DOI: 10.

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The Pathologic Complete Response Open Question in Primary

Therapy
Caterina Marchiò, Anna Sapino
Correspondence to: Anna Sapino, MD, Department of Biomedical Sciences and Human Oncology, University of Turin, Via Santena 7, Turin 10126, Italy
(e-mail: [email protected]).

Accurate pathological diagnosis of tumor mass before treatment and careful examination of specimens after treatment are two
main objectives in the diagnostic process of neoadjuvant-treated breast cancer. To achieve the first objective, multiple core
biopsies can be taken to assess intratumor heterogeneity and thus to address a more targeted therapeutic protocol. At the same

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time, fine needle aspiration cytology of lymph nodes found suspicious at ultrasound examination may be useful to plan surgical
treatment. As for the second objective, a careful examination of specimens after primary systemic therapy is mandatory to
evaluate the effect of treatment. In fact, clinical response does not necessarily correlate with pathological response. Pathological
complete response (no residual invasive tumor, in situ carcinoma can be present, and no residual lymph node metastasis) con-
stitutes an independent predictor of outcome in neoadjuvant-treated patients. Residual isolated tumor cells in primary tumor
and in lymph nodes do not affect patient outcome.

J Natl Cancer Inst Monogr 2011;43:86–90

Neoadjuvant chemotherapy is planned for patients with locally (3) and Sataloff (4) classifications and found that the pCR rate was
advanced carcinomas or with tumors primarily not suitable for 14.3% according to the Chevallier and 25.8% according to the
breast-conserving surgery; thus, one of the aims of this therapeutic Sataloff classification. This was due to the different definition of
option is to downsize the disease burden (primary tumor + lymph pCR, being labeled as “disappearance of all invasive tumor” by
node metastasis). A crucial point of the whole concept of preopera- Chevallier and as “total therapeutic effect or minimal residual
tive systemic treatment is represented by the degree of response to disease (scattered cells accounting for less than 5% of the tumor
therapy that has been shown to correlate with patient outcome. surface)” by Sataloff. However, patients with either pCR or almost
Clinical response can be recorded according to the International pCR displayed a similar behavior in terms of overall-and disease-
Union Against Cancer (UICC) (1) and the TNM systems. It is free survival (5). A correct and standardized evaluation of the
worth mentioning that both systems do not contemplate histological residual tumor burden is highly dependent on the precise evaluation
assessment of the degree of response, and therefore, clinical of the invasive carcinoma characteristics before chemotherapy. It
response does not necessarily correlate with the pathological is therefore essential, for the pathological assessment of response,
response (2) (Table 1), which is measured by the amount of tumor to correctly define the nature of the different lesions that form large
cells persisting in the surgical specimen after treatment. According tumor masses and the dimension and histology of the infiltrating
to this principle, a pathological complete response (pCR) is defined carcinoma, which is the only target of neoadjuvant chemotherapy.
in the primary tumor as either 1) no residual carcinoma, or 2) no In our routine experience, sampling of different tumor areas by
residual invasive tumor but presence of in situ carcinoma in the core biopsy is helpful to define the precise nature of the lesion
surgical specimen. In the lymph nodes, pCR is defined as no evi- (benign vs malignant, in situ vs invasive), the different tumor
dence of metastatic disease. histotypes present in the mass, and the heterogeneity of the
Even though this definition of pCR is universally accepted, expression of predictive markers such as hormone receptors,
different systems are currently being used to categorize response HER2, and Ki67 (Figure 1). For example, among the histological
to preoperative systemic treatment in breast cancer (both for the parameters to be assessed for treatment response, cellularity of the
primary tumor and for the lymph nodes) (2,11). One may wonder residual tumor may be somewhat subjective. Some authors have
which one should be the method of choice, however, no thorough proposed a graphical illustration (available on the Internet) to show
comparisons have been performed so far. As a general concept, it how to evaluate this parameter (8). However, hypocellularity does not
should be considered that all of the systems recognize a category necessarily equate to tumor response because some tumor types
of pCR and a category of no response, with a variable number of are sclerotic and hypocellular. In addition, in the case of non-pCR,
categories of partial response (11) (for a detailed description of the the morphological and immunophenotypical parameters (hormone
different available classifications see Table 1). receptors, HER2, Ki67) evaluated before treatment have to be
Penault-Llorca et al. (5) have conducted a review of 710 patients reconsidered and accurately revaluated after treatment to
with breast cancer treated with neoadjuvant therapy to assess the distinguish between partial responder and nonresponders and
residual disease in breast and nodes according to the Chevallier eventually to address toward further specific treatments.

