvant chemotherapy; OS, overall survival.

nodes (P ¼ .02; HR, 2.36; 95% CI, 1.26–5.51). RDBN continuous RCB score (P ¼ .07 and .14, respectively) (Figure
remained a strong but not significant independent predictor 3, A and B; Table 2).
in models with age and AJCC grouping of lymph nodes (P ¼
.07; HR, 1.83; 95% CI, 1.04–3.94) and the maximum size of Lymph Node Status Predicts Survival After NACT
lymph node metastases (P ¼ .07; HR, 1.79; 95% CI, 1.02– More positive lymph nodes after NACT correlated with
3.51). The small number of observed distant recurrences (n worse outcome (Figure 4, A and B; Table 1). The size of the
¼ 16 among patients with scored samples) precluded largest lymph node deposit as measured microscopically
evaluation of more complex models. also predicted DDFS (P ¼ .01; HR, 1.1; 95% CI, 1.04–1.33)
Median DDFS and OS were shorter among patients with but not OS (P ¼ .17; HR, 1.1; 95% CI, 0.95–1.27). Seventeen
higher RCB scores, but the associations were not significant patients had been diagnosed with axillary lymph node
either by age-unadjusted log-rank test (P ¼ .09 and .08, metastases by cytology (n ¼ 5) or sentinel node excision (n ¼
respectively) or by age-adjusted Cox regression for the 12) before NACT; the lymph node status pre-NACT was not
Arch Pathol Lab Med—Vol 137, August 2013 Breast Cancer Patients Treated With Neoadjuvant Chemotherapy––Corben et al 1077
Figure 2. Residual Disease in Breast and Nodes (RDBN) response in relation to distant disease-free survival (A) and overall survival (B) by age-
adjusted Kaplan-Meier survival analysis. Best outcome in patients with pathologic complete response (RDBN group 1, n ¼ 3), followed by those with
RDBN index 0.1–2.9 (group 2, n ¼ 20), 3–4.3 (group 3, n ¼ 24) and ,4.4 (group 4, n ¼ 13).
Figure 3. Residual Cancer Burden (RCB) response in relation to distant disease-free survival (A) and overall survival (B), by age-adjusted Kaplan-
Meier survival analysis. Best outcome in patients with pathologic complete response (group 0, n ¼ 2) and RCB-I (group 1, minimal residual disease,
good prognosis, n ¼ 1), followed by RCB-II (group 2, moderate residual disease, intermediate prognosis, n ¼ 32) and RCB-III (group 3, extensive
residual disease, unfavorable prognosis, n ¼ 21).
Figure 4. Lymph node involvement after neoadjuvant chemotherapy is an important predictor of survival with favorable outcome for N0 and
unfavorable outcome for N3. LN_AJCC: Lymph nodes following the American Joint Committee on Cancer (AJCC) staging system. Age-adjusted
Kaplan-Meier survival analysis shown for distant disease-free survival (A) and overall survival (B).

