An Inclusive Civil Society Dialogue for Successful Implementation of the EU HTA Regulation: Call to Action to Ensure Appropriate Involvement of Stakeholders and Collaborators.

OBJECTIVES: Stakeholder involvement has long been considered a success factor for a joint European health technology assessment (HTA) process, and its relevance is now anchored in the EU HTA Regulation's (EU HTAR) legislative wording. Therefore, we aimed to explore the roles, challenges, and most important activities to increase the level of involvement per stakeholder group. METHODS: At the 2022 Fall Convention of the European Access Academy (EAA), working groups addressed the involvement of patients, clinicians, regulators, health technology developers (HTD), and national HTA bodies and payers within the EU HTA process. Each working group revisited the pre-convention survey results, determined key role characteristics for each stakeholder, and agreed on the most important activities to fulfill the role profile. Finally, the activities suggested per group were prioritized by plenary group. RESULTS: The prioritized actions for patients included training and capacity building, the establishment of a patient involvement committee, and the establishment of a patient unit at the EC secretariat. For clinicians, it included alignment on evidence assessment from a clinical vs. HTA point of view, capacity building, and standardization of processes. The most important actions for regulators are to develop joint regulatory-HTA guidance documents, align processes and interfaces under the regulation, and share discussions on post-licensing evidence generation. HTDs prioritized scientific advice capacity and the review of the scoping process, and further development of the scope of the assessment report fact checks. The top three actions for national HTA bodies and payers included clarification on the early HTD dialogue process, political support and commitment, and clarification on financial support. CONCLUSIONS: Addressing the activities identified as the most important for stakeholders/collaborators in the EU HTA process (e.g., in the implementation of the EU HTA Stakeholder Network and of the guidance documents developed by the EUnetHTA 21 consortium) will be key to starting an "inclusive civil society dialogue", as suggested by the European Commission's Pharmaceutical Strategy.

The role of stakeholder involvement in the evolving EU HTA process: Insights generated through the European Access Academy's multi-stakeholder pre-convention questionnaire.

Involvement of all relevant stakeholders will be of utmost importance for the success of the developing EU HTA harmonization process. A multi-step procedure was applied to develop a survey across stakeholders/collaborators within the EU HTA framework to assess their current level of involvement, determine their suggested future role, identify challenges to contribution, and highlight efficient ways to fulfilling their role. The 'key' stakeholder groups identified and covered by this research included: patients', clinicians', regulatory, and Health Technology Developer representatives. The survey was circulated to a wide expert audience including all relevant stakeholder groups in order to determine self-perception by the 'key' stakeholders regarding involvement in the HTA process (self-rating), and in a second, slightly modified version of the questionnaire, to determine the perception of 'key' stakeholder involvement by HTA bodies, payers, and policymakers (external rating). Predefined analyses were conducted on the submitted responses. Fifty-four responses were received (patients 9; clinicians: 8; regulators: 4; HTDs 14; HTA bodies: 7; Payers: 5; policymakers 3; others 4). The mean self-perceived involvement score was consistently lower for each of the 'key' stakeholder groups than the respective external ratings. Based on the qualitative insights generated in the survey, a RACI Chart (Responsible/Accountable/Consulted/Informed) was developed for each of the stakeholder groups to determine their roles and involvement in the current EU HTA process. Our findings suggest extensive effort and a distinct research agenda are required to ensure adequate involvement of the key stakeholder groups in the evolving EU HTA process.

Neoadjuvant Trastuzumab and Pertuzumab for Early HER2-Positive Breast Cancer: A Real World Experience.

