Stefania Redana

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

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.

Metastatic breast cancer subtypes and central nervous system metastases

BACKGROUND Breast cancer (BC) subtypes have different survival and response to therapy. We studied predictors of central nervous system metastases (CNS-M) and outcome after CNS-M diagnosis according to tumor subtype. PATIENTS AND METHODS 488 patients with diagnosis of metastatic BC were retrospectively evaluated. According to the combination of hormone receptors (HR) and HER2 status, tumors were grouped in: Luminal (Lum), Luminal/HER2+, pure HER2-positive (pHER2+) and triple negative (TN). Time to CNS progression, CNS-M free interval and Overall Survival (OS) after CNS-M occurrence were compared by the log-rank test. Cox-proportional hazard models were used to study predictor factors associated with CNS progression, including tumor subtype and all potentially clinical relevant variables. RESULTS 115 patients (pts) developed CNS-M with a median time to CNS progression of 31 months. The rate of CNS-M by subtype was: Lum 14%, Lum/HER2+ 35%, pHER2+ 49%, TN 22% (p < 0.001). Compared with Lum tumors, Lum/HER2+ (HR 2.514, p < 0.001), pHER2+ (HR 6.799, p < 0.0001) and TN (HR = 3.179, p < 0.001) subtypes were at higher risk of CNS-M. Median OS in months after CNS-M was: Lum 7.4, Lum/HER2+ 19.2, pHER2+ 7, TN 4.9 (p < 0.002). Belonging to the Lum/HER2+ subtype (HR 0.48, p < 0.037) and having isolated CNS (HR 0.37, p < 0.004) predicted significantly reduced risk of death. CONCLUSIONS After CNS-M, the Lum/HER2+ subtype appears associated with the longest OS. Prospective clinical trials would be required for evaluating the potential role of screening for asymptomatic CNS lesions and of more aggressive CNS-M treatment in Lum/HER2+ subtype.

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.

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

BackgroundCombinations 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.MethodsFrom 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.ResultsDocetaxel-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).ConclusionDocetaxel 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.

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.

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

BackgroundThe 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.MethodsWe 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.ResultsIn 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.Conclusionour 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.

Underuse of Anthracyclines in Women with HER-2+ Advanced Breast Cancer

This article examines how discouraging the use of anthracyclines in combination with trastuzumab in patients with human epidermal growth factor receptor 2 positive metastatic breast cancer because of fears of cardiotoxicity has influenced the use of these agents in this patient setting.

Concurrent radiotherapy does not affect adjuvant CMF delivery but is associated with increased toxicity in women with early breast cancer.

Abstract We evaluated whether concurrent radiotherapy (RT) affected delivery and toxicity of adjuvant intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) in women with operable breast cancer. The medical charts of 321 consecutive breast cancer patients who received CMF either alone for 6 cycles, or for 4 cycles following of an anthracycline (A-CMF) were reviewed. One hundred forty-four women underwent radiotherapy concurrently with CMF. Optimal CMF delivery (success as opposite to failure) was defined as the combined achievement of an average relative dose intensity (aRDI) ≥85% and an average percent of the total dose (aPTD) ≥90% for the three drugs in the CMF regimen. Multivariate logistic regression analysis showed that concurrent-RT did not affect CMF delivery (OR for success 1.391 p=0.230). The sequential A-CMF regimen (OR for success 0.208, 95% C.I. 0.120-0.360, p<0.001) and age ≥56 (OR for success 0.351, 95% C.I. 0.200- 0.161, p<0.001) were independently associated with suboptimal CMF delivery. Moreover, concurrent RT was independently associated with increased leukopenia, thrombocytopenia, upper abdominal pain, mucositis and fatigue. Our retrospective analysis suggests that concurrent-RT has no impact on optimal CMF delivery, but it increases the burden of CMF-related toxicity.

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.

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.