Prognostic significance of germline BRCA mutations in patients with HER2-POSITIVE breast cancer.

BACKGROUND: HER2-positive breast cancers are rare amongst BRCA mutation carriers. No data exist regarding clinicopathological characteristics and prognosis of this subgroup of patients. MATERIALS AND METHODS: Using a retrospective matched cohort design, we collected data from 700 women who were diagnosed with operable invasive breast cancer from January 2006 to December 2016 and were screened for germline BRCA mutations. Clinicopathological features and survival rates were analyzed by BRCA and HER2 status. RESULTS: One hundred and fifteen HER2-positive/BRCA mutated cases were evaluated in comparison to the three control groups: HER2-positive/BRCA wild type (n = 129), HER2-negative/BRCA mutated (n = 222), HER2-negative/BRCA wild type (n = 234). HER2-positive breast cancers were more likely to have high histologic grade and high proliferation rate than HER2-negative neoplasms, regardless of BRCA mutation status. An interaction between BRCA mutations and HER2-positive status was found to correlate with worse survival after adjusting for prognostic variables (HR = 3.4; 95% CI: 1.3-16.7). CONCLUSIONS: Co-occurrence of BRCA mutations and HER2-positive status is a poor prognostic factor in patients with early or locally advanced breast cancer. This finding may be a proof of concept that a combined pharmacological intervention directed to these targets could be synergistic.

Drug-drug interactions between palbociclib and proton pump inhibitors may significantly affect clinical outcome of metastatic breast cancer patients.

BACKGROUND: Proton-pump-inhibitors (PPIs) are frequently prescribed for the management of anticancer drug-related gastrointestinal symptoms. Palbociclib is a weak base with pH-dependent solubility and potential drug-drug interaction at the absorption level may affect clinical pharmacokinetics. The current study was aimed at investigating the effect of co-administration of PPIs and palbociclib on progression-free survival (PFS) in metastatic breast cancer (mBC) patients. PATIENTS AND METHODS: Patients affected by estrogen receptor-positive, human epidermal growth factor receptor 2-negative mBC, who were candidates for first-line treatment with palbociclib, were enrolled in this retrospective observational study. Patients were defined as 'no concomitant PPIs' if no PPIs were administered during palbociclib treatment, and as 'concomitant PPIs' if the administration of PPIs covered the entire or not less than two-thirds of treatment with palbociclib. All clinical interventions were made according to clinical practice. RESULTS: A total of 112 patients were enrolled in the study; 56 belonged to the 'no concomitant PPIs' group and 56 to the 'concomitant PPIs' group. Seventy-one patients were endocrine-sensitive and received palbociclib and letrozole, and 43 were endocrine-resistant and were treated with palbociclib and fulvestrant. The most prescribed PPI was lansoprazole. Patients taking PPIs had a shorter PFS than those taking palbociclib and endocrine therapy alone (14.0 versus 37.9 months, P < 0.0001). Multivariate analysis confirmed concomitant PPIs as the only independent predictive factor for shorter PFS (P = 0.0002). PFS was significantly longer in estrogen-sensitive mBC with no concomitant PPIs compared with patients taking PPIs or estrogen-resistant patients, with and without PPIs (P < 0.0001). No correlation with adverse events was found when considering grade >2 hematological toxicities [Common Terminology Criteria for Adverse Events (CTCAE) scale]. CONCLUSIONS: The present study demonstrates that concomitant use of PPIs in mBC patients treated with palbociclib has a detrimental effect on PFS. Therefore, it is recommended to prescribe PPIs with caution in these patients, strictly adhering to the indications in the summary of product characteristics (RCP).

Quality of life of therapies for hormone receptor positive advanced/metastatic breast cancer: Regulatory aspects and clinical impact in Europe.

In recent years, the number of trials incorporating health-related quality of life (HRQoL) data has increased. The impact of HRQoL on regulatory decision making in the European context and on clinical practice is not well established. We conducted an analysis of the role of QoL data extracted from the clinical trials of the drugs approved for hormone receptor positive/HER2-negative advanced/metastatic breast cancer (mBC). The results from the HRQoL were collected and a meta-analysis was performed to evaluate the impact of experimental drugs compared to standard treatments. The results showed a non-detrimental effect in HRQoL from the new treatments. As regards the approval process, from an examination of the European Medicine Agency (EMA) documents, HRQoL was reported nonextensively and contained and discussed in the European assessment reports (EPARs) for eleven trials in the approval process and cited in three cases in the EPARs and summary of medicinal product characteristics (SmPC). An effort should be made by all the stakeholders to increase the visibility of the HRQoL results in order to allow increased consideration in the approval process to make QoL data more easily and visibly available for the clinician and the patients. The evaluation should be reflected in the SmPC in order to increase the amount of information provided to the physician.

Two-month stop in mammographic screening significantly impacts on breast cancer stage at diagnosis and upfront treatment in the COVID era.

INTRODUCTION: The present analysis aims to evaluate the consequences of a 2-month interruption of mammographic screening on breast cancer (BC) stage at diagnosis and upfront treatments in a region of Northern Italy highly affected by the severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) virus. METHODS: This retrospective single-institution analysis compared the clinical pathological characteristics of BC diagnosed between May 2020 and July 2020, after a 2-month screening interruption, with BC diagnosed in the same trimester of 2019 when mammographic screening was regularly carried out. RESULTS: The 2-month stop in mammographic screening produced a significant decrease in in situ BC diagnosis (-10.4%) and an increase in node-positive (+11.2%) and stage III BC (+10.3%). A major impact was on the subgroup of patients with BC at high proliferation rates. Among these, the rate of node-positive BC increased by 18.5% and stage III by 11.4%. In the subgroup of patients with low proliferation rates, a 9.3% increase in stage III tumors was observed, although node-positive tumors remained stable. Despite screening interruption, procedures to establish a definitive diagnosis and treatment start were subsequently carried out without delay. CONCLUSION: Our data showed an increase in node-positive and stage III BC after a 2-month stop in BC screening. These findings support recommendations for a quick restoration of BC screening at full capacity, with adequate prioritization strategies to mitigate harm and meet infection prevention requirements.

Phase II study of eribulin in combination with gemcitabine for the treatment of patients with locally advanced or metastatic triple negative breast cancer (ERIGE trial). Clinical and pharmacogenetic results on behalf of the Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC).

BACKGROUND: The combination of a microtubule inhibitor (eribulin) with a nucleoside analog (gemcitabine) may synergistically induce tumor cell death, particularly in triple negative breast cancer (TNBC) characterized by high cell proliferation, aggressive behavior, and chemo-resistance. PATIENTS AND METHODS: This is an open-label, multicenter phase II study evaluating the combination of eribulin (0.88 mg/m2) plus gemcitabine (1000 mg/m2) on days 1 and 8 of a 21-day cycle as either first- or second-line treatment of locally advanced or metastatic TNBC. The primary endpoint was the objective response for evaluable patients. A prospective, molecular correlative study was carried out to assess the role of germinal BRCA pathogenic variants and single nucleotide polymorphisms (SNPs) in predicting efficacy and toxicity of the combination regimen. RESULTS: From July 2013 to September 2016, 83 evaluable patients were enrolled. They received a median number of six cycles of treatment. An overall response rate (ORR) of 37.3% (31 patients) was observed, with a complete response rate of 2.4% and a partial response rate of 34.9%; the clinical benefit rate was 48.8%. With a median follow-up of 28.8 months, the median response duration was 6.6 months, the median progression-free survival (PFS) was 5.1 months, and the median overall survival (OS) was 14.5 months. The most common grade 3-4 adverse events were aminotransferase elevation (in 25% of the patients) and neutropenia (in 23.8%). Women with BRCA1/2 pathogenic variants were associated with worse ORR, PFS, and OS than BRCA1/2 wild-type carriers. CYP3A4 and FGD4 SNPs were associated with increased risk of liver toxicity. Three different SNPs in CDA∗2, RRM1, and CYP2C8 genes were significantly associated with poorer OS. CONCLUSIONS: The combination of eribulin and gemcitabine showed promising activity and a moderate toxicity profile in metastatic TNBC. BRCA status and pharmacogenetics tests may help identify patients with high probability of response with negligible toxicity. EUDRACT NUMBER: 2012-003505-10.

Induced membrane technique using enriched bone grafts for treatment of posttraumatic segmental long bone defects.

