Enhancing global access to cancer medicines.

Globally, cancer is the second leading cause of death, with numbers greatly exceeding those for human immunodeficiency virus/acquired immunodeficiency syndrome, tuberculosis, and malaria combined. Limited access to timely diagnosis, to affordable, effective treatment, and to high-quality care are just some of the factors that lead to disparities in cancer survival between countries and within countries. In this article, the authors consider various factors that prevent access to cancer medicines (particularly access to essential cancer medicines). Even if an essential cancer medicine is included on a national medicines list, cost might preclude its use, it might be prescribed or used inappropriately, weak infrastructure might prevent it being accessed by those who could benefit, or quality might not be guaranteed. Potential strategies to address the access problems are discussed, including universal health coverage for essential cancer medicines, fairer methods for pricing cancer medicines, reducing development costs, optimizing regulation, and improving reliability in the global supply chain. Optimizing schedules for cancer therapy could reduce not only costs, but also adverse events, and improve access. More and better biomarkers are required to target patients who are most likely to benefit from cancer medicines. The optimum use of cancer medicines depends on the effective delivery of several services allied to oncology (including laboratory, imaging, surgery, and radiotherapy). Investment is necessary in all aspects of cancer care, from these supportive services to technologies, and the training of health care workers and other staff.

Interrupting Endocrine Therapy to Attempt Pregnancy after Breast Cancer.

BACKGROUND: Prospective data on the risk of recurrence among women with hormone receptor-positive early breast cancer who temporarily discontinue endocrine therapy to attempt pregnancy are lacking. METHODS: We conducted a single-group trial in which we evaluated the temporary interruption of adjuvant endocrine therapy to attempt pregnancy in young women with previous breast cancer. Eligible women were 42 years of age or younger; had had stage I, II, or III disease; had received adjuvant endocrine therapy for 18 to 30 months; and desired pregnancy. The primary end point was the number of breast cancer events (defined as local, regional, or distant recurrence of invasive breast cancer or new contralateral invasive breast cancer) during follow-up. The primary analysis was planned to be performed after 1600 patient-years of follow-up. The prespecified safety threshold was the occurrence of 46 breast cancer events during this period. Breast cancer outcomes in this treatment-interruption group were compared with those in an external control cohort consisting of women who would have met the entry criteria for the current trial. RESULTS: Among 516 women, the median age was 37 years, the median time from breast cancer diagnosis to enrollment was 29 months, and 93.4% had stage I or II disease. Among 497 women who were followed for pregnancy status, 368 (74.0%) had at least one pregnancy and 317 (63.8%) had at least one live birth. In total, 365 babies were born. At 1638 patient-years of follow-up (median follow-up, 41 months), 44 patients had a breast cancer event, a result that did not exceed the safety threshold. The 3-year incidence of breast cancer events was 8.9% (95% confidence interval [CI], 6.3 to 11.6) in the treatment-interruption group and 9.2% (95% CI, 7.6 to 10.8) in the control cohort. CONCLUSIONS: Among select women with previous hormone receptor-positive early breast cancer, temporary interruption of endocrine therapy to attempt pregnancy did not confer a greater short-term risk of breast cancer events, including distant recurrence, than that in the external control cohort. Further follow-up is critical to inform longer-term safety. (Funded by ETOP IBCSG Partners Foundation and others; POSITIVE ClinicalTrials.gov number, NCT02308085.).

Event-free Survival with Pembrolizumab in Early Triple-Negative Breast Cancer.

BACKGROUND: The addition of pembrolizumab to neoadjuvant chemotherapy led to a significantly higher percentage of patients with early triple-negative breast cancer having a pathological complete response (defined as no invasive cancer in the breast and negative nodes) at definitive surgery in an earlier analysis of this phase 3 trial of neoadjuvant and adjuvant therapy. The primary results regarding event-free survival in this trial have not been reported. METHODS: We randomly assigned, in a 2:1 ratio, patients with previously untreated stage II or III triple-negative breast cancer to receive neoadjuvant therapy with four cycles of pembrolizumab (at a dose of 200 mg) or placebo every 3 weeks plus paclitaxel and carboplatin, followed by four cycles of pembrolizumab or placebo plus doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide. After definitive surgery, patients received adjuvant pembrolizumab (pembrolizumab-chemotherapy group) or placebo (placebo-chemotherapy group) every 3 weeks for up to nine cycles. The primary end points were pathological complete response (the results for which have been reported previously) and event-free survival, defined as the time from randomization to the date of disease progression that precluded definitive surgery, local or distant recurrence, occurrence of a second primary cancer, or death from any cause. Safety was also assessed. RESULTS: Of the 1174 patients who underwent randomization, 784 were assigned to the pembrolizumab-chemotherapy group and 390 to the placebo-chemotherapy group. The median follow-up at this fourth planned interim analysis (data cutoff, March 23, 2021) was 39.1 months. The estimated event-free survival at 36 months was 84.5% (95% confidence interval [CI], 81.7 to 86.9) in the pembrolizumab-chemotