Angela Sciandivasci

A meta-analysis of oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 discordance between primary breast cancer and metastases.

BACKGROUND The discordance in oestrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor 2 (HER2) status between primary and recurrent breast cancer is being intensively investigated and a large amount of data have been produced. However, results from different studies are heterogeneous and often conflicting. To highlight this issue, a meta-analysis of published data was performed. METHODS A literature search was performed using Medline, and all the studies published from 1983 to 2011 comparing changes in ER, PgR and/or HER2 status in patients with matched breast primary and recurrent tumours were included. We used random-effects models to estimate pooled discordance proportions. RESULTS We selected 48 articles, mostly reporting retrospective studies. Thirty-three, 24 and 31 articles were focused on ER, PgR and HER2 changes, respectively. A total of 4200, 2739 and 2987 tumours were evaluated for ER, PgR and HER2 discordance, respectively. The heterogeneity between study-specific discordance proportions was high for ER (I(2)=91%, p<0.0001), PgR (I(2)=79%, p<0.0001) and HER2 (I(2)=77%, p<0.0001). Pooled discordance proportions were 20% (95% confidence interval (CI): 16-35%) for ER, 33% (95% CI: 29-38%) for PgR and 8% (95% CI: 6-10%) for HER2. Pooled proportions of tumours shifting from positive to negative and from negative to positive were 24% and 14% for ER (p=0.0183), respectively. The same figures were 46% and 15% for PgR (p<0.0001), and 13% and 5% for HER2 (p=0.0004). CONCLUSION Our findings strengthen the concept that changes in receptor expression may occur during the natural history of breast cancer, suggesting clinical implications and a possible impact on treatment choice.

Prognostic Value of Circulating Tumor Cells According to Immunohistochemically Defined Molecular Subtypes in Advanced Breast Cancer

BACKGROUND Breast cancer is a heterogeneous disease. Circulating tumor cell (CTC) enumeration might be useful to identify different risk categories within each molecular subtype. METHODS We retrospectively analyzed 203 consecutive patients with metastatic breast cancer with baseline CTC enumeration performed with CellSearch (Veridex Corp, Warren, NJ) between March 2005 and July 2011. Patients were categorized into 3 prognostic groups based on the number of CTCs (0, 1-4, and ≥ 5) and into 5 categories based on tumor biological characteristics: luminal-A (estrogen receptor [ER] and progesterone receptor [PR] > 1%, grade 1/2, human epidermal growth factor 2 [HER2]-negative [HER2(-)], Ki67 value < 14%); luminal-B (ER and/or PR > 1%, grade 3, HER2(-), Ki67 value > 14%); luminal-B HER2-positive [HER2(+)] (ER and/or PR > 1%, any grade, HER2(+), Ki-67 value any); HER2(+) (HER2 overexpressed/fluorescence in situ hybridization [FISH] amplified, ER and PR absent); triple negative (TN) (ER and PR 0%, HER2 not overexpressed/FISH not amplified). RESULTS Median age was 57 years (range 31-78 years). Twenty-seven patients (13.3%) had luminal-A category, 105 (51.7%) patients had luminal-B, 29 (14.3%) patients had luminal-B HER2(+), 24 patients (11.8%) had HER2(+), and 18 patients (8.9%) had TN. CTCs were mostly found in patients with luminal-A/luminal-B HER2(-) subtype. At multivariable analysis, CTC count was a significant predictive factor for overall survival (OS) in all molecular subtypes (log-rank P < .01). Patients with 0 CTCs/7.5 mL blood and all subtypes, except HER2(+), seem to perform better compared with other categories. CONCLUSION These findings confirm CTCs as an important prognostic factor for metastatic breast cancer in all molecular subtypes. Larger studies could help identify metastatic breast cancer subgroups in which CTC analysis would be particularly useful.

Discordant hormone receptor and human epidermal growth factor receptor 2 status in bone metastases compared to primary breast cancer

Abstract Background. In patients with metastatic breast cancer, the evaluation of the biological characteristics of metastatic bone deposits may be a valuable adjunct in clinical practice. We assessed the discordance in expression levels for estrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor 2 (HER2) between primary tumor and bone metastases and its clinical impact on patient management. Material and methods. We retrospectively reviewed 363 CT-guided bone biopsies performed from January 1997 to December 2009. The proportions of ER, PgR and HER2 positive tumors at primary diagnosis and bone metastases, determined by IHC and/or FISH, were compared using McNemars test. The impact of the biopsy reassessment on treatment choice was evaluated with Fishers exact test. Results. We selected 109 metastatic breast cancer patients with histologically confirmed bone metastases. Among 107 assessable patients the overall discordance rate was detected in 22 (20.5%) and in 47 (43.9%) patients for ER and PgR, respectively, and in six of 86 assessable patients (6.9%) for HER2 status. The indication to change endocrine therapy occurred in 62% and 30% of patients with ER discordance and ER concordance, respectively (p = 0.01). The indication to change targeted therapy occurred in 67% and 8% of patients with HER2 discordance and HER2 concordance, respectively (p = 0.002). Conclusions. We confirm that biopsy of metastases, including bone metastases, for reassessment of biology should be considered, since it is likely to impact on treatment choice.