BACKGROUND: Reconstruction of posttraumatic bone defects represents a difficult challenge. The induced membrane technique is an effective two-stage procedure for bone defect reconstruction. To overcome the problems of autologous bone grafting, different graft substitutes have been investigated. The aim of the present study is to evaluate our clinical experience in reconstruction of critical posttraumatic bone defects using an induced membrane technique based on a combination of autologous graft and allograft (cancellous bone) enriched with platelet-rich plasma (PRP) and bone marrow concentrate aspirate (BMCA). MATERIALS AND METHODS: Between 2009 and 2014, we reconstructed 18 posttraumatic bone defects in 16 patients. Their average length was 6.4 cm (range 1.6-13.2 cm). The defect location was the femur in nine cases (50%), the tibia in eight (44%) cases, and the humerus in one (6%) case. In all cases, we used a combination of autologous and cancellous allograft graft enriched with PRP and BMCA. Bone fixation was achieved using intramedullary nailing in 2 cases (11%), plating in 15 cases (66%), and external fixation in 1 case (6%). RESULTS: Both clinical and radiographic union were achieved in 13 (72%) cases (13 patients). Five (28%) cases (four patients) developed nonunion. Nonunion was observed in two of eight (25%) tibial defects and in three (33%) of nine femoral defects (ns). Three of 4 (75%) double defects had delayed union, whereas 2 of 14 (14%) single defects did not heal (p = 0.016). The average length of the 13 defects that united was 6 cm (range 1.6-11.8 cm), while the length of the 5 defects that did not unite was 10.3 cm (range 6-13.2 cm) (p = 0.009). CONCLUSIONS: In this series using an induced membrane technique based on a combination of autograft and allograft enriched with BMCA and PRP, the healing rate was lower than in other series where autologous bone graft alone was employed. Nonunion was more frequent in longer and double defects. Further research aimed at developing effective alternative options to autogenous cancellous bone graft is desirable. LEVEL OF EVIDENCE: III.

Association of tumor-infiltrating lymphocytes with distant disease-free survival in the ShortHER randomized adjuvant trial for patients with early HER2+ breast cancer.

BACKGROUND: There is the need to identify new prognostic markers to refine risk stratification for HER2-positive early breast cancer patients. The aim of this study was to evaluate the association of tumor-infiltrating lymphocytes (TILs) with distant disease-free survival (DDFS) in patients with HER2-positive early breast cancer enrolled in the ShortHER adjuvant trial which compared 9 weeks versus 1-year trastuzumab in addition to chemotherapy, and to test the interaction between TILs and treatment arm. PATIENTS AND METHODS: Stromal TILs were assessed for 866 cases on centralized hematoxylin and eosin-stained tumor slides. The association of TILs as 10% increments with DDFS was assessed with Cox models. Kaplan-Meier curves were estimated for patients with TILs ≥20% and TILs <20%. Median follow-up was 6.1 years. RESULTS: Median TILs was 5% (Q1-Q3 1%-15%). Increased TILs were independently associated with better DDFS in multivariable model [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.59-0.89, P = 0.006, for each 10% TILs increment]. Five years DDFS rates were 91.1% for patients with TILs <20% and 95.7% for patients with TILs ≥20% (P = 0.025). The association between 10% TILs increments and DDFS was significant for patients randomized to 9 weeks of trastuzumab (HR 0.60, 95% CI 0.41-0.88) but not for patients treated with 1 year of trastuzumab (HR 0.89, 95% CI 0.71-1.12; test for interaction P = 0.088). For patients with TILs <20%, the HR for the comparison between the short versus the long arm was 1.75 (95% CI 1.09-2.80, P=0.021); whereas, for patients with TILs ≥20% the HR for the comparison of short versus long arm was 0.23 (95% CI 0.05-1.09, P = 0.064), resulting in a significant interaction (P = 0.015). CONCLUSIONS: TILs are an independent prognostic factor for HER2-positive early breast cancer patients treated with adjuvant chemotherapy and trastuzumab and may refine the ability to identify patients at low risk of relapse eligible for de-escalated adjuvant therapy.

Nine weeks versus 1 year adjuvant trastuzumab in combination with chemotherapy: final results of the phase III randomized Short-HER study‡.