associated with survival (data not shown). Lymph node pCR Indicates Favorable Outcome
score according to the Sataloff system was associated with
DDFS by Kaplan-Meier (Figure 5, A; Table 2) and Cox 29% of all patients (n ¼ 18) developed distant metastases
regression analysis (P ¼ .04 and .04, respectively), but not during follow-up, whereas none of the patients with no
with OS (P ¼ .11). residual carcinoma in the breast after NACT relapsed (Table
1078 Arch Pathol Lab Med—Vol 137, August 2013 Breast Cancer Patients Treated With Neoadjuvant Chemotherapy––Corben et al
 Table 2. Comparison of Several Classifications to Evaluate Pathologic Response After Neoadjuvant Chemotherapy
Median
Distant Died of Survival,
Total Relapse Disease mo DDFS OS
Score No. % No. % No. % DDFS OS P HR 95% CI P HR 95% CI
RDBN (N ¼ 60) 60 100 16 100 12 100
Index ¼ 0, pCR in RDBN-1 3 5 0 0 0 0 89 89 .01 2.56 1.34– .07 2.06 0.99–
breast and lymph 5.33 4.79
nodes
Index 0.1–2.9, residual RDBN-2 20 33 2 12 2 16 87 96
carcinoma
Index 3.0–4.3, residual RDBN-3 24 40 6 38 5 42 89 90
carcinoma
Index 4.4, residual RDBN-4 13 22 8 50 5 42 56 85
carcinoma
RCB (N ¼ 56) 56 100 15 100 11 100
pCR in breast and RCB-0 2 3 0 0 0 0 108 108 .11 2.08 0.89– .13 2.38 0.84–
lymph nodes 5.43 8.15
Minimal residual RCB-1 1 2 0 0 0 0 114 114
disease
Moderate residual RCB-2 32 57 7 47 5 45 86 92
disease
Extensive residual RCB-3 21 38 8 53 6 55 79 88
disease
Sataloff nodes (N ¼ 58) 58 100 15 100 11 100
No nodal metastasis, N-A 1 2 0 0 0 0 88 88 .04 1.77 1.04– .11 1.71 0.90–
therapeutic effect 3.15 3.45
present
No nodal metastasis, N-B 27 46 4 27 3 27 89 90
no therapeutic effect
Nodal metastasis, N-C 12 21 3 20 3 27 83 96
therapeutic effect
present
Nodal metastasis, no N-D 18 31 8 53 5 46 81 89
therapeutic effect
Sataloff tumor (N ¼ 57) 57 100 15 100 11 100
Total or near-total T-A 12 21 3 20 3 27 88 88 .17 0.71 0.42– .09 0.58 0.29–
therapeutic effect 1.15 1.06
Subjectively .50% T-B 17 30 6 40 5 46 59 88
but less than total/
near total
,50% therapeutic T-C 17 30 5 33 2 18 84 90
effect
No therapeutic effect T-D 11 19 1 7 1 9 98 98
MPG (N ¼ 57) 57 100 15 100 11 100
No reduction in Grade 1 11 19 1 7 1 9 98 98 .34 1.22 0.80– .19 1.41 0.85–
overall cellularity 1.86 2.39
Minor (,30%) loss of Grade 2 9 16 3 20 1 9 84 89
cellularity
Estimated 30%–90% Grade 3 22 38 7 46 5 46 72 89
reduction of tumor
cells
.90% loss of tumor Grade 4 10 18 4 27 4 36 81 81
cells
No invasive Grade 5 5 9 0 0 0 0 103 103
carcinoma; DCIS
may be present
NSABP-B18 (N ¼ 57) 57 100 15 100 11 100
pCR pCR 5 9 0 0 0 0 103 103 .99 NA NA . .99 NA NA
pINV pINV 52 91 15 100 11 100 84 89
Abbreviations: CI, confidence interval; DCIS, ductal carcinoma in situ; DDFS, distant disease-free survival; HR, hazard ratio; MPG, Miller-Payne
grading; NA, not available; NSABP, National Surgical Adjuvant Breast and Bowel Project; OS, overall survival; pCR, pathologic complete response;
pINV, residual invasive carcinoma; RCB, residual cancer burden; RDBN, residual disease in breast and nodes.

2). Absence of invasive tumor cells in the breast (n ¼ 5) post- axillary lymph nodes; they were subsequently excluded from
NACT was considered pCR with the NSABP-B18, and grade the RDBN level 1 (pCR) category (n ¼ 3), which requires
5 with the Miller-Payne classification. Two patients with absence of invasive tumor in both breast and lymph nodes
pCR in the breast had micrometastatic deposits in the (Figure 2; Table 2). Pathologic complete response according
Arch Pathol Lab Med—Vol 137, August 2013 Breast Cancer Patients Treated With Neoadjuvant Chemotherapy––Corben et al 1079
Figure 5. Several other postneoadjuvant treatment classifications and outcome: Sataloff lymph node classification (SAT_N) evaluates post–
neoadjuvant chemotherapy lymph node status and is correlated with distant disease-free survival (DDFS; A). Sataloff tumor classification (SAT_T; B),
Miller-Payne grading (MPG; C), and National Surgical Adjuvant Breast and Bowel Project (NSABP)–B18 (D) measure residual tumor in the breast
and were not associated with DDFS or overall survival in this cohort by age-adjusted Kaplan-Meier survival analysis.

