Hormone-receptor expression and activity of trastuzumab with chemotherapy in HER2-positive advanced breast cancer patients.

BACKGROUND: The relationship between quantitative immunohistochemical hormone receptor expression and response to the combination of trastuzumab with chemotherapy in HER2-positive advanced breast cancer is currently unknown. METHODS: Estrogen receptor (ER) and progesterone receptor expression was studied both as a dichotomous variable (positivity set at ≥ 1% of positive cells) and as a continuous variable. The effect of hormone receptor expression on overall response rate and progression-free survival in patients receiving trastuzumab-based treatment was studied by univariate and multivariate analysis. RESULTS: One hundred eleven of 227 consecutive advanced breast cancer patients treated at 2 Institutions had hormone receptor-positive tumors (49%). High expression of ER (≥ 30% of tumor cells) predicted reduced probability of tumor response to trastuzumab plus chemotherapy (multivariate odds ratio, 0.422; 95% confidence interval [CI], 0.222-0.803; P = .009). In patients with hormone receptor-positive tumors (≥ 1% of tumor cells), maintenance endocrine therapy added to trastuzumab upon the completion of chemotherapy was associated with a significant progression-free survival benefit (hazard ratio, 0.521; 95% CI, 0.3325-0.836; P = .007). CONCLUSIONS: Our results suggest a predictive role of hormone receptor expression in HER2-positive tumors. Further investigation in this patient subset is warranted to optimize the use of HER2-targeting agents, chemotherapy, and endocrine therapy.

Moderate immunohistochemical expression of HER-2 (2+) without HER-2 gene amplification is a negative prognostic factor in early breast cancer.

BACKGROUND: Human epidermal growth factor receptor (HER)-2 testing in patients with operable breast cancer is aimed at identifying candidates for adjuvant anti-HER-2 treatment. However, commonly defined "HER-2(-)" tumors express variable levels of the HER-2 protein, which can influence prognosis. We compared the clinical outcomes of operable breast cancer patients stratified according to a common HER-2 testing algorithm. METHODS: We studied 1,150 women (median age, 58 years; range, 22-94 years) undergoing surgery for early breast cancer at our institution. HER-2 status was determined using the HercepTest™ (Dako, Glostrup, Denmark) and, when needed, by fluorescence in situ hybridization (FISH). Patients receiving adjuvant trastuzumab were excluded. The impact of HER-2 status on the disease-free survival (DFS) time was studied using multivariate Cox proportional regression analysis. RESULTS: Four hundred-fifty seven (40%), 454 (39%), 116 (10%), and 123 (11%) patients were considered HER-2 0+, HER-2 1+, HER-2 2+/HER-2(-) by FISH, and HER-2(+) (3+ or HER-2(+) by FISH), respectively. Compared with a HER-2 0 or 1+ status, a HER-2 2+/HER-2(-) by FISH status was associated with a worse DFS outcome on multivariate analysis. Compared with a HER-2(+) status, a HER-2 2+/HER-2(-) status showed a time-dependent effect on the DFS probability, with an initial advantage that worsened every year by a factor of 1.649. CONCLUSION: A HER-2 2+/HER-2(-) status is an adverse prognostic factor in patients with operable breast cancer. Because of suggestions from randomized trials that the benefits of adjuvant trastuzumab may not be limited to patients with HER-2(+) tumors, patients with a HER-2 2+/HER-2(-) status are ideal candidates for studies testing this hypothesis.

Correlations between diffusion-weighted imaging and breast cancer biomarkers.

OBJECTIVE: We evaluated whether the apparent diffusion coefficient (ADC) provided by diffusion-weighted imaging (DWI) varies according to biological features in breast cancer. METHODS: DWI was performed in 190 patients undergoing dynamic contrast-enhanced magnetic resonance imaging (MRI) for local staging. For each of the 192 index cancers we studied the correlation between ADC and classical histopathological and immunohistochemical breast tumour features (size, histological type, grade, oestrogen receptor [ER] and Ki-67 expression, HER2 status). ADC was compared with immunohistochemical surrogates of the intrinsic subtypes (Luminal A; Luminal B; HER2-enriched; triple-negative). Correlations were analysed using the Mann-Whitney U and Kruskal-Wallis H tests. RESULTS: A weak, statistically significant correlation was observed between ADC values and the percentage of ER-positive cells (-0.168, P = 0.020). Median ADC values were significantly higher in ER-negative than in ER-positive tumours (1.110 vs 1.050 × 10(-3) mm(2)/s, P = 0.015). HER2-enriched tumours had the highest median ADC value (1.190 × 10(-3) mm(2)/s, range 0.950-2.090). Multiple comparisons showed that this value was significantly higher than that of Luminal A (1.025 × 10(-3) mm(2)/s [0.700-1.340], P = 0.004) and Luminal B/HER2-negative (1.060 × 10(-3) mm(2)/s [0.470-2.420], P = 0.008) tumours. A trend towards statistical significance (P = 0.018) was seen with Luminal B/HER2-positive tumours. CONCLUSIONS: ADC values vary significantly according to biological tumour features, suggesting that cancer heterogeneity influences imaging parameters. KEY POINTS: DWI may identify biological heterogeneity of breast neoplasms. • ADC values vary significantly according to biological features of breast cancer. • Compared with other types, HER2-enriched tumours show highest median ADC value. • Knowledge of biological heterogeneity of breast neoplasm may improve imaging interpretation.

Underuse of anthracyclines in women with HER-2+ advanced breast cancer.

Anthracyclines are among the most active drugs in breast cancer. Because of excessive cardiotoxicity, their use in combination with trastuzumab has been discouraged in patients with human epidermal growth factor receptor (HER)-2(+) metastatic breast cancer. We sought to describe how this treatment paradigm influenced the use of anthracyclines in this patient setting. We analyzed a multi-institutional database containing the treatment history of 450 patients who received at least one trastuzumab-based regimen for HER-2(+) metastatic breast cancer. Patients were considered eligible for anthracyclines for metastatic disease if they were never exposed (NE) or had been previously exposed (PE) to an anthracycline in the neoadjuvant or adjuvant setting and had relapsed after 12 months from the last dose. We then assessed the use of anthracycline-based therapy after failure with the first trastuzumab-based regimen in eligible patients. Three-hundred twenty-one patients were considered eligible for anthracyclines. In total, 190 eligible patients developing disease progression during the initial trastuzumab-based therapy were analyzed. An anthracycline was administered as first salvage treatment in 14 NE and two PE patients. Another 15 NE and nine PE patients received an anthracycline as a further line of therapy. Of 119 eligible patients who died from breast cancer, only 30 received an anthracycline for metastatic disease. In conclusion, despite the fact that two thirds of the patients receiving trastuzumab-based therapy for HER-2 metastatic breast cancer are eligible for anthracyclines, these drugs are infrequently used nowadays to treat trastuzumab-refractory disease. A role for these compounds should be redefined in this patient subset.

Trastuzumab with either docetaxel or vinorelbine as first-line treatment for patients with HER2-positive advanced breast cancer: a retrospective comparison.

BACKGROUND: Combinations of trastuzumab with either docetaxel or vinorelbine are considered valuable treatment options for HER2-positive metastatic breast cancer patients. We performed a retrospective comparison of the clinical outcomes associated with either one of these combinations. METHODS: From a multi-institutional database we retrieved 179 patients treated with either docetaxel or vinorelbine plus trastuzumab as first-line therapy for HER2-positive advanced breast cancer. RESULTS: Docetaxel-trastuzumab was superior to vinorelbine-trastuzumab in terms of response rate (RR: 77 vs 57%, p = 0.01) and median overall survival (OS: 35 vs 23 months, p = 0.04), but not in median time to progression (TTP: 12 vs 10 months, p = 0.53). At multivariate analysis, type of treatment was not associated with TTP but was an independent predictor of OS, with a significant reduction in the risk of death in favor of docetaxel-trastuzumab (HR 0.474, 95% IC 0,303-0.742, p < 0.01). CONCLUSION: Docetaxel or vinorelbine, when combined with trastuzumab, provide excellent rates of tumor control in patients with previously untreated HER2-positive advanced breast cancer. Docetaxel may offer some advantage in terms of response rate and resulted in a significantly prolonged overall survival, which, because of the retrospective design of our study, deserves further investigation in prospective trials.

Retrospective evaluation of clinical outcomes in patients with HER2-positive advanced breast cancer progressing on trastuzumab-based therapy in the pre-lapatinib era.

BACKGROUND: Patients with HER2-positive breast cancer whose disease has become resistant to the anti-HER2 monoclonal antibody trastuzumab can benefit from lapatinib, a dual epidermal growth factor receptor/HER2 tyrosine kinase (TK) inhibitor. Before the availability of this compound, trastuzumab was often continued beyond disease progression, usually in addition to further chemotherapy, an approach which was not based on randomized studies. We sought to retrospectively compare the clinical outcomes of patients who, upon progression during an initial trastuzumab-based regimen, stopped or continued trastuzumab in addition to further chemotherapy. PATIENTS AND METHODS: From the clinical records of 407 patients with HER2-positive advanced breast cancer, we identified 279 patients progressing during an initial trastuzumab-based treatment. Of these patients, 83 continued trastuzumab in addition to chemotherapy, and 112 received chemotherapy alone. RESULTS: We found no difference in response rate (28% vs. 30%; P = .5), median time to second tumor progression (8.4 months vs. 7 months; P = .24), or median postprogression survival (20.6 months and 15.4 months; P = .29) according to whether patients continued or stopped trastuzumab. At multivariate analysis, continuation of trastuzumab was associated with a statistically insignificant trend toward reduced risk of second progression (hazard ratio, 0.753; P = .08). CONCLUSION: Patients with HER2-positive advanced breast cancer developing tumor progression during an initial trastuzumab-based regimen did not seem to benefit significantly from the continuation of trastuzumab in addition to chemotherapy. For these patients, there is evidence from a large randomized trial that effective HER2 targeting can be accomplished by inhibiting the HER2 TK activity with lapatinib.

Vinorelbine-based salvage therapy in HER2-positive metastatic breast cancer patients progressing during trastuzumab-containing regimens: a retrospective study.

BACKGROUND: The vinka-alkaloyd vinorelbine is a potentially valuable treatment in patients with HER2-positive, trastuzumab-resistant advanced breast cancer. We sought to document the clinical activity of vinorelbine-based salvage treatments in this clinical setting. METHODS: We analyzed a cohort of 424 consecutive women receiving trastuzumab-based therapy for HER2-positive advanced breast cancer. Of these, 299 were identified as progressing during the initial trastuzumab-based treatment, and 77 received vinorelbine-based therapy as first salvage treatment. Central review of pathological specimens revealed that 70 patients had HER2-amplification detected by FISH. For these patients we determined overall response rate (ORR = complete-CR + partial-PR) and clinical benefit (CB = CR+PR+ Stable disease lasting at least 6 months), time to progression (TTP) and overall survival (OS) from the initiation of vinorelbine-based salvage therapy. RESULTS: In 60 patients who were evaluable for tumor response, ORR and CB rates were 28% (95% C.I. 18%-41%) and 50% (95% C.I. 38%-62%), respectively. Median follow-up from the initiation of salvage therapy was 15 months (range 1-63 months). Median TTP and OS were 7.1 months (95% C.I. 6.6-7.7 months) and 21 months (95% C.I. 14.3-27.7 months), respectively. No differences in clinical outcomes were observed according to whether vinorelbine was administered as a single agent or in combination with other cytostatics, or whether trastuzumab was stopped or continued beyond disease progression. CONCLUSION: our findings suggests that vinorelbine-based combinations are active and should be further evaluated in studies conducted in trastuzumab-resistant patients, including those evaluating newer HER2-targeting agents.

Treatment and prognosis of leptomeningeal disease secondary to metastatic breast cancer: A single-centre experience.