Background: Chemotherapy plus 1-year trastuzumab is the standard adjuvant treatment of HER2-positive breast cancer. The efficacy of less extended trastuzumab exposure is under investigation. The short-HER study was aimed to assess the non-inferiority of 9 weeks versus 1 year of adjuvant trastuzumab combined with chemotherapy. Patients and methods: HER2-positive breast cancer patients with node-positive or, if node negative, with at least one risk factor (pT>2 cm, G3, lympho-vascular invasion, Ki-67 > 20%, age ≤35 years, or hormone receptor negativity) were randomly assigned to receive sequential anthracycline-taxane combinations plus 1-year trastuzumab (arm A, long) or plus 9 weeks trastuzumab (arm B, short). This study was designed as a non-inferiority trial with disease-free survival (DFS) as primary end point. A DFS hazard ratio (HR) <1.29 was chosen as the non-inferiority margin. Analyses according to the frequentist and Bayesian approach were planned. Secondary end points included 2-year failure rate and cardiac safety. Results: A total of 1254 patients from 82 centers were randomized (arm A, long: n = 627; arm B, short: n = 626). Five-year DFS is 88% in the long and 85% in the short arm. The HR is 1.13 (90% CI 0.89-1.42), with the upper limit of the CI crossing the non-inferiority margin. According to the Bayesian analysis, the probability that the short arm is non-inferior to the long one is 80%. The 5-year overall survival (OS) is 95.2% in the long and 95.0% in the short arm (HR 1.07, 90% CI 0.74-1.56). Cardiac events are significantly lower in the short arm (risk-ratio 0.33, 95% CI 0.22-0.50, P < 0.0001). Conclusions: This study failed to show the non-inferiority of a shorter trastuzumab administration. One-year trastuzumab remains the standard. However, a 9-week administration decreases the risk of severe cardiac toxicity and can be an option for patients with cardiac events during treatment and for those with a low risk of relapse. Trial Registration: EUDRACT number: 2007-004326-25; NCI ClinicalTrials.gov number: NCT00629278.

Tumor-infiltrating lymphocytes and molecular response after neoadjuvant therapy for HR+/HER2- breast cancer: results from two prospective trials.

PURPOSE: The aim was to evaluate the role of tumor-infiltrating lymphocytes (TIL) in predicting molecular response after preoperative endocrine or cytotoxic treatment for HR+/HER2- patients who do not achieve a pathological complete response. METHODS: Stromal (Str) TIL were centrally evaluated on samples from diagnostic core-biopsies of HR+/HER2- patients included in two prospective randomized trials: the LETLOB trial (neoadjuvant endocrine-based treatment) and the GIOB trial (neoadjuvant chemotherapy-based treatment). Pre- and post-treatment Ki67 was centrally assessed. RESULTS: StrTIL were evaluable in 111 cases (n = 73 from the LETLOB trial and n = 38 from the GIOB trial). Median StrTIL was 2%. Patients with high StrTIL (StrTIL ≥10%, n = 28) had more frequently breast cancer of ductal histology (p = 0.02), high grade (p = 0.049), and high Ki67 (p = 0.02). After neoadjuvant endocrine treatment (LETLOB cohort), a significant Ki67 suppression (p < 0.01) from pre- to post-treatment was observed in both the low and high StrTIL groups. High StrTIL patients achieve more frequently a relative Ki67 suppression ≥50% from baseline as compared to low StrTIL patients (55 vs. 35%, p non significant). After neoadjuvant chemotherapy (GIOB cohort), a significant Ki67 suppression was observed only for low StrTIL patients (Wilcoxon p = 0.001) and not in the high StrTIL group (p = 0.612). In this cohort, the rate of patients achieving a relative Ki67 suppression ≥50% from baseline was significantly higher in the low vs high StrTIL group (64% vs 10%, p = 0.003). Geometric mean Ki67 suppression was evaluated in each cohort according to StrTIL: the lowest value (-41%) was observed for high StrTIL cases treated with chemotherapy. CONCLUSIONS: This hypothesis-generating study suggests that in HR+/HER2- breast cancer StrTIL at baseline may influence the achievement of a molecular response after neoadjuvant treatment. Further evaluation in large studies is needed, and interaction with the type of treatment warrants to be explored.

Impact of time to surgery after neoadjuvant chemotherapy in operable breast cancer patients.