to the RCB criteria requires absence of invasive carcinoma in DDFS but not for OS when adjusted for age. In age-
both breast and lymph nodes for the most favorable unadjusted calculations, however, both were significant. The
categories (Figure 3; Table 2). authors think that qualitative interpretation of the survival
analysis presented in this study is valuable despite those
Sataloff Tumor, Miller-Payne Grading, and NSABP-B18 limitations, and that results should subsequently be
Are Not Associated With Clinical Outcome validated on larger sample sizes and different cohorts.
We found no statistically significant association between Our study confirms that the number of positive lymph
NSABP-B18 categories and DDFS or OS by log-rank test or nodes is a highly important parameter for the long-term
Cox regression. Incongruent patterns of the Kaplan-Meier outcome after NACT. We showed that the number of
survival curves, that is, better survival of patients with larger involved lymph nodes as well as the size of metastases is
tumor or score grades or with less regressive changes over relevant for long-term outcome (Figure 4; Table 1).38 When
those with smaller tumors, were observed with classifica- comparing different classification schemes, those that
tions based exclusively on tumor size or estimates of tumor integrate lymph node involvement, such as RDBN and
cellularity such as Miller-Payne grading or Sataloff tumor RCB, demonstrated better correlation with long-term
(Table 2; Figure 5, B through D). outcome than those based only on breast tumor size or
cellularity.
COMMENT Pathologic complete response indicates an overall favor-
In our study, the composite index RDBN to assess able survival in breast cancer after NACT, but pCR is defined
histologic response after NACT was associated with differently in different classifications and may be redefined
relapse-free survival by age-adjusted univariate and multi- for future practice.5 Both the RDBN and RCB systems
variate analysis. Because of the small size of our cohort and require absence of invasive carcinoma in both breast and
rare events in certain groups, statistical evaluation had lymph nodes.23,26 Both NSABP-B18 and Miller-Payne
limitations. Residual disease in breast and nodes and lymph grading require absence of invasive carcinoma in the breast
node status for this cohort were statistically significant for but do not include the assessment of the lymph nodes.6,21
1080 Arch Pathol Lab Med—Vol 137, August 2013 Breast Cancer Patients Treated With Neoadjuvant Chemotherapy––Corben et al
The Sataloff T-A category is defined as ‘‘total or near-total However, practical considerations will contribute to the
therapeutic effect,’’ which may include a proportion of decision which classification, if any, is chosen by an
residual invasive carcinoma, whereas the Sataloff N-A/B institution to report breast carcinoma response after
category refers to negative lymph nodes.22,32 The number of NACT.
patients with pCR in the cohort of this study was small (n ¼ References
5), and included patients with no residual tumor in both 1. Bonadonna G, Valagussa P, Brambilla C, et al. Primary chemotherapy in
breast and lymph nodes (n ¼ 3), as well as those with no operable breast cancer: eight-year experience at the Milan Cancer Institute. J Clin
tumor in the breast but with residual tumor in the lymph Oncol. 1998;16(1):93–100.
2. Gralow JR, Burstein HJ, Wood W, et al. Preoperative therapy in invasive
nodes (n ¼ 2). breast cancer: pathologic assessment and systemic therapy issues in operable
Histologic grade is a well-established prognostic factor for disease. J Clin Oncol. 2008;26(5):814–819.
treatment-naı̈ve breast cancer, which also has predictive 3. Wolmark N, Wang J, Mamounas E, Bryant J, Fisher B. Preoperative
chemotherapy in patients with operable breast cancer: nine-year results from
value for post-NACT breast cancer evaluation.25,31,36 In National Surgical Adjuvant Breast and Bowel Project B-18. J Natl Cancer Inst
RDBN, high tumor grade weighs in as a negative prognostic Monogr. 2001(30):96–102.
factor when residual tumor is present, in addition to lymph 4. Buzdar AU, Valero V, Ibrahim NK, et al. Neoadjuvant therapy with
paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide
node involvement and tumor size.26 Other post-NACT chemotherapy and concurrent trastuzumab in human epidermal growth factor
response classifications discussed in this study do not receptor 2-positive operable breast cancer: an update of the initial randomized
consider histologic grade.6,21–23,25,36,39 The favorable survival study population and data of additional patients treated with the same regimen.
of low-grade tumors in our cohort coincided with the one of Clin Cancer Res. 2007;13(1):228–233.