Background: Randomized studies of neoadjuvant (NA) trastuzumab and pertuzumab combined with chemotherapy for HER2-positive breast cancers (BC) have reported pathological complete response (pCR) rates of 39 to 61%. This study aimed to determine the real-world efficacy and toxicity of NA trastuzumab and pertuzumab combined with chemotherapy in a UK tertiary referral cancer centre. Methods: HER2-positive early BC patients given neoadjuvant chemotherapy with trastuzumab and pertuzumab between October 2016 and February 2018 at our tertiary referral cancer centre were identified via pharmacy records. Clinico-pathological information, treatment regimens, treatment-emergent toxicities, operative details, and pathological responses and outcomes were recorded. Results: 78 female patients were identified; 2 had bilateral diseases and 48 of 78 (62%) were node positive at presentation. 55 of 80 (71%) tumours were ER-positive. PCR occurred in 37 of 78 (46.3%; 95% CI: 35.3-57.2%) patients. 14 of 23 (60.8%) patients with ER-negative tumours achieved pCR; 23 of 55 (41.8%) were ER-positive and 6 of 19 (31.6%) were ER-positive and PgR-positive. No cardiac toxicity was documented. Diarrhoea occurred in 53 of 72 (74%) patients. Grade 3-4 toxicity occurred in ≥2% patients. These were diarrhoea, fatigue, and infection. The Median follow up period was 45.2 months (95% CI 43.8-46.3) with 71 of 78 (91.0%) remaining disease-free and 72 of 78 (92.3%) alive. Estimated OS at 2 years 86% (95% CI: 75-99%). Conclusion: This data confirms the efficacy of neoadjuvant chemotherapy combined with dual HER2 directed therapy. While no cardiac toxicity was observed, diarrhoea occurred frequently. The low pCR rate observed in ER and PgR-positive BCs warrants further investigation and consideration of strategies to increase the pCR rate.

Knowledge and use of biosimilars in oncology: a survey by the European Society for Medical Oncology.

BACKGROUND: Biosimilars can potentially improve the sustainability of cancer care; however, uptake is sometimes limited by safety concerns and a lack of understanding of the concept of extrapolation. The European Society for Medical Oncology (ESMO) conducted a survey to assess the current level of knowledge, understanding and comfort of use of biosimilars among prescribers specialised in oncology. METHODS: A 19-question survey was developed using the SurveyMonkey online platform (https://www.surveymonkey.com/). Data collection occurred between September and October 2017 and included paper and online responses. RESULTS: Overall, 393 responses were received from prescribers. Overall, 49.0% of prescribers use biosimilars in clinical practice and most (79.2%) rate their general knowledge of biosimilars as average to very high. Potential increased risk of immunogenicity remains a significant concern of switching. Gaps in knowledge identified by the survey include biosimilar development, clinical trial design and endpoint selection, and requirements for extrapolation, which should form the focus of future educational initiatives. A substantial demand remains for further educational activities with equal preference for online and face-to-face initiatives. A higher rate of biosimilar use (56.3% vs 46.5%), knowledge of biosimilar development and trial design, and comfort with extrapolation, but a lower knowledge of European Medicines Agency definitions, was found among prescribers from Asia-Pacific versus those from Europe. CONCLUSION: Encouraging levels of prescriber use and general knowledge of biosimilars were found, but a substantial need for further education remains. Efforts should be made worldwide to align terms, definitions and guidelines for the development and approval of biosimilars.

Preparing for the incoming wave of biosimilars in oncology.

With the imminent arrival of oncology biosimilars in the therapeutic paradigm, stakeholders including a clinician, specialist nurse, patient advocate, regulator and economist provide their perspective on optimising the uptake of these new agents in the treatment of cancer. A number of key messages emerge, based on the discussion that took place during a session of the European Society for Medical Oncology's Annual Congress, ESMO Madrid 2017. First, for successful integration of biosimilars into the global healthcare paradigm, informing and educating the full scope of stakeholders, including clinicians, nurses, pharmacists and patients, is primordial. Success is dependent on providing solid evidence and ensuring all voices are heard. Second, for oncology medicines, much can be learnt from the growing experience of approved biosimilars in other disease indications, with success stories for patients, their healthcare providers and healthcare budgets alike. Finally, effective sustainability of the impact on healthcare budgets and the redirection of these savings require education and transparency.

Biosimilars: a position paper of the European Society for Medical Oncology, with particular reference to oncology prescribers.

Biosimilars present a necessary and timely opportunity for physicians, patients and healthcare systems. If suitably developed clinically, manufactured to the correct standards and used appropriately, they can positively impact on the financial sustainability of healthcare systems. A critical consideration regarding the introduction of biosimilars into the clinic centres on the required information concerning all the respective procedures. This position paper aims to describe the issues revolving around biosimilars that are relevant to the field of oncology, especially the prescribers. More specifically, we discuss aspects related to definition, forms of biosimilars, labelling, extrapolation, interchangeability, switching, automatic substitution, clinical standards on safety and efficacy, responsibilities among prescribers and pharmacists, potential impact on financial burden in healthcare and the current scenario and future prospects of biosimilars in Europe and the rest of the world.