BACKGROUND: The optimal time interval between the end of neoadjuvant systemic therapy (NST) and breast surgery is still unclear. It is not known if a delay in surgery might influence the benefit of primary chemotherapy. The aim of this study is to evaluate the relationship between time to surgery (TTS) and survival outcomes. PATIENTS AND METHODS: According to TTS, women with diagnosis of BC treated with NST were divided into two cohorts: group A = 21 days or fewer and group B = longer than 21 days. OS and RFS were estimated and compared according to TTS and known prognostic factors. RESULTS: A total of 319 patients were included in the study: 61 in group A and 258 in group B. Median TTS was 34 days. No association between clinical stage, nuclear grade, type of chemotherapy, type of surgery and TTS was detected. OS and RFS were significantly worse for group B compared with group A, with a hazard ratio of 3.1 (95% CI, 1.1-8.6 p = 0.03) and 3.1 (95% CI, 1.3-7.1 p = 0.008) respectively. Multivariate analysis confirmed that TTS was an independent prognostic factor in term of OS (p = 0.03) and RFS (p = 0.01). Even in the subgroup of patients with pCR, TTS continued to be an independent prognostic factor for both OS and RFS (p = 0.05 and p = 0.03). CONCLUSIONS: TTS after NST seems to influence survival outcomes. BC patients underwent surgery within 21 days experienced maximal benefit from previous treatment: this advantage is consistent and maintained over time.

Integrated evaluation of PAM50 subtypes and immune modulation of pCR in HER2-positive breast cancer patients treated with chemotherapy and HER2-targeted agents in the CherLOB trial.

BACKGROUND: The aim of this work was to evaluate the impact of (and relative contribution of) tumor-related and immune-related diversity of HER2-positive disease on the response to neoadjuvant chemotherapy plus anti-HER2 agents. PATIENTS AND METHODS: The CherLOB phase II study randomized 121 HER2-positive breast cancer patients to neoadjuvant chemotherapy plus trastuzumab, lapatinib or both. Tumor samples from diagnostic core biopsy were centralized. Tumor-infiltrating lymphocytes (TILs) were evaluated on H&E slides. Intrinsic subtyping was carried out using the research-based 50-gene prediction analysis of a microarray (PAM50) subtype predictor. Immune-related gene signatures were also evaluated. RESULTS: Continuous Str-TILs and It-TILs were significantly associated with pCR [OR 1.03, 95% CI 1.02-1.05 (P < 0.001) and OR 1.09, 95% CI 1.04-1.15 (P < 0.001) for Str-TILs and It-TILs, respectively]. According to PAM50, the subtype distribution was as follows: HER2-enriched 26.7%, Luminal A 25.6%, Luminal B 16.3%, Basal-like 14% and Normal-like 17.4%. The highest rate of pCR was observed for the HER2-enriched subtype (50%), followed by Basal-like, Luminal B and Luminal A (χ(2) test, P = 0.026). Immune gene signatures significantly associated with pCR in univariate analyses were identified: most of them maintained a significant association with pCR in multivariate analyses corrected for PAM50 subtypes, whereas TILs did not. CONCLUSIONS: In this study, both tumor-related and immune-related features contribute to the modulation of pCR after neoadjuvant chemotherapy plus anti-HER2 agents. Immune signatures rather than TILs added significant prediction of pCR beyond PAM50 intrinsic subtypes.

Immunoglobulin G fragment C receptor polymorphisms and efficacy of preoperative chemotherapy plus trastuzumab and lapatinib in HER2-positive breast cancer.

Lapatinib enhances antibody-dependent cell-mediated cytotoxicity (ADCC) activity of trastuzumab. FcγR polymorphisms have been associated with both ADCC and clinical activity of trastuzumab in HER2+ breast cancer (BC) patients (pts). We analyzed FcγRIIa-H131R and FcγRIIIa-V158F polymorphisms in the CHER-LOB trial population of HER2+ BCs treated with preoperative chemotherapy plus trastuzumab (arm A), lapatinib (arm B) or both (arm C). Genotyping was successfully performed in 73/121 (60%) pts. A significant improvement in pathological complete response (pCR) rate was observed for the combination arm C, but only in FcγRIIIa V allele carriers (C vs A, 67 vs 27%, P=0.043; C vs B, 67 vs 22%, P=0.012). An independent interaction between arm C and FcγRIIIa V allele was found for pCR (odds ratio=9.4; 95% confidence interval, 2.3-39.6; P=0.003). No significant associations were observed between pCR and FcγRIIa polymorphism, and between pre-treatment tumor-infiltrating lymphocytes and FcγR polymorphisms. Our study provides evidence for a FcγRIIIa V allele-restricted pCR benefit from neoadjuvant trastuzumab plus lapatinib in HER2+ BC.