PURPOSE: Leptomeningeal disease (LMD) is an uncommon complication of advanced breast cancer. The prognosis is poor, and although radiotherapy (RT), systemic and intra-thecal (IT) chemotherapy are accepted treatment modalities, efficacy data are limited. This study was designed to evaluate potential predictors of survival in this patient group. METHODS: Breast cancer patients with LMD diagnosed by MRI in a 10-year period (2004-2014) were identified from electronic patient records. PFS and OS estimates were calculated using Kaplan-Meier method, with planned sub-group analysis by treatment modality. Cox regression was employed to identify significant prognostic variables. RESULTS: We identified 182 eligible patients; all female, median age at LMD diagnosis 52.5 years (range 23-80). Ninety patients (49.5%) were ER positive/HER2 negative; 48 (26.4%) were HER2 positive, and 27 (14.8%) were triple negative. HER2 status was unknown in 17 (9.3%). Initial management of LMD was most commonly whole or partial brain RT in 62 (34.1%), systemic therapy in 45 (24.7%) or supportive care alone in 37 (20.3%). Fourteen patients (7.7%) underwent IT chemotherapy, of whom two also received IT trastuzumab. From diagnosis of LMD, the median PFS was 3.9 months (95%CI 3.2-5.0) and median OS was 5.4 months (95%CI 4.2-6.6). Patients treated with systemic therapy had the longest OS (median 8.8 months, 95%CI 5.5-11.1), compared to RT; 6.1 months (95%CI 4.2-7.9 months), IT therapy; 2.9 months (95%CI 1.2-5.8) and supportive care; 1.7 months (95%CI 0.9-3.0). On multivariable analysis, triple negative histology, concomitant brain metastases, and LMD involving both the brain and spinal cord were associated with poor OS. CONCLUSIONS: Breast cancer patients with triple negative LMD, concomitant brain metastases or LMD affecting both the spine and brain have the poorest prognosis. Clinical trials to identify more effective treatments for these patients are urgently needed.

Oral chemotherapy and patient perspective in solid tumors: a national survey by the Italian association of medical oncology.

AIM: To assess patient perception toward oral chemotherapy for solid tumors, the Italian Association of Medical Oncology performed a large multi-institutional national survey. METHODS: A 17-item anonymous questionnaire including 7 general and 10 investigational questions with free-text, single-choice, or multiple-choice answers was administered. Analysis of response distribution according to predefined factors was described by summary measures and conducted by χ2 test and other nonparametric tests. RESULTS: From January to June 2010, 581 patients completed the questionnaire; data of 404 patients constituted the final study sample. Three groups could be distinguished according to treatment: IV chemotherapy (IV group, n = 313), oral chemotherapy (oral group, n = 48), or combined therapy (combined group, n = 43). Thirty-one (72%) patients in the combined group and 187 (60%) in the IV group expressed preference for oral therapy (p = 0.028). Limitations in family and work commitment were more frequently perceived by patients on IV than oral chemotherapy (147 (47%) vs 14 (29%) patients, p<0.05, and 134 (43%) vs 11 (23%) patients, p<0.05). A total of 134 (43%) patients on IV chemotherapy versus 15 (31%) patients in the oral group did not point out any limitation for number of tablets per day (p = 0.004). CONCLUSIONS: We observed a propensity from the patient perspective in favor of oral chemotherapy that was considered to have a lower impact on family and work commitments than IV chemotherapy. The treatment that patients were taking when the questionnaire was administered likely influenced their perception and related results.

HER2 gene-amplified breast cancers with monosomy of chromosome 17 are poorly responsive to trastuzumab-based treatment.

