Neoadjuvant Study With Chemotherapy, Lapatinib And Trastuzumab In Breast Cancer

Pathological Complete Response (pCR) is defined by the complete absence of infiltrating tumor cells in the breast and in the lymph nodes. The pathological response in the breast was evaluated according to the criteria of Miller and Payne as follows: Grade 1, no change or some alteration to individual malignant cells, but no reduction in overall cellularity; Grade 2, a minor loss in tumor cells (up to 30%); Grade 3, between an estimated 30% and 90% reduction in tumor cells; Grade 4, marked disappearance of tumor cells, with only a small cluster or a dispersed cell remaining (more than 90% loss); Grade 5, no identifiable malignant cells. Ductal carcinoma in situ (DCIS) may be present. Grades were interpreted as follows: Grade 1-2=no response; Grade 3-4=partial response; Grade 5=complete response. pCR was defined by comparing specimens obtained at Baseline (biopsy) to those obtained upon surgery.

Time frame: At Baseline and surgery (within 5 weeks after the last chemotherapy administration) (assessed up to Study Week 29)

Population: Efficacy Analysis Population: all participants in the Intent-to-Treat Population (all participants who were randomized), except for the 2 participants who were excluded because of withdraw of consent and major protocol deviation

An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect. Medical or scientific judgment had been exercised in deciding whether reporting was appropriate in other situations.

Time frame: From the first dose of randomized therapy to 30 days after the last dose of randomized therapy (assessed up to Study Week 29)

Population: Safety Population: all randomized participants

Treatment failure is defined as the occurrence of local tumor progression (including ipsilateral and controlateral breast), distant tumor progression, permanent treatment discontinuation (either for the experimental or conventional arm), or death due to any cause.

Time frame: From randomization up to 29 weeks

Population: ITT Population

Analysis of mutations in the PI3KCA gene was performed from RNA extracted from frozen tumor tissue samples (sections). A gene is either a wild-type (no mutation) or mutated (presence of a mutation). Exons 9 and 20 of the PI3KCA gene were accessed (high frequency mutation at these two spots).

Time frame: Baseline

Population: ITT Population. Only those participants for which high-quality tumor tissue samples were available were analyzed.

The percentage of inhibition of intermediate (EGFR, HER2, pMAPK, pAKT, PTEN, and PI3KCA) and final (TUNEL and Ki67) biomarkers of the proliferation and apoptosis pathways was calculated as the difference between the staining scores before (Baseline \[biopsy\]) and after treatment (withdrawal).

Time frame: At Baseline and Withdrawal (assessed up to Study Week 29)

Population: ITT Population. Only those participants contributing data to the indicated time points were analyzed.

The percentage of participants who had BCS and mastectomy and who were initiallycandidates for mastectomy and who actually had BCS was measured. At Baseline, the surgeon stated, within 4 weeks before starting the primary treatment, which type of surgical treatment he would perform in the absence of primary therapy and in the case of primary therapy (if the tumor size was reduced by the primary treatment to less than 3 centimeters), and the reasons for these choices. The rules for choosing the type of surgical treatment are reported in the Consensus Conference on Primary Treatment of Early Breast Cancer. The surgeon was to have re-evaluated the participant after primary treatment. In cases in which the type of surgical procedure was different from that originally programmed, the reason for this chance was to have been reported.

Time frame: At Baseline and at surgery (up to Study Week 29)

Population: Efficacy Analysis Population

The clinical response was evaluated by comparing the tumor size (largest tumor diameter) before (at Baseline \[biopsy\]) and after treatment (before surgery), as assessed by ultrasonography examination. The clinical response was scored by Response Evaluation Criteria in Solid Tumors (RECIST) as follows: complete clinical response: the nodule is not detectable and all the ultrasound abnormality detected at diagnosis disappeared (margins circumscribed, round oval shape, parallel orientation, isoechoic echo pattern, no posterior acoustic features, echogenic lesion boundary, and tumor vascularity not present); partial clinical response: the longest diameter of the tumor has been reduced by \>50%, and the ultrasound characteristics of the tumor persist; no response (stable disease): the longest diameter of the tumor has been reduced by \<50% or has increased by no more than 20% from the starting value; progressive disease: tumor longest diameter has increased \>20% from the starting value.

Time frame: At Baseline and after primary treatment (within 2 weeks before surgery; up to Study Week 27)

Population: Efficacy Analysis Population

Time to treatment failure (TTF) is defined as the interval of time between the date of randomization and the earliest date of disease progression, premature treatment discontinuation and death due to any cause. The overall disease progression date is the earlier of the two disease progression dates from ultrasonography and mammography assessments. For ultrasonography, disease progression is defined as at least 20% increase in the longest diameter of the primary lesion at pre-surgery comparing to Baseline. For mammography, disease progression is defined as at least 20% increase in the larger nodule dimension at pre-surgery comparing to Baseline. For participants who has neither progressed, pre-maturely withdrawn or died, time to treatment failure will be censored at the latest date of ultrasonography and mammography tumor assessments.

Time frame: From randomization up to Study Week 307

Population: ITT Population: all participants who were randomized