5. von Minckwitz G, Untch M, Blohmer JU, et al. Definition and impact of
complete responders, and those were high grade.25,26,31,40 pathologic complete response on prognosis after neoadjuvant chemotherapy in
Prior studies emphasized the lack of response to NACT for various intrinsic breast cancer subtypes. J Clin Oncol. 2012;30(15):1796–1804.
invasive lobular carcinomas or other low-grade breast 6. Fisher B, Bryant J, Wolmark N, et al. Effect of preoperative chemotherapy
on the outcome of women with operable breast cancer. J Clin Oncol. 1998;16(8):
cancers.8,41,42 Overall, high tumor grade was associated with 2672–2685.
less favorable survival, which is in agreement with other 7. Fisher ER, Wang J, Bryant J, Fisher B, Mamounas E, Wolmark N.
studies whose classifications use histologic grade.25,26,31,40 Pathobiology of preoperative chemotherapy: findings from the National Surgical
Adjuvant Breast and Bowel (NSABP) protocol B-18. Cancer. 2002;95(4):681–
Histologic grade was reassessed for tumors in pre-NACT 695.
core biopsies and post-NACT excision or mastectomy 8. Katz A, Saad ED, Porter P, Pusztai L. Primary systemic chemotherapy of
specimens by histologic slide review; minor differences invasive lobular carcinoma of the breast. Lancet Oncol. 2007;8(1):55–62.
9. Rastogi P, Anderson SJ, Bear HD, et al. Preoperative chemotherapy:
between pre- and post-NACT grade were observed for low- updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18
grade tumors (Table 1). The limiting factor for grading core and B-27. J Clin Oncol. 2008;26(5):778–785.
biopsies was small sample size and poor preservation in 3 10. Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant chemotherapy
with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant
cases. The authors conclude that histologic grade on post- chemotherapy alone, in patients with HER2-positive locally advanced breast
NACT specimens is feasible, mostly congruent with the pre- cancer (the NOAH trial): a randomised controlled superiority trial with a parallel
NACT tumor grade, and important to report. HER2-negative cohort. Lancet. 2010;375(9712):377–384.
Related to histologic grade and proliferative activity are 11. Untch M, Rezai M, Loibl S, et al. Neoadjuvant treatment with trastuzumab
in HER2-positive breast cancer: results from the GeparQuattro study. J Clin
molecular subtypes of breast cancer, which are increasingly Oncol. 2010;28(12):2024–2031.
used for prediction of neoadjuvant response.5,43,44 Indepen- 12. Bhargava R, Beriwal S, Dabbs DJ, et al. Immunohistochemical surrogate
dently of their genomic subtype, the post-NACT breast markers of breast cancer molecular classes predicts response to neoadjuvant
chemotherapy: a single institutional experience with 359 cases. Cancer. 2010;
excision or mastectomy specimens still have to be evaluated 116(6):1431–1439.
by a pathologist to assess individual response. 13. Fisher B, Dignam J, Tan-Chiu E, et al. Prognosis and treatment of patients
Classifications based on routine staging and grading with breast tumors of one centimeter or less and negative axillary lymph nodes. J
Natl Cancer Inst. 2001;93(2):112–120.
parameters (eg, tumor size, lymph node involvement, 14. Pinder SE, Provenzano E, Earl H, Ellis IO. Laboratory handling and
histologic grade) were easier to apply in this retrospective histology reporting of breast specimens from patients who have received
setting than those that require dedicated or prospective neoadjuvant chemotherapy. Histopathology. 2007;50(4):409–417.
