Hamed:

This is an excellent question, still fraught with confusion, controversy and lack of consensus, so I will try below to clarify the issues involved and suggest

DEFINING pCR (PATHOLOGICAL COMPLETE RESPONSE)

TROUBLE IN PARADISE: NO CONSENSUS

The core of any definition of pCR is achieving no residual histological evidence of tumor after chemotherapy at the time of surgery (i.e. a pathological complete response (pCR)). But, past this, as noted by FDA experts Tatiana Prowell and Patricia Cortazar of the FDA's Breast Oncology Group [1], the definition of pCR itself has no universal consensus: it may be construed as:

(1) absence of invasive cancer in the breast only;

OR

(2) absence of invasive cancer in the breast AND axillary lymph nodes;

OR

(3) absence of invasive AND in situ cancer in the breast only;

OR

(4) absence of invasive AND in situ cancer in the breast AND axillary lymph nodes

showing that some investigators evaluate pCR based on the state of the primary lesion alone, whereas others evaluate it based on the states of both the primary lesion and axillary lymph nodes, and investigators are also split has to whether in situ disease (DCIS) is allowed or not.

Furthermore, there is no standard method for grading pathological response of breast tumors to neoadjuvant chemotherapy and a number of different classification systems have been proposed [2,3,4,5,6,7]. Most, but not all, of these grading schemes have included both no residual disease of any sort and residual ductal carcinoma in situ (DCIS) without invasive disease in the definition of pCR, that is, they allowed for residual DCIS as long as there was otherwise no residual histological evidence of tumor.

WHAT A DIFFERENCE A DEFINITION MAKES

A clear demonstration that differences in definition can matter as to what the computed response rates are is given by Frederique Penault-Llorca and colleagues in France [8] who conducted a review of neoadjuvant therapy for 710 breast cancer patients in order to assess the residual disease in breast and nodes according to either the pTNM system of Chevallier [2] as opposed to that of the Sataloff classification [3]. What they found was that the pCR rate is 14.3% according to the pTNM system but almost double that (25.8%) when computed under the Sataloff classification. Why, we ask? This is entirely due to the different definitions of pCR being used: under the pTNM system, pCR is defined as the “disappearance of all invasive tumor” but under the Sataloff classification the definition of pCR is far more relaxed and permissive, being “total therapeutic effect or minimal residual disease (scattered cells accounting for less than 5% of the tumor surface)”.

THE DILEMMA SOLVED

The Royal Marsden team's retrospective analysis of a prospectively maintained database found no difference in disease-free survival (DFS) and overall survival (OS) between patients with residual DCIS and those with no invasive or in situ disease following neoadjuvant chemotherapy for breast cancer [9]. This settles the question as to whether the definition of pCR needs to explicitly include the absence of in situ cancer, and the answer is that it does not, as this does not give rise to any clinically relevant impact on either DFS or OS outcomes. This leaves the definition as "absence of invasive cancer in the breast" (regardless of the presence or absence of any in situ disease), and this brings it essentially in agreement with the NSABP (National Surgical Adjuvant Breast and Bowel Project) definition in their NSABP B 18 trial [4] which allows specimens with intraductal (that is, in situ) residual tumor cells. That leaves, to my mind, only the M.D. Anderson (MDA) Cancer Center trial’s pCR criteria [10] as requiring not only complete response of the primary lesion but also the disappearance of axillary lymph node metastasis, and it strikes me that this is a more radical and not widely adopted criteria (remember: axillary lymph node disease often requires radiotherapy, above and beyond, chemotherapy, to be regressed, so this goes beyond the customary definition of pCR as the consequence of chemotherapy). In addition, if we use the reasonable criteria of:

(1) the most accurate prognosis,

(2) a sufficient number of patients and

(3) thorough follow-up;

then only the NSABP B18 trial pCR definition ("absence of invasive cancer in the breast" (regardless of the presence or absence of any in situ disease)) meets these conditions, but there can still be some divergence in definition here so an interim suggestion is that every study explicitly and clearly provide their definition of pCR so we know what criteria are being used.

WHAT IS STILL NEEDED

However, in conclusion, although the NSABP definition of pCR seems the most compelling, nonetheless there still remains a vital need to adopt a singular cohesive authoritative definition to avoid cross-trial lack of translatability, and that it seems to me requires the authority of an organization like ASCO in conjunction with comparable European, Japanese, and other national, regional and international guideline organizations to finally promulgate a consensus statement to be used across all clinical trials.