Oral Metronomic Cyclophosphamide and Methotrexate Plus Fulvestrant in Advanced Breast Cancer Patients: A Mono‐Institutional Case‐Cohort Report

Abstract:  Fulvestrant is effective in postmenopausal women with estrogen receptor‐positive advanced breast cancer (ABC). So far, no published data exist on fulvestrant combined with chemotherapy. We retrospectively assessed the role of combining oral metronomic cyclophosphamide and methotrexate (CM) to fulvestrant in two cohorts (A and B) of heavily pre‐treated estrogen receptor‐positive advanced ABC patients. From October 2006 to September 2009, 33 postmenopausal patients received fulvestrant 250 mg via i.m. injection q28 days. In A, 20 patients added metronomic cyclophosphamide (50 mg p.o. daily) and methotrexate (2.5 mg p.o. twice daily on day 1 and day 4 weekly) after disease progression, continuing fulvestrant at the same dose. In B, 13 patients started fulvestrant plus metronomic CM upfront. Thirty‐two patients were evaluable for response. Clinical benefit (partial response + stable disease >24 months) for A + B was 56% (95% CI 38–74%). The addition of metronomic CM did not determine relevant toxicities. Treatment with fulvestrant plus metronomic CM was effective in advanced ABC and was minimally toxic providing long‐term disease control in a high proportion of patients. The prolonged clinical benefit, often desirable in such patients, supports this regimen as an additional and useful therapeutic tool.

Prognostic value of circulating tumor cells in primary and metastatic breast cancer

In patients with breast cancer, there is evidence correlating the presence of circulating tumor cells (CTCs) with disease-free survival, progression-free survival and overall survival. The detection of CTCs may be useful in gaining a better understanding of the mechanisms of tumor growth and in the improvement of patient management. This review analyzes the prognostic and predictive relevance of CTCs through the principal published studies, cytometric techniques and nucleic acid-based approaches to detect CTCs, phenotypic expression of specific receptors, molecular pathways and genetic signatures for potential tailored therapies.

Safety and efficacy study of metronomic vinorelbine, cyclophosphamide plus capecitabine in metastatic breast cancer: A phase II trial

In a phase II study we assessed the safety and efficacy of metronomic oral chemotherapy with vinorelbine, cyclophosphamide capecitabine in patients with metastatic breast cancer, either as first-line (naïve group) or second-line or greater therapy (pre-treated group). Eligible patients had histologically or cytologically proven, hormone-receptor positive metastatic breast cancer. The primary end point was median time to progression (TTP). A total of 43 patients in the naïve group and 65 in the pre-treated group were enrolled. The median TTP was 25.1 months in the naïve group and 11.2 months in the pre-treated group. The most frequently reported grade 2 treatment-related adverse events were leukopenia and hand and foot syndrome. Metronomic combination of cyclophosphamide, capecitabine and vinorelbine showed significant activity and good tolerability in patients hormonal receptor positive, metastatic breast cancer patients.

Outcome and clinico-biological characteristics of advanced breast cancer patients with surgically resected brain metastases: A multidisciplinary approach

Background: Despite improvements in brain surgery and radiotherapy, patients with brain metastases (BM) from breast cancer still have a poor prognosis. The aim of the present study is to evaluate the outcome of a multimodal therapeutic strategy in an unselected cohort of patients. Methods: We retrospectively reviewed 24 breast cancer patients who developed BM and were treated with brain surgery, radiotherapy, and/or systemic therapy in the same institutions. Results: Primary treatment for BM was surgery in the whole cohort, radiotherapy in 11 patients, radiotherapy combined with systemic therapy in nine patients, and systemic therapy as single treatment in six patients (chemo/targeted therapy n= 4; hormonal therapy n=2). The median time from breast cancer diagnosis to brain surgery was 57.6 months (range 1.8–130.7 months). The overall survival from surgery for BM was 22 months and the overall survival from BM surgery by presence of other metastatic sites at surgery was 25 months for patients with BM only and 11 months for patients with other metastatic sites (p=0.046). Conclusion: Although this study is retrospective and limited by the small number of patients, the overall survival of 22 months from the time of brain surgery represents an excellent outcome. The multidisciplinary approach that combines the efforts of specialists from different disciplines leads to satisfactory results for patients in terms of survival in the current clinical practice and prospective subtype-oriented trials are urgently required in this category of patients.

Mutations targeting the coagulation pathway are enriched in brain metastases

Brain metastases (BMs) are the most common malignancy of the central nervous system. Recently it has been demonstrated that plasminogen activator inhibitor serpins promote brain metastatic colonization, suggesting that mutations in serpins or other members of the coagulation cascade can provide critical advantages during BM formation. We performed whole-exome sequencing on matched samples of breast cancer and BMs and found mutations in the coagulation pathway genes in 5 out of 10 BM samples. We then investigated the mutational status of 33 genes belonging to the coagulation cascade in a panel of 29 BMs and we identified 56 Single Nucleotide Variants (SNVs). The frequency of gene mutations of the pathway was significantly higher in BMs than in primary tumours, and SERPINI1 was the most frequently mutated gene in BMs. These findings provide direction in the development of new strategies for the treatment of BMs.