Although HER2 gene status determines the eligibility of breast cancer patients to trastuzumab therapy, only a fraction of HER2 gene-amplified cancers are actually responsive, indicating that complex genotypical profiles might sustain HER2-targeted therapy responsiveness. To identify genetic factors modulating the response to HER2-targeted therapy, the numerical status of chromosome 17 was evaluated in HER2 gene-amplified tumor specimens from 43 patients who received trastuzumab-based treatment for advanced breast cancer, and in 60 unamplified breast carcinomas. Archival tumor specimens were analyzed by interphase fluorescence in situ hybridization (FISH) using a centromeric probe for chromosome 17 simultaneously with the HER2/neu human gene-specific probe. In the 43 patients who received trastuzumab-based treatment, response rate and time to progression (TTP) were compared between subgroups according to chromosome 17 status. Numerical aberrations of chromosome 17 were found in 65% of HER2-amplified tumors (single centromeric signal, 44%; >3 centromeric signals, 21%) and 60% of unamplified cancers (single centromeric signal, 43%; >3 centromeric, 17%). In the 43 treated metastatic breast cancer patients, trastuzumab was combined with docetaxel (35 patients), paclitaxel (2 patients), or vinorelbine (6 patients). Response rate was 92% in patients with >2 centromeric signals (chromosome 17 eusomy/polysomy), and 53% in patients whose tumor showed a single signal (chromosome 17 monosomy) (p=0.005). Chromosome 17 numerical status was not found to affect TTP. Multivariate logistic regression analysis confirmed that the effect of chromosome 17 monosomy on tumor response was independent of other potential clinical variables. Our findings suggest that 17 monosomy defines a subgroup of HER2 gene-amplified breast cancer characterized by reduced responsiveness to trastuzumab-based treatment. Further studies on the imbalance between the amplified HER2 gene and functionally antagonist gene(s) on chromosome 17 are warranted.

FDG avidity at PET/CT during adjuvant hormonal therapy in patients with breast cancer.

BACKGROUND: We aim to retrospectively evaluate the impact of hormone therapy (HT) on FDG avidity of metastatic lesions in patients with breast cancer (BC) undergoing PET/CT. PATIENTS AND METHODS: Three hundred eight patients with BC were scanned with PET/CT at 2 Italian institutions (mean time from diagnosis 4 yrs, range: 1-24 yrs). Main indications for PET/CT were elevation of tumor markers (34.4%) and clinical or radiological suspicion of relapse (65.6%). The diagnostic accuracy of FDG PET/CT was computed according to the standard method. Student t test was used to assess the mean differences between the study groups, whereas categorical data were compared with chi-square test. Significance was set at P <0.05. RESULTS: Two hundred sixty-four patients with positive estrogen receptor and who had received adjuvant HT were included in the analysis. At the time of PET/CT scan, HT was ongoing in 176 patients (66.7%) and 88 (33.3%) had completed adjuvant HT. Ninety-eight (55.7%) patients on HT and 59 (67%) off HT had a positive PET/CT; therefore, the scan resulted negative in the remaining 107 patients, 78 and 29 on and off HT, 44.3% and 33%, respectively (P < 0.001). At a median follow-up of 7 months (range 1-48 mos), disease recurrence was confirmed in either clinical or radiological examinations in 126 (47.7%) patients; 72 (40.9%) versus 54 (61.4%) patients on and off HT, respectively (P < 0.005). True-positive PET/CT results were found in 82% and 91% of patients on and off HT, respectively, whereas it failed to identify disease relapse in 13 (18%) and 5 (9%) patients on and off HT, respectively. CONCLUSIONS: In our series, FDG PET/CT shows a similar diagnostic accuracy in detecting disease relapse between patients with BC on adjuvant HT versus those who have completed therapy. These preliminary results suggest that the glucose metabolism is not altered by hormonal suppression at the time of the scan.

Clinical outcome in women with HER2-positive de novo or recurring stage IV breast cancer receiving trastuzumab-based therapy.

BACKGROUND: Five to 10% of women with newly diagnosed breast cancer have synchronous metastases (de novo stage IV). A further 20% will develop metastases during follow-up (recurring stage IV). We compared the clinical outcomes of women with HER2-positive metastatic breast cancer (MBC) receiving first-line trastuzumab-based therapy according to type of metastatic presentation. PATIENTS AND METHODS: Retrospective analysis of 331 MBC patients receiving first-line trastuzumab-based treatment. Response rates (RR) were compared by the chi-square test. Time-to progression (TTP) and overall survival (OS) curves were compared by the log-rank test. Cox-proportional hazards models were used to study predictors of PFS and OS, including the type of metastatic presentation. RESULTS: Seventy-seven patients (23%) had de novo stage IV disease. Forty-six of these patients underwent surgery of the primary ("de novo/surgery"). Response rates to first-line trastuzumab-based therapy and median progression-free survival did not differ in patients with "recurring", "de novo/surgery" and "de novo" without surgery ("de novo/no surgery) stage IV breast cancer. However, women with "de novo/surgery" stage IV breast cancer had the longest median OS (60 months), and those with "de novo/no surgery" stage IV breast cancer the shortest (26 months). For women with recurring metastatic breast cancer median OS was 40 months (overall log-rank test, p < 0.01). Multivariate analysis confirmed these findings. CONCLUSION: Our analysis shows that response rates and PFS to first-line trastuzumab-based therapy do not differ significantly between de novo and recurring stage IV, HER2 positive breast cancer. The observed difference in OS favoring women with de novo stage IV disease submitted to surgery of the primary tumor could be the result of a selection bias.