REFERENCES

1. Prowell T, Cortazar P. Pathologic Complete Response in Neoadjuvant Treatment of High-Risk Early-Stage Breast Cancer: Use of an Endpoint to Support Accelerated Approval. Office of Hematology Oncology Products Breast Oncology Group. FDA Webinar. June 28, 2012. At: http://www.fda.gov/downloads/Drugs/UCM310088.pdf.

2. Chevallier B, Roche H, Olivier JP, Chollet P, Hurteloup P (1993) Inflammatory breast cancer. Pilot study of intensive chemotherapy (FEC-HD) results in a high histologic response rate. Am J Clin Oncol 16: 223–228.

3. Sataloff DM, Mason BA, Prestipino AJ, Seinige UL, Leiber CP, Baloch Z (1995) Pathologic response to induction chemotherapy in locally advanced carcinoma of the breast: a determinant of outcome. Am J Coll Surg 180: 297–306.

4. Fisher B, Brown A, Mamounas E, Wieand S, Robidoux A, Margolese RG, Cruz AB, Fisher ER, Wickerham DL, Wolmark N, DeCillis A, Hoehn JL, Lees AW, Dimitrov NV (1997) Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from the National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol 15: 2483–2493.

5. Honkoop AH, van Diest PJ, de Jong JS, Linn SC, Giaccone G, Hoekman K, Wagstaff J, Pinedo HM (1998) Prognostic role of clinical, pathological and biological characteristics in patients with locally advanced breast cancer. Br J Cancer 77: 621–626,

6. Kuerer HM, Newman LA, Buzdar AU, Dhingra K, Hunt KK, Buchholz TA, Binkley SM, Strom EA, Ames FC, Ross MI, Feig BW, McNeese MD, Hortobagyi GN, Singletary SE (1998) Pathologic tumour response in the breast following neoadjuvant chemotherapy predicts axillary lymph node status. Cancer J Sci Am 4: 230–236.

7. Ogston KN, Miller ID, Payne S, Hutcheon AW, Sarkar TK, Smith I, Schofield A, Heys SD (2003) A new histological grading system to assess response of breast cancers to primary chemotherapy: prognostic significance and survival. Breast 12: 320–327.

8. Penault-Llorca F, Abrial C, Raoelfils I, et al. Comparison of the prognostic significance of Chevallier and Sataloff’s pathologic classifications after neoadjuvant chemotherapy of operable breast cancer. Hum Pathol. 2008;39(8):1221-1228.

9. Jones RL, Lakhani SR, Ring AE, Ashley S, Walsh G, Smith IE. Pathological complete response and residual DCIS following neoadjuvant chemotherapy for breast carcinoma. Br J Cancer 2006 Feb 13; 94(3):358-62.

10. Green MC, Buzdar AU, Smith T et al (2005) Weekly paclitaxel improves pathologic complete remission in operable breast cancer when compared with paclitaxel once every 3 weeks. J Clin Oncol 23:5983–5992.

Amazing answer Constantine! It was pleasure to read it.

Alexander:

Thanks for the appreciation, and I follow your own exceptional work and responses, learning much from them.

Constantine

Constantin .... Thank you

Professor

Giorgio Mustacchi .... Thank you too

Thanks . Constantine Kaniklidis

https://www.fda.gov/media/83507/download#:~:text=Pathological%20complete%20response%20(pCR)%20is,completion%20of%20neoadjuvant%20systemic%20therapy

pCR: Pathological Complete Resposnse:

Loco-regionally advance breast cancer are recommended to start treatment with Neo-Adjuvant Chemotherapy (NACT). This leads to resolution/ regression of tumour in body inclusding Breast and Axilla, Supra clavicular region.

Post chemotherapy if no tumour is palpated on clinical examination including Sonogram/ CT/ MRI, it will be documented as cCR (Clinical complete response). However, in spiet of clinical complete response many of these patient ultimately demonstrate viable tumour in pathology specimen.

1. However, in 20% to 30% of triple negative breast cancer there will be no viable tumour detected in breast and Axilla, both! This is pCR! it denotes that NACT has been very effective and no further chemotherapy is recommended. However, Triple negative breast cancer , post NACT, tumour is detected in pathology specimen, additional 6 months of Capasitabine chemotherapy is recommended as it will improve survival.

2. pCR is also considered as surrogate marker for better survival for breast cancer patients.