Loss of HER2 positivity and prognosis after neoadjuvant therapy in HER2-positive breast cancer patients.

BACKGROUND: Emerging literature data are showing that a change in human epidermal growth factor receptor (HER2) status adversely affects breast cancer patient's prognosis. The aim of this study was to evaluate the prognostic impact of HER2 loss in patients with HER2-positive disease treated with neoadjuvant therapy with or without anti-HER2 agents. METHODS: One hundred and seven consecutive HER2-positive patients were identified from a prospectively maintained database. The first cohort includes 40 patients treated with chemotherapy (CT) alone. The second cohort includes 67 patients treated with neoadjuvant CT plus anti-HER2 agents (trastuzumab and/or lapatinib). HER2 expression was evaluated by immunihistochemistry or fluorescence in situ hybridization on pretreatment core biopsy and on surgical specimen after therapy. RESULTS: The rates of pathologic complete response (pCR) and breast-conserving surgery were higher in the CT + anti-HER2 cohort. A loss of HER2 expression was observed in 40% of the patients with residual disease after CT alone versus 14.7% of the patients after CT + anti-HER2 agents (P = 0.019). Patients not achieving a pCR have a significant increase in the risk of relapse when compared with those achieving a pCR (hazard ratio [HR] 9.55, P = 0.028). Patients with HER2 loss tended to have a higher risk of relapse as comparing to patients with maintained HER2 positivity (HR 2.41, P = 0.063). CONCLUSION: The pCR is confirmed as a powerful predictor of long-term outcome. The rate of HER2 loss is higher in patients receiving neoadjuvant CT without anti-HER2 agents. HER2 status on residual disease after preoperative therapy can be helpful in selecting patients at different risk of relapse, to be included in prospective trial exploring further adjuvant therapy.

Discordance in receptor status between primary and recurrent breast cancer has a prognostic impact: a single-institution analysis.

BACKGROUND: Tumor phenotype may change during breast cancer progression. This study evaluates the prognostic impact of receptor discordance between paired primaries and recurrences. PATIENTS AND METHODS: One hundred and thirty-nine patients underwent histological sampling of suspected breast cancer recurrence. All the pathology assessments [ER, PgR and human epidermal growth factor receptor 2 (HER2)] on both primaries and confirmed recurrences were performed at the same laboratory. RESULTS: A breast cancer recurrence was confirmed in 119 cases. Rates of discordance were 13.4%, 39% and 11.8% for ER, PgR and HER2, respectively. Ninety-two patients maintained the same tumor phenotype [i.e. the same hormone receptors (HR) and HER2 status], whereas 27 (22.7%) changed during progression. The loss of HR positivity and the loss of HER2 positivity resulted in a worse post-recurrence survival (P=0.01 and P=0.008, respectively) and overall survival (OS; P=0.06 and P=0.0002, respectively), compared with the corresponding concordant-positive cases. Tumor phenotype discordance was associated with worse post-recurrence and OS (P=0.006 and P=0.002, respectively); those cases who turned into triple-negative experienced the poorest outcome, respect to the concordant group (P=0.001, OS). CONCLUSIONS: We demonstrated for the first time an impact on OS of phenotype discordance between primary breast cancer and relapse. Among discordant cases, receptor loss resulted in the main determinant of poorer outcome.

Anti-HER2 neoadjuvant and adjuvant therapies in HER2 positive breast cancer.