86   Journal of the National Cancer Institute Monographs, No. 43, 2011
 Another issue to be considered is related to the presence of in shown that large format paraffin-embedded sections may be
situ carcinoma after neoadjuvant chemotherapy. As mentioned particularly suitable to assess the extension of ductal in situ carci-
before, this finding has no clinical significance as long as the surgical nomas and the margin status of specimens derived from breast-
margins are free of disease (12). In a previous study (13), we have conserving surgery. In our experience, large sections are particularly

Table 1. Description of systems for categorization of response to primary therapy*

Classification Clinical vs
system pathological Primary tumor Lymph nodes

UICC (1) Clinical Complete response: absence of remaining tumor. //

Partial response: 50% reduction in the product of the two
  largest perpendicular dimensions of the lesion.
Progressive disease: >25% increase in tumor size.
Stable disease: all other lesions.

pTNM Pathological ypT ypN

Chevallier Pathological 1. D isappearance of all tumors both on macroscopic and
  et al. (3) microscopic assessment.

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2. In situ carcinoma present but no residual invasive tumor
and no metastatic lymph nodes.
3. Invasive carcinoma present with stromal changes
(sclerosis, fibrosis).
4. Few modifications of the appearance of the tumor.

Sataloff Pathological T-A: total or near total therapeutic effect (in the latter case: N-A: evidence of therapeutic
  et al. (4)   scattered cells accounting for >5% of the tumor surface).   effect, no metastatic disease.
T-B: subjectively >50% therapeutic effect but less than total or N-B: no nodal metastatis or
  near total.   therapeutic effect.
T-C: >50% therapeutic effect. N-C: evidence of therapeutic
T-D: no therapeutic effect evident.   effect but nodal metastasis
  still present.
N-D: viable metastatic disease,
  no therapeutic effect.

Penault-Llorca Pathological Class I regroups Ch(1+2) and TANA–NB = complete or almost

  et al. (5)   complete response in breast and absence of node involvement
Class II regroups Ch(3), TANC–ND and TB or C any N = partial
  responders, any N/complete or almost complete
  responders and node involvement
Class III regroups Ch(4) and TD any N = nonresponders

Bonadonna Pathological Grade 1: some alteration to individual cells but no overall reduction //
  et al (6)   in numbers when compared with pretreatment core biopsy.
Grade 2: mild loss on invasive cells but still with high cellularity.
Grade 3: considerable reduction in cells, up to 90% loss.
Grade 4: marked reduction, that is, only clusters of widely
  dispersed cells detected.
Grade 5: no invasive carcinoma identified; in situ carcinoma or
  tumor stroma may still be noted.

Smith (7) Pathological G1: no reduction in overall numbers of tumor cells compared A: true negative, no metastasis,
  with pretreatment core biopsy.   and no alterations.
G2: mild loss of tumor cells, but overall cellularity B: metastasis with no histological
  remaining high.   alterations.
G3: up to 90% reduction in tumor cells. C: metastasis with alterations.
G4: marked disappearance with only small clusters remaining. D: no metastasis with alterations.
G5: no invasive tumor; in situ carcinoma or tumor remaining.

RCB system (8) Pathological RCB index (RCB is calculated as a continuous index combining
  pathological measurements of primary tumor
  [size and cellularity] and nodal metastases [number
  and size] for prediction of distant relapse-free survival in
  multivariate Cox regression analyses; see:
  http://www.mdanderson.org/breastcancer_RCB).
RCB-0: no carcinoma in breast or lymph node.
RCB-I: partial response.
RCB-II: partial response.
RCB-III: chemoresistant.

(Table continues)

Journal of the National Cancer Institute Monographs, No. 43, 2011   87

Table 1 (Continued).

Classification Clinical vs
system pathological Primary tumor Lymph nodes

Miller-Payne Pathological Grade 1: no change or some alteration to individual malignant //

  system (9)   cells, but no reduction in overall cellularity.
Grade 2: a minor loss of tumor cells, but overall cellularity
  still high; up to 30% loss (pPR).
Grade 3: between an estimated 30% and 90% reduction
  in tumor cells (pPR).
Grade 4: a marked disappearance of tumor cells such that
  only small clusters or widely dispersed individual cells remain;
  >90% loss of tumor cells (almost pCR).
Grade 5: no malignant cells identifiable in sections from the
  site of the tumor; only vascular fibroelastotic stroma remains,
  often containing macrophages; DCIS maybe present (pCR).
NSABP B-18 (10) Pathological pCR: no recognizable invasive tumor cells present. //
pPR: the presence of scattered individual or small clusters of