Hitting multiple targets in HER2-positive breast cancer: proof of principle or therapeutic opportunity?

INTRODUCTION: Pharmacological targeting of the tyrosine kinase receptor HER2 with the monoclonal antibody trastuzumab has dramatically changed the outlook of HER2-positive breast cancer patients. However, HER2 is part of a more complex biological network that, when deregulated, plays a central role in sustaining the cancer phenotype. These interactions account for primary or acquired resistance to drugs that hit a single biological target, like trastuzumab. Several preclinical models suggest that simultaneous targeting of crucial metabolic pathways has the potential to circumvent or delay the onset of resistance phenomena in HER2-positive breast cancer cells. AREAS COVERED: This review describes the rationale and results of clinical trials using biologically targeted agents in HER2-positive breast cancer patients. Single drugs that hit multiple targets and cocktails of biologically targeted agents are considered, whereas combinations with chemotherapy are not addressed. EXPERT OPINION: Most of the studies using biological agents to hit multiple targets in HER2-positive breast cancer patients confirm that resistance to single-agent HER2-targeting can be overcome. Further developments will include combination of multi-targeting strategies with chemotherapy in patients with earlier-stage disease. In addition, it is possible that newer molecular predictive factors may allow a more rationale choice of the most appropriate targeting for each individual patient.

Cigarette smoking habit does not reduce the benefit from first line trastuzumab-based treatment in advanced breast cancer patients.

Many ErbB2-positive cancers may show intrinsic resistance, and the frequent development of acquired resistance to ErbB-targeted agents represents a substantial clinical problem. The constitutive NF-κB activation in some HER-2/neu positive breast cancer may represent a potential cause of resistance to trastuzumab therapy. Preclinical data revealed that 4-(N-Methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), the tobacco-specific nitrosamine is able to enhance NF-κB DNA binding activity and theoretically to increase the resistance to trastuzumab. Two hundred and forty-eight women with pathologically confirmed, uni- or bidimensionally measurable, HER-2-positive metastatic breast cancer (MBC) treated with trastuzumab-based therapy as first line combination for metastatic disease were considered eligible. For all included patients data on smoking habit were detectable from medical records. We retrospectively analysed the smoking habits of 248 MBC patients and correlated these habits with activity and efficacy of trastuzumab-based therapy. No statistically significant difference in terms of response rate (RR), time to progression (TTP) and overall survival (OS) was identified between smokers (former plus active smokers) and never smokers. Moreover, no statistically significant difference in terms of RR, TTP and OS was identified either comparing active smokers and former smokers. Moreover, we did not observed any significant statistical difference in terms of TTP and OS between smokers ≥10 cigarettes/day and <10 cigarettes/day. This study clearly showed lack of any correlation between cigarette smoking habit and both activity and efficacy of trastuzumab-based first line therapy in metastatic HER2/neu positive breast cancer patients.

Recent advances in the medical management of breast cancer: highlights from the 29th San Antonio Breast Cancer Conference San Antonio, TX, USA, 14-17 December 2007.

The 29th edition of the San Antonio Breast Cancer Symposium was attended by a total of > 8000 basic scientists, translational researchers, clinical investigators and physicians gathering from approximately 80 countries worldwide. This is the largest meeting focusing on breast cancer, encompassing a wide array of topics from prevention, aetiology and diagnosis to molecular biology and treatment. From the main presentations at the meeting, it seems clear that combined efforts at prevention and treatment of this disease have translated into small, but significant, achievements. Much of the research in the area is focused on improving the therapeutic ratio of available treatments by better selection of patients.

Relationship between DCE-MRI morphological and functional features and histopathological characteristics of breast cancer.

