Feasibility of breast conservation after neoadjuvant chemotherapy in 58 patients with locally advanced breast cancer using p53 and mdr1 genes as predictors of response

Abstract EN

Purpose : the aim of this prospective trial was to evaluate the feasibility and outcome of breast conservation therapy for patients with locally advanced breast cancer after neoadjuvant chemotherapy.

We studied also the value of p53 and MDR1 as predictors to neoadjuvant chemotherapy.

Patients and methods : between August 1997 and May 2000, 58 patients with locally advanced breast carcinoma (stages IIIA and IIIB) completed treatment consisting of 5-fluorouracil 600 mg/m2, epirubicin 60 mg / m2 and cyclo-phosphamide 600 mg / m2 (FEC) administered intravenously, at intervals of 3 weeks.

The number of cycles of chemotherapy given depended on the clinical tumor response.

Surgery (local excision if sufficiently downstaged, or mastectomy if not, both with axillary dissection) was performed.

Surgery was followed by radiation therapy and 4 more cycles of FEC chemotherapy as an adjuvant therapy.

P53 and MDR1 were assessed in the initial tissue biopsy by means of reverse transcriptase-mediated polymerase chain reaction (RT-PCR).

p53 and MDR1 findings were correlated with treatment response and linkage between p53 function and cellular response was assessed by terminal deoxynucleotidyl transferase-mediated nick end labeling assay.

Results : the overall response (CR+PR) was 87.9 %, with a clinical complete response rate of 29.3 %.

Six patients had a pathological complete response and 10 patients had only minimal residual disease.

Median follow-up from the start of chemotherapy was 24 months (range 6 to 40).

Twenty two patients (43 %) underwent BCS with actuarial 3-year disease-free and overall survival of 58 % and 75% respectively.

Cosmetic results were good to excellent in 77.2 % of the patients.

Modified radical mastectomy was done in 29 / 51 (56.9 %) patients with actuarial 3-year disease-free and overall survival of 60% and 78 % respectively.

In 13 out of 58 patients (22.4 %), p53 mutations could be identified, including eight point mutations, three minor deletions and two complex deletions.

Mutations were located in exons 4, 6, 7, 8 and 10 of the p53 gene, including two mutations in the intron region affecting the splice sites.

The seven non-responders showed p53 mutations while 6 / 51 responding patients had p53 mutations.

Treatment failure was related to the presence of p53 gene mutations (p = 0.0029).

Presence of apoptosis was related to a normal p53 status and treatment response (p < 0.0001).

In patients responding to FEC, the mean percentage of apoptotic cells was seven.

Of 7 patients with treatment failure, 5 had 0 % and two patients had 1% apoptotic cells.

Twelve patients showed the specific band corresponding to the MDR1 mRNA.

All patients with no response to neoadjuvant chemotherapy had MDR1 gene expression.

MDR1 expression was significantly correlated with resistance to neoadjuvant chemotherapy (p = 0.0026).

The remaining five patients with MDR1 expression had (PR) to neoadjuvant chemotherapy and also had p53 mutations.

Conclusion : in conclusion, the results of the present study compare favorably with previous studies in patients with locally advanced breast cancer (LABC).

Our results suggest that breast conservation was feasible and safe for patients with LABC, with careful selection based on response to chemotherapy.

We have demonstrated that p53 plays a distinct drug-specific role in chemoresistance.

The response to a combination of FEC was directly related to normal p53 and tumor cell apoptosis in breast cancer patients.

These results provide clinical evidence of a p53-dependent cytotoxic effect of these DNA-damaging agents.

It seems that resistance to chemotherapy is a multi-factorial phenomenon, in which many genes are involved.