Since the introduction of anti-Her2 agents, the prognosis of HER2 positive breast cancer patients significantly improved. In the adjuvant setting, the monoclonal antibody trastuzumab has been evaluated in six randomized trials including more than 10,000 patients. Different modes of administration (concurrent versus sequential), durations (one year, two years or 9 weeks) and different chemotherapy regimens have been evaluated. To date, one year of trastuzumab in combination or after chemotherapy is the standard adjuvant therapy for patients with HER2 overexpressing tumors. Cardiac safety is still a major clinical issue, in particular in the treatment of early breast cancer. Several large randomized trials exploring shorter, and potentially less toxic, regimens are ongoing across several European countries. In the neoadjuvant setting, the addition of trastuzumab to chemotherapy resulted in a significantly higher activity as compared to chemotherapy alone. Unfortunately, primary and secondary resistance to trastuzumab is observed both in early and advanced disease. Several mechanisms are described as possible determinants of trastuzumab failure, and several new antiHER2 strategies are in development. Lapatinib, the HER1-2 TK inhibitor is currently approved in advanced disease after trastuzumab failure. Lapatinib is under evaluation in a large adjuvant trial, and in several neoadjuvant studies. Other molecules such pertuzumab, which binds the HER2 dimerization domain, or the pan-erbB TK inhibitor neratinib are under evaluation in the (neo)-adjuvant setting.

A prognostic model based on nodal status and Ki-67 predicts the risk of recurrence and death in breast cancer patients with residual disease after preoperative chemotherapy.

BACKGROUND: Preoperative chemotherapy (PCT) allows for in vivo testing of treatment effects on tumor and its microenvironment. Aim of this analysis was to evaluate the effect of PCT on tumor biomarker expression and to evaluate the prognostic role of treatment-induced variation of these biomarkers (molecular response). METHODS: Two hundred and twenty-one stage II-III breast cancer patients were included. The following parameters were evaluated at baseline and on surgical specimens after PCT: estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), Ki-67, p53, human epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor 2 (VEGFR2), and apoptosis. RESULTS: A pathological complete response was observed in 8.8% of the patients. PCT induced a significant reduction in the expression of ER, PgR, Ki-67, and apoptosis. As by multivariable model, Ki-67 > or = 15% and nodal positivity after preoperative chemotherapy (PCT) were significant predictors of worse disease-free survival [hazard ratio (HR) 3.79, P < 0.0001 and HR 2.31, P = 0.037, respectively]. Ki-67 > or = 15% after PCT was also a significant predictor of overall survival (HR 3.75, P = 0.013). On the basis of these two parameters, patients were classified into three groups: (i) low risk (negative nodes and Ki-67 <15%), (ii) intermediate risk (nodal positivity or Ki-67 > or = 15%), and (iii) high risk (nodal positivity and Ki-67 > or = 15%). As compared with the low-risk group, the HRs for recurrence were 3.1 and 9.3 for the intermediate- and high-risk group, respectively (P = 0.0001); the HRs for death were 2.4 and 6.5 for the intermediate- and high-risk group, respectively (P = 0.042). CONCLUSIONS: Ki-67 and nodal status have been used to generate a simple and easily reproducible prognostic model, able to discriminate patients with worse prognosis among the heterogeneous group of women with residual disease after PCT.

[Intraoperative cholangiography during laparoscopic cholecystectomy: selective or routine?]. / Colangiografia intraoperatoria in corso di colecistectomia laparoscopica: selettiva o di routine?

Since its presentation by Mirizzi in 1931, the role of intraoperative cholangiography (ICHO) has been controversial and has become an argument even more disputed with the introduction of laparoscopic cholecystectomy (VLC) in 1988. The Authors reviewed their experience to determine the most appropriate use of ICHO during VLC on the basis of a retrospective analysis of cases of selective ICHO. From December 1991 to January 2001, 597 patients, 552 elective procedure and 45 emergency procedure, were reviewed. Of 552 patients 62 presented with at least one diagnostic criterion for symptomatic gallstone disease and were treated by means of ERCP completed with endoscopic sphincterectomy (ES) when a stone of the common bile duct was found, while the remaining 490 patients underwent VLC; a total of 10 ICHO were performed, two of which in the ERCP group and 8 in the VLC group. The 45 patients treated in emergency underwent VLC; in 43 cases ICHO was performed. Of all patients, there were 2 cases of common bile duct injuries (0.33%) and in both cases ICHO was not performed. A cholangiogram added 27 min to the average duration of surgery. On the basis of both the literature and Authors' experience, it can be stated that the routine use of ICHO is not useful to reduce bile duct injuries, while it significantly increases the cost of the surgical procedure due to the increase of average operative time. The use of ICHO seems to be effective to demonstrate clinically unsuspected choledocholitiasis, although, at present, the real clinical advantage deriving from the detection of these stones is not clear. The Authors conclude that further prospective, randomized studies are necessary to assess the precise role of ICHO with regard to VLC.