The European Medicines Agency Review of Pertuzumab for the treatment of adult patients with HER2-positive metastatic or locally recurrent unresectable breast cancer: summary of the scientific assessment of the committee for medicinal products for human use.

Pertuzumab is a recombinant humanized monoclonal antibody that specifically targets the extracellular dimerization domain (subdomain II) of HER2. Based on the positive opinion from the European Medicines Agency (EMA) on March 4, 2013, a marketing authorization valid throughout the European Union (EU) was issued for pertuzumab (Perjeta) for use in combination with trastuzumab and docetaxel for the treatment of adult patients with HER2-positive metastatic or locally recurrent unresectable breast cancer who have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease. The demonstration of clinical benefit for pertuzumab was based on a single, phase III, randomized, double-blind, placebo-controlled trial comparing the efficacy and safety of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel in previously untreated patients with locally advanced or metastatic HER2-positive breast cancer. In the primary analysis, median progression-free survival was 18.5 months in the pertuzumab group compared with 12.4 months in the placebo group (hazard ratio [HR]: 0.62; 95% confidence interval [CI]: 0.51-0.75; p < .0001). For the secondary endpoints, overall survival (HR: 0.66; 95% CI: 0.52-0.84; p = .0008) and objective response rate (80.2% vs. 69.3%) were also favored in the pertuzumab group. Toxicity was similar between groups except for higher incidence of diarrhea, rash, mucosal inflammation, dry skin, and neutropenia for pertuzumab compared with placebo. This paper summarizes the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the EMA website (http://www.ema.europa.eu).

The European medicines agency review of abiraterone for the treatment of metastatic castration-resistant prostate cancer in adult men after docetaxel chemotherapy and in chemotherapy-naive disease: summary of the scientific assessment of the committee for medicinal products for human use.

On September 5, 2011, abiraterone was approved in the European Union in combination with prednisone or prednisolone for the treatment of metastatic castration-resistant prostate cancer (CRPC) in adult men whose disease has progressed on or after a docetaxel-based chemotherapy regimen. On December 18, 2012, the therapeutic indication was extended to include the use of abiraterone in combination with prednisone or prednisolone for the treatment of metastatic CRPC in adult men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated. Abiraterone is a selective, irreversible inhibitor of cytochrome P450 17α, an enzyme that is key in the production of androgens. Inhibition of androgen biosynthesis deprives prostate cancer cells from important signals for growth, even in cases of resistance to castration. At the time of European Union approval and in a phase III trial in CRPC patients who had failed at least one docetaxel-based chemotherapy regimen, median overall survival for patients treated with abiraterone was 14.8 months versus 10.9 months for those receiving placebo (hazard ratio, 0.65; 95% confidence interval 0.54-0.77; p < .0001). In a subsequent phase III trial in a similar but chemotherapy-naïve patient population, median radiographic progression-free survival was 16.5 months for patients in the abiraterone treatment arm versus 8.3 months for patients in the placebo arm (hazard ratio, 0.53; 95% confidence interval, 0.45-0.62; p < .0001). Abiraterone was most commonly associated with adverse reactions resulting from increased or excessive mineralocorticoid activity. These were generally manageable with basic medical interventions. The most common side effects (affecting more than 10% of patients) were urinary tract infection, hypokalemia, hypertension, and peripheral edema.

The European Medicines Agency review of vemurafenib (Zelboraf®) for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma: summary of the scientific assessment of the Committee for Medicinal Products for Human Use.