Prognostic significance of Ki-67 in node-negative (pN0), triple-negative (TN) breast cancer (BC).

1056 Background: TNBCs occur more frequently in younger women, tend to relapse and metastasize early and have a poor prognosis. They are associated with a range of adverse features including high Ki-67 values. The aim of this analysis was to investigate if Ki-67 could help to identify different prognostic subgroups within the primary pN0 TNBCs. METHODS Patients (pts) with pN0 BC and with ER negative (0%), PgR negative (0%), HER2 scores of 0 and/or FISH not amplified were identified through the institutional clinical database. All pts underwent surgery at the European Institute of Oncology, Milan, Italy, between January 1997 and December 2005 and did not receive neoadjuvant treatment. The association between Ki-67 and other tumour characteristics was evaluated with the Kruskal-Wallis test. The relationship between Ki-67 and the risk of breast-related deaths was evaluated with a multivariable Cox regression model. Cubic splines were applied to the Cox model to analyze Ki-67 as a continuous variable. RESULTS We identified 496 consecutive pN0 M0 TNBC pts with a median age of 52 years; 443 pts underwent quadrantectomy (89%), and 425 pts (86%) received adjuvant chemotherapy, mainly classical CMF (n=315/425 pts, 74%). The median Ki-67 was 48% (range 4-95). The median follow up was 6 years (range 0.5 -13). Total deaths and deaths from BC were 52 (10.5%) and 38 (7.7%), respectively. Ki-67 was significantly higher in ductal TNBC when compared to other histological types (p<0.01). Moreover, Ki-67 increased with decreasing age (p<0.01), increasing tumour size (p<0.01) and grade (p<0.01). When analyzing Ki-67 as a continuous variable, the risk of death from BC increased steeply with increasing Ki-67 up to about 35% and remained flat thereafter (adjusted effect of Ki-67 P=0.049; adjusted non-linear effect P=0.021). Accordingly, when dividing pts into lower (≤35%)and higher (>35%) Ki-67 subgroups, the 5-year cumulative incidence of breast related deaths were 2.3% and 9.0%, respectively, with an adjusted HR>35 vs ≤35of 2.5 (95% CI 1.0 - 6.0, p=0.046). CONCLUSIONS Within the group of pts with pN0 TNBC, Ki-67 value was associated with different prognoses. Ki-67 value might be useful in the design of trials of risk-adapted adjuvant therapies.

Abstract P6-11-14: Long-Term Disease Control with Vinorelbine, Cisplatin and Continuous Infusion of 5-Fluorouracil -ViFuP Regimen-in Metastatic Triple Negative Breast Cancer Patients

Background: Triple negative breast cancers (TNBCs) are characterized by lack of estrogen, progesterone, HER-2-neu receptors expression and comprise 15% to 20% of all breast cancers. Studies have suggested that TNBCs may be more sensitive to DNA damaging agents like cisplatin. Our previous experience had identified a combination chemotherapy -the ViFuP regimen-with noteworthy efficacy and safety as a first or subsequent line treatment for metastatic breast cancer (MBC) patients (pts). In this view we retrospectively examined the activity of ViFuP regimen in 2 cohorts (A and B) of metastatic TNBC pts. Material and Methods: From January 2000 to December 2008, 115 pts with MBC were treated with ViFuP regimen, at the European Institute of Oncology, Milan, Italy. Among these, 35 pts (30%) had TNBC. Pts received continuous infusion 5-fluorouracil 200 mg/m2/day, vinorelbine 20 mg iv on days 1 and 3 and cisplatin 60 mg/m2on day 1. Therapy was given every three weeks. In A 22 pts (63%) were triple negative on primary tumor and in B 13 pts (37%) were triple negative in metastatic site. Median age was 54 years (range 35-73), 11 pts (31%) were pre-treated for MBC and 21 pts (60%) had ≥3 metastatic sites. Results: Thirty three pts were evaluable for response and 34 pts were assessable for toxicity. Median duration of treatment was 3.57 months (range 1-5.7). Four pts (12%) had complete responses, 14 pts (42%) had partial responses and 11 pts (33%) had stable disease with a clinical benefit (CB) of 73% (95% CI, 55%-87%). Four pts (12%) had progressive disease. Median time to progression was 6 months (95% CI, 5-8 months). Main toxicity was haematological with 62% of the pts showing grade 3/4 leuco-neutropenia. Alopecia was almost absent. Discussion: Treatment with ViFuP regimen was effective and safe in metastatic TNBC providing long-term disease control in a high proportion of pts. The prolonged CB supports this regimen as an additional therapeutic opportunity in this category of pts. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-11-14.