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  tumor cells in a desmoplastic or hyaline stroma.
pNR: tumors not exhibiting the changes listed above.
Pinder et al (2) Pathological 1. Complete pathological response: i) no residual carcinoma, or ii) 1. No evidence of metastatic
  no residual invasive tumor but DCIS present.   disease and no
2. Partial response to therapy, either i) minimal residual   evidence of changes in
  disease/near total effect (eg, <10% of tumor remaining) or   the lymph nodes.
  ii) evidence of response to therapy but with 10%–50% of 2. Metastatic tumor not
  tumor remaining, or iii) >50% of tumor cellularity remains   detected but evidence
  evident when compared with the previous core biopsy   of response/downstaging
  sample, although some features of response to therapy present.   (eg, fibrosis).
3. No evidence of response to therapy. 3. Metastatic disease present
  but also evidence of
  response, such as nodal fibrosis.
4. Metastatic disease present
  with no evidence of
  response to therapy.

* DCIS = ductal carcinoma in situ; pCR = pathological complete response; pPR = pathological partial response; pNR = pathological no response; RBC = residual cancer
burden; ypT = pathological tumor size assessed on specimens after neoadjuvant treatment; ypN = pathological lymph node status assessed after neoadjuvant
treatment; //: not available.

suitable to process surgical samples after neoadjuvant treatment as and whether sentinel lymph node is sensitive enough to be consid-
well because they may allow to best evaluate both margin status ered a good surrogate for lymph node status (14,15,18). In analogy
and the residual tumor burden. to the classification of pCR in primary tumor, it should be noted that
The other issue is represented by pCR assessment in the presence of “isolated tumor cells” in lymph nodes does not impact
axillary lymph nodes. If we consider pCR as a comparison of the on the disease-free survival of patients (19), therefore, routine
same target (histology) at two different time points (before and immunocytochemical procedure using cytokeratins as marker of
after chemotherapy), it is evident that the presurgical assessment of epithelial cells is not recommended after primary chemotherapy.
the lymph nodes is more difficult than in the primary tumor. From a pathological standpoint, a final consideration is related
In fact, multiple core biopsies can be taken from the primary to the possibility to discriminate responders, from partial
tumor, whereas the evaluation of multiple lymph nodes by tru-cut responders and nonresponders before treatment using pathological
biopsies in the preoperative setting is more troublesome. An alter- variables. For example, among the different histological types of
native procedure may be the cytological study of fine needle aspi- breast cancer, it has been demonstrated that invasive lobular carci-
ration of lymph nodes found suspicious at ultrasound examination nomas of classical morphology have a pCR rate of 2% or less (20).
of the axilla (14–17). This diagnostic tool is routinely used in the On the contrary, among the standard immunophenotypical markers,
presurgical setting of breast cancer patients in general and acquires it is well known that estrogen receptor expression influences
even more importance in the decision of the surgical protocol in tumor response, so that estrogen receptor–negative tumors show
the neoadjuvant context. By evaluating fine needle aspiration of significantly higher pCR rates than estrogen receptor–positive
ultrasound suspicious axillary nodes, patients who are definitely tumors (21–25). Therefore, we believe that a wide sampling of
proven node negative may be candidate to sentinel node biopsy tumors before treatment is mandatory to account not only for
prior chemotherapy and, if the negative result is confirmed at histol- intertumor but also for intratumor heterogeneity. The biological
ogy, they may be spared from axillary dissection after chemotherapy diversity of the disease, demonstrated by morphological mapping
(14,15) (Figure 1). A persistent controversy has been as whether obtained with multiple core biopsies, can represent indeed a reliable
sentinel node biopsy should be performed before or after treatment guide for the selection of the best neoadjuvant protocol. In addition, a

88   Journal of the National Cancer Institute Monographs, No. 43, 2011
Figure 1.  Schematic representation of assess-
ment of primary tumor and lymph node status
in patients candidate to neoadjuvant treatment.
DCIS = ductal carcinoma in situ; ER = estrogen
receptor; FAD = fibroadenoma; FNA = fine nee-
dle aspiration; IDC = invasive ductal carcinoma;
ILC = invasive lobular carcinoma; LIN = lobular
intraepithelial neoplasia; LND = lymph node;
PR = progesterone receptor; PST = primary
systemic therapy; US = ultrasound.

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wide sampling is important to avoid overtreatment of both noninva- 8. Symmans WF, Peintinger F, Hatzois C, et al. Measurement of residual
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J Clin Oncol. 2007;25(28):4414–4422.
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9. Ogston KN, Miller ID, Payne S, et al. A new histological grading system
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vant chemotherapy should be as accurate as possible for two rea- significance and survival. Breast. 2003;12(5):320–327.
sons. First of all, pCR in the primary tumor and in the axillary 10. Fisher ER, Wang J, Bryant J, Fisher B, Mamounas E, Wolmark N.
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