The applicant company Roche Registration Ltd. submitted to the European Medicines Agency (EMA) an application for marketing authorisation for vemurafenib. Vemurafenib is a low molecular weight, orally available, inhibitor of oncogenic V600 BRAF serine-threonine kinase. Mutations in the BRAF gene which substitute the valine at amino acid position 600 constitutively activate BRAF proteins, which will drive cell proliferation in the absence of growth factors. Results from a phase 3 trial (N=675) comparing vemurafenib 960 mg twice daily (taken either with or without food) to standard treatment dacarbazine (DTIC) in patients with BRAF V600E mutation-positive unresectable or metastatic melanoma were submitted. The study met its primary efficacy objective after an interim analysis of overall survival. Patients were allowed to cross-over to the experimental arm following disclosure of the study results after the first interim analysis. In the update of the analysis, the median overall survival (OS) was 9.9 months versus 13.2 months for DTIC and vemurafenib, respectively (HR=0.67; 95% confidence interval (CI): 0.54, 0.84; cut-off 3 October 2011). Based on the updated analysis, the CHMP concluded that a survival benefit over DTIC had been convincingly demonstrated, in the overall population. The follow-up was considered sufficiently mature with close to 50% of the events observed. The most common side effects (affecting more than 30% of patients) in vemurafenib treated patients included arthralgia, fatigue, rash, photosensitivity reaction, nausea, alopecia and pruritus. Some patients treated with vemurafenib developed cutaneous squamous cell carcinoma which was readily treated by local surgery. The objective of this paper is to summarise the scientific review of the application leading to regulatory approval in the European Union (EU). The full scientific assessment report and product information, including the Summary of Product Characteristics (SmPC), are available on the EMA website (www.ema.europa.eu).

An open-label, dose-finding study of the combination of satraplatin and gemcitabine in patients with advanced solid tumors.

PURPOSE: Satraplatin is a third generation oral platinum, which has demonstrated antitumor activity. The aim of this phase I study was to determine the maximum tolerated dose (MTD) of the combination of satraplatin and gemcitabine in patients previously treated with chemotherapy and in patients without prior chemotherapy. PATIENTS AND METHODS: Two separate MTDs were planned in two different patient groups (those with and without prior chemotherapy treatment). Dose escalations were planned in cohorts of three patients. Tumor measurements were obtained every two cycles. Assessment of response was performed according to Response Evaluation Criteria in Solid Tumors (RECIST criteria v.1.0). RESULTS: Thirty subjects were enrolled. A MTD of gemcitabine 1000 mg/m(2) days 1 and 8 plus satraplatin 60 mg/m(2) days 1-3, every 21 days was determined in the prior chemotherapy group. No MTD could be determined for the no prior chemotherapy group treated with this schedule. Five patients completed 12 treatment cycles; 22 serious adverse events (SAE) were observed. Although not an entry criteria, overall confirmed response was observed in 17 (24%) evaluable patients (complete response, CR = 1 and partial response, PR = 3) and in 3/7 (43%) patients with measure prostate cancer lesions. CONCLUSIONS: In this phase Ib study, the combination of satraplatin and gemcitabine demonstrated to be safe and efficacious in particular in patients with prostate cancer.

The European medicines agency review of eribulin for the treatment of patients with locally advanced or metastatic breast cancer: summary of the scientific assessment of the committee for medicinal products for human use.

The European Commission issued on March 17, 2011, a marketing authorization valid throughout the European Union (EU) for eribulin (Halaven; Eisai Limited). The decision was based on the favorable opinion of the Committee for Medicinal Products for Human Use recommending a marketing authorization for the treatment of patients with locally advanced or metastatic breast cancer who have progressed after at least 2 chemotherapeutic regimens for advanced disease. Eribulin mesylate is a structurally simplified synthetic analogue of halichondrin B, which is a natural product isolated from the marine sponge Halichondria okadai (ATC code L01XX41). Eribulin is a nontaxane, microtubule dynamics inhibitor belonging to the halichondrin class of antineoplastic agents. Eribulin inhibits the growth phase of microtubules without affecting the shortening phase and sequesters tubulin into nonproductive aggregates leading to G(2)-M cell-cycle block, disruption of mitotic spindles, and, ultimately, apoptotic cell death after prolonged mitotic blockage. The recommended dose of eribulin is 1.23 mg/m(2) (equivalent to 1.4 mg/m(2) eribulin mesylate) to be administered intravenously over 2 to 5 min on days 1 and 8 of a 3-week cycle. In the pivotal trial, eribulin was associated with increased overall survival in patients with locally advanced or metastatic breast cancer who received at least 2 prior chemotherapy lines for advanced disease (median overall survival was 13.2 months in the eribulin arm vs. 10.6 months in the control arm; HR = 0.805; 95% confidence interval, 0.677-0.958; P = 0.014). The most common side effects are asthenia or fatigue and neutropenia. The objective of this article is to summarize the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary report and product information, including product characteristics, are available on the European Medicines Agency website.