We studied whether dynamic contrast-enhanced MRI (DCE-MRI) could identify histopathological characteristics of breast cancer. Seventy-five patients with breast cancer underwent DCE-MRI followed by core biopsy. DCE-MRI findings were evaluated following the scoring system published by Fischer in 1999. In this scoring system, five DCE-MRI features, three morphological (shape, margins, enhancement kinetic) and two functional (initial peak of signal intensity (SI) increase and behavior of signal intensity curve), are defined by 14 parameters. Each parameter is assigned points ranging from 0 to 1 or 0 to 2, with higher points for those that are more likely to be associated with malignancy. The sum of all the points defines the degree of suspicion of malignancy, with a score 0 representing the lowest and 8 the highest degree of suspicion. Associations between DCE-MRI features and tumor histopathological characteristics assessed on core biopsies (histological type, grading, estrogen and progesterone receptor status, Ki67 and HER2 status) were studied by contingency tables and logistic regression analysis. We found a significant inverse association between the Fischer's score and HER2-overexpression (odds ratio-OR 0.608, p = 0.02). Based on our results, we suggest that lesions with intermediate-low suspicious DCE-MRI parameters may represent a subset of tumor with poor histopathological characteristics.

Outcome of patients with HER2-positive advanced breast cancer progressing during trastuzumab-based therapy.

We sought to describe patterns of treatment and clinical outcome in patients with HER2-positive advanced breast cancer progressing on trastuzumab-based therapy. One hundred eighty-four consecutive HER2-positive advanced breast cancer patients received trastuzumab-based therapy between September 1999 and September 2004. Patients were followed up until death or May 2005. For patients progressing on trastuzumab-based therapy, we calculated the response rate (RR) to the first post-progression treatment, overall survival (OS) from the first administration of trastuzumab, time to second progression (TT-SP), and post-progression survival (PPS), according to treatment. At the time of this analysis, 132 patients had progressed on trastuzumab-based therapy, and 89 had died. Of the progressing patients, 21 experienced rapid progression and could not receive additional anticancer treatments;40 patients continued trastuzumab either alone (12 patients with isolated central nervous system progression), with chemotherapy (23 patients), or with endocrine therapy (5 patients); and 71 stopped trastuzumab and received chemotherapy (61 patients) or endocrine therapy (10 patients) as the first post-progression treatment. Excluding patients with rapid progression, clinical outcomes were similar whether trastuzumab was continued or not, in terms of RR (18% and 27%, respectively), OS (31 and 30 months, respectively), TT-SP (6 and 7 months, respectively), and PPS (21 and 19 months, respectively). The clinical outcome of patients with HER2-positive advanced breast cancer progressing during trastuzumab-based therapy might not be influenced by continuing trastuzumab. The optimal therapeutic strategy in this setting of patients needs evaluation in randomized trials.

Controversies in breast cancer: adjuvant and neoadjuvant therapy.

Initial randomised studies of chemotherapy and endocrine therapy showed that systemic treatments had a substantial impact on the survival of women with early breast cancer. The original assumption was that the efficacy of these treatments was limited to those patients presenting with more adverse prognostic features. Subsequently, meta-analyses of randomised trials revealed that the benefits of chemotherapy and endocrine therapy are not mutually exclusive and extend to all the prognostic subgroups. However, the absolute benefit varies according to baseline characteristics such as tumour stage and other biological factors. Over the last 10 years, considerable progress has been made with the introduction of new drugs into the adjuvant and neoadjuvant treatment of women with breast cancer. Taxanes and third-generation aromatase inhibitors are providing proof of additional benefits compared with standard reference treatments. In parallel, research on the biology of breast cancer is establishing novel prognostic and predictive factors, which may allow better treatment tailoring. Currently, however, women with early breast cancer and their doctors face the difficult task of making therapeutic decisions often based on early results from positive studies. In a disease where follow up is crucial to fully assess the benefit and long-term toxicities of an intervention, current knowledge leaves unanswered questions that generate debate and controversy. This review will summarise recent results from randomised trials of adjuvant and neoadjuvant therapy in women with early breast cancer and focus on the current controversies.