15. Sahoo S, Lester SC. Pathology of breast carcinomas after neoadjuvant
measurements to obtain the information in the grossing chemotherapy: an overview with recommendations on specimen processing and
area or at the microscope (eg, tumor bed size, comparison reporting. Arch Pathol Lab Med. 2009;133(4):633–642.
with prior core biopsy, cellularity estimates). Direct mor- 16. Feldman LD, Hortobagyi GN, Buzdar AU, Ames FC, Blumenschein GR.
phologic comparison with the core biopsy is of course Pathological assessment of response to induction chemotherapy in breast cancer.
Cancer Res. 1986;46(5):2578–2581.
desirable, but may not always be possible in practice 17. Sharkey FE, Addington SL, Fowler LJ, Page CP, Cruz AB. Effects of
because some patients have their diagnostic core biopsy at preoperative chemotherapy on the morphology of resectable breast carcinoma.
a different hospital. Also, the core biopsy might not Mod Pathol. 1996;9(9):893–900.
18. Moll UM, Chumas J. Morphologic effects of neoadjuvant chemotherapy in
necessarily be representative of the entire tumor. locally advanced breast cancer. Pathol Res Pract. 1997;193(3):187–196.
In summary, we confirmed the favorable prognosis of 19. Rajan R, Poniecka A, Smith TL, et al. Change in tumor cellularity of breast
patients with pCR after NACT, none of whom relapsed. carcinoma after neoadjuvant chemotherapy as a variable in the pathologic
assessment of response. Cancer. 2004;100(7):1365–1373.
Overall, 29% of patients (n ¼ 18) developed distant 20. Rabban JT, Glidden D, Kwan ML, Chen YY. Pure and predominantly pure
metastases during follow-up of up to 10 years. Because intralymphatic breast carcinoma after neoadjuvant chemotherapy: an unusual
the majority of breast carcinomas treated with NACT in and adverse pattern of residual disease. Am J Surg Pathol. 2009;33(2):256–263.
21. Ogston KN, Miller ID, Payne S, et al. A new histological grading system to
mixed cohorts do not show pCR, the pathologist needs to assess response of breast cancers to primary chemotherapy: prognostic
determine the extent of residual tumor in breast and lymph significance and survival. Breast. 2003;12(5):320–327.
nodes. Among the different classifications used to assess 22. Sataloff DM, Mason BA, Prestipino AJ, Seinige UL, Lieber CP, Baloch Z.
Pathologic response to induction chemotherapy in locally advanced carcinoma of
pathologic response after NACT, composite classifications the breast: a determinant of outcome. J Am Coll Surg. 1995;180(3):297–306.
that integrate features of primary tumor and lymph node 23. Symmans WF, Peintinger F, Hatzis C, et al. Measurement of residual breast
status showed better associations with outcome than those cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol.
using only a single tumor characteristic, for example, tumor 2007;25(28):4414–4422.
24. MD Anderson Residual Cancer Burden Calculator. http://www3.
size or cellularity. In this study, RDBN was associated with mdanderson.org/app/medcalc/index.cfm?pagename¼jsconvert3. Published
clinical outcome by univariate and multivariate analysis. 2007. Accessed October 24, 2012.

Arch Pathol Lab Med—Vol 137, August 2013 Breast Cancer Patients Treated With Neoadjuvant Chemotherapy––Corben et al 1081
 25. Chollet P, Amat S, Belembaogo E, et al. Is Nottingham prognostic index treated with neoadjuvant chemotherapy: clinical implications. J Clin Oncol.
useful after induction chemotherapy in operable breast cancer? Br J Cancer. 2005;23(9):1951–1961.
2003;89(7):1185–1191. 35. Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical
26. Chollet P, Abrial C, Durando X, et al. A new prognostic classification after Oncology/College of American Pathologists guideline recommendations for
primary chemotherapy for breast cancer: residual disease in breast and nodes human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol.
(RDBN). Cancer J. 2008;14(2):128–132. 2007;25(1):118–145.
27. Abrial SC, Penault-Llorca F, Delva R, et al. High prognostic significance of 36. Elston CW, Ellis IO. Pathological prognostic factors in breast cancer, I: the
residual disease after neoadjuvant chemotherapy: a retrospective study in 710 value of histological grade in breast cancer: experience from a large study with
patients with operable breast cancer. Breast Cancer Res Treat. 2005;94(3):255– long-term follow-up. Histopathology. 1991;19(5):403–410.
263. 37. Robbins P, Pinder S, de Klerk N, et al. Histological grading of breast
28. Mazouni C, Peintinger F, Wan-Kau S, et al. Residual ductal carcinoma in carcinomas: a study of interobserver agreement. Hum Pathol. 1995;26(8):873–
situ in patients with complete eradication of invasive breast cancer after 879.
neoadjuvant chemotherapy does not adversely affect patient outcome. J Clin 38. Klauber-DeMore N, Ollila DW, Moore DT, et al. Size of residual lymph
Oncol. 2007;25(19):2650–2655. node metastasis after neoadjuvant chemotherapy in locally advanced breast
29. Edge SB, Byrd SB, Compton CC, Fritz AG, Greene FL, Trotti A, eds.
cancer patients is prognostic. Ann Surg Oncol. 2006;13(5):685–691.
American Joint Committee on Cancer (AJCC) Cancer Staging Manual 7th ed.
39. Galea MH, Blamey RW, Elston CE, Ellis IO. The Nottingham Prognostic
Breast, pages 347–376. Springer 2010, New York.
Index in primary breast cancer. Breast Cancer Res Treat. 1992;22(3):207–219.
30. Chevallier B, Chollet P, Merrouche Y, et al. Lenograstim prevents morbidity
40. Schneeweiss A, Katretchko J, Sinn HP, et al. Only grading has independent
from intensive induction chemotherapy in the treatment of inflammatory breast
cancer. J Clin Oncol. 1995;13(7):1564–1571. impact on breast cancer survival after adjustment for pathological response to
31. Rouzier R, Pusztai L, Delaloge S, et al. Nomograms to predict pathologic preoperative chemotherapy. Anticancer Drugs. 2004;15(2):127–135.
complete response and metastasis-free survival after preoperative chemotherapy 41. Sullivan PS, Apple SK. Should histologic type be taken into account when
for breast cancer. J Clin Oncol. 2005;23(33):8331–8339. considering neoadjuvant chemotherapy in breast carcinoma? Breast J. 2009;
32. Penault-Llorca F, Abrial C, Raoelfils I, et al. Comparison of the prognostic 15(2):146–154.
significance of Chevallier and Sataloff’s pathologic classifications after neo- 42. Purushotham A, Pinder S, Cariati M, Harries M, Goldhirsch A. Neo-
adjuvant chemotherapy of operable breast cancer. Hum Pathol. 2008;39(8): adjuvant chemotherapy: not the best option in estrogen receptor-positive, HER2-
1221–1228. negative, invasive classical lobular carcinoma of the breast? J Clin Oncol. 2010;
33. Shien T, Shimizu C, Seki K, et al. Comparison among different 28(22):3552–3554.
classification systems regarding the pathological response of preoperative 43. Parker JS, Mullins M, Cheang MC, et al. Supervised risk predictor of breast
chemotherapy in relation to the long-term outcome. Breast Cancer Res Treat. cancer based on intrinsic subtypes. J Clin Oncol. 2009;27(8):1160–1167.
2009;113(2):307–313. 44. Tordai A, Wang J, Andre F, et al. Evaluation of biological pathways
34. Taghian AG, Abi-Raad R, Assaad SI, et al. Paclitaxel decreases the involved in chemotherapy response in breast cancer. Breast Cancer Res. 2008;
interstitial fluid pressure and improves oxygenation in breast cancers in patients 10(2):R37.

1082 Arch Pathol Lab Med—Vol 137, August 2013 Breast Cancer Patients Treated With Neoadjuvant Chemotherapy––Corben et al
Copyright of Archives of Pathology & Laboratory Medicine is the property of College of
American Pathologists and its content may not be copied or emailed to multiple sites or
posted to a listserv without the copyright holder's express written permission. However, users
may print, download, or email articles for individual use.