The effect of body mass index on overall and disease-free survival in node-positive breast cancer patients treated with docetaxel and doxorubicin-containing adjuvant chemotherapy: the experience of the BIG 02-98 trial.

BACKGROUND: Obesity has been shown to be an indicator of poor prognosis for patients with primary breast cancer (BC) regardless of the use of adjuvant systemic therapy. PATIENTS AND METHODS: This is a retrospective analysis of 2,887 node-positive BC patients enrolled in the BIG 02-98 adjuvant study, a randomised phase III trial whose primary objective was to evaluate disease-free survival (DFS) by adding docetaxel to doxorubicin-based chemotherapy. In the current analysis, the effect of body mass index (BMI) on DFS and overall survival (OS) was assessed. BMI was obtained before the first cycle of chemotherapy. Obesity was defined as a BMI >or= 30 kg/m2. RESULTS: In total, 547 (19%) patients were obese at baseline, while 2,340 (81%) patients were non-obese. Estimated 5-year OS was 87.5% for non-obese and 82.9% for obese patients (HR 1.34; P = 0.013). Estimated 5-years DFS was 75.9% for nonobese and 70.0% for obese patients (HR 1.20; P = 0.041). Ina multivariate model, obesity remained an independent prognostic factor for OS and DFS. CONCLUSIONS: In this study,obesity was associated with poorer outcome in node-positive BC patients. Given the increasing prevalence of obesity worldwide, more research on improving the treatment of obese BC patients is needed.

Quantitation of HER2 expression or HER2:HER2 dimers and differential survival in a cohort of metastatic breast cancer patients carefully selected for trastuzumab treatment primarily by FISH.

The selection of patients with HER2-positive breast cancer for treatment with trastuzumab is based on the measurement of HER2 protein expression by immunohistochemistry, or the presence of HER2 gene amplification by fluorescence in situ hybridization (FISH). By using multivariate analyses, we investigate the relationship between quantitative measurements of HER2 expression or HER2:HER2 dimers and objective response (Response Evaluation Criteria in Solid Tumors), time to progression, and breast cancer survival after trastuzumab treatment in a cohort of patients with metastatic breast cancer who were primarily selected for treatment by FISH. The VeraTag assay, a proximity-based assay designed to quantitate protein expression and dimerization in formalin-fixed, paraffin-embedded tissue specimens, was used to measure HER2 protein expression and HER2:HER2 dimer levels. In a Cox proportional hazards analysis, higher HER2 expression or HER2:HER2 dimer levels were both correlated with longer survival (P=0.0058 and P=0.016, respectively) after treatment with trastuzumab in a population of patients that were either FISH-positive (90%) or immunohistochemistry 3+ (10%). Patients with higher levels of HER2 expression or HER2:HER2 dimers seemed to derive little benefit from the addition of concomitant chemotherapy to trastuzumab, whereas those with lower levels benefited significantly [interaction test P=0.43 (HER2 expression), P=0.27 (HER2:HER2 dimers)]. These data suggest that more quantitative or functional measurements of HER2 status may facilitate the development of more personalized treatment strategies for patients with metastatic breast cancer.

Phosphorylated HER-2 tyrosine kinase and Her-2/neu gene amplification as predictive factors of response to trastuzumab in patients with HER-2 overexpressing metastatic breast cancer (MBC).

AIM: Trastuzumab (T), a humanised monoclonal antibody against HER-2, is active in HER-2-positive MBC patients. However, nearly 60% of the patients do not benefit from T, stressing the need for additional predictive markers. The following markers could be implicated in response to T: (1) the magnitude of Her-2 gene amplification; (2) the co-expression of the other HER family receptors, possibly responsible for HER-2 trans-activation; (3) the activated status of HER-2; (4) the activated status of downstream effectors as mitogen-activated protein kinases (MAPKs), p38 and p27. METHODS: Medical files of patients with MBC treated with T either as a single agent or in combination with chemotherapy (CT) were reviewed. HER family members (EGFR, HER-2, HER-3, HER-4), the phosphorylated forms of EGFR (p-EGFR), HER-2 (p-HER-2) and of the downstream effectors were evaluated in the archival tumours. The correlation between clinical outcome and the expression of these markers was investigated. RESULTS: (1) Increasing values of Her-2 amplification were associated with a higher probability of achieving an objective response; (2) no statistical significant correlation between the expression of the HER family receptors was found; (3) p-HER-2 was predictive of response in patients treated with T+CT; (4) a statistically significant correlation between p-ERK 1/2, p-p38 and p-HER-2 emerged, pointing to the activated vertical pathway p-HER-2-->p-MAPKs. CONCLUSIONS: p-HER-2 and the magnitude of Her-2 amplification were predictive of response to T and their role deserves to be analysed in larger and more homogenous T-treated populations such as those from large phase III trials.

Risk of acute myeloid leukemia and myelodysplastic syndrome in trials of adjuvant epirubicin for early breast cancer: correlation with doses of epirubicin and cyclophosphamide.

PURPOSE: We reviewed follow-up of patients treated in 19 randomized trials of adjuvant epirubicin in early breast cancer to determine incidence, risk, and risk factors for subsequent acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). PATIENTS AND METHODS: The patients (N = 9,796) were observed from the start of adjuvant treatment (53,080 patient-years). Cases of AML or MDS (AML/MDS) were reported, with disease characteristics. Incidence and cumulative risk were compared for possible risk factors, for assigned regimens, and for administered cumulative doses of epirubicin and cyclophosphamide. RESULTS: In 7,110 patients treated with epirubicin-containing regimens (92% of whom also received cyclophosphamide), 8-year cumulative probability of AML/MDS was 0.55% (95% CI, 0.33% to 0.78%). The risk of developing AML/MDS increased in relation to planned epirubicin dose per cycle, planned epirubicin dose-intensity, and administered cumulative doses of epirubicin and cyclophosphamide. Patients with administered cumulative doses of both epirubicin and cyclophosphamide not exceeding those used in standard regimens (

Hepatic arterial continuous infusion (HACI) of oxaliplatin in patients with unresectable liver metastases from colorectal cancer.

BACKGROUND: Oxaliplatin, a new DACH-platinum compound, has provided high response rates both in untreated and 5-FU-resistant patients. AIM: To define the feasibility and toxicity profile of Oxaliplatin administered as a continuous hepatic aterial infusion. PATIENTS AND METHODS: Seventeen patients with pretreated metastatic liver colorectal cancer were treated with Oxaliplatin 20 mg/m2/day by HACI x 5 days every 3 weeks. RESULTS: Toxicity grade 3 included pain (4 out of 17), asthenia (1 out of 17) and nausea (1 out of 17). Abdominal pain grade 4 (WHO) was noted in only one patient. Overall, severe abdominal pain (main dose-limiting toxicity) was observed in 41% of patients and no chemical hepatitis and sclerosing cholangitis pain-related was proven by an endoscopic retrograde cholangiography. The response rate was not a primary end-point; nonetheless among 15 evaluable patients we observed partial responses (PR) in 7 patients (46%) and stable disease (SD) in 21% of cases for an overall tumor growth control of 67%. Progression to disease (PD) was 33%. Following chemotherapy, one patient underwent surgical removal of residual metastases, with curative intent. The 1-year survival rate was 64%. The median duration of survival was 19 months. The median delay to hepatic progression was 10 months. CONCLUSION: Further studies are required to define the role of HACI Oxaliplatin, the schedule of administration (bolus vs continuous infusion) and the combination, also in this setting, with fluoropyrimidines.

Predictive molecular markers in the adjuvant therapy of breast cancer: state of the art in the year 2002.

In the present article, an extensive review of the current knowledge regarding predictive molecular markers in breast cancer is presented. The main emphasis has been given to the adjuvant therapy setting, because of the lack of well-designed studies evaluating predictive markers in the metastatic setting. In the first part of the article some general concepts have been summarized, mainly to emphasize the difference between prognostic and predictive markers. In the second part of the article, studies evaluating molecular markers with predictive value for the most commonly used drugs or regimens (i.e., cyclophosphamide, methotrexate, 5-fluorouracil [CMF], anthracyclines, taxanes, and herceptin) have been reviewed and discussed. An attempt has been made to provide for each single predictive marker the currently available level of evidence, to allow the reader to have immediate information regarding the impact of the evaluated marker in daily clinical practice. In the last part of the article, the most important findings have been summarized and future avenues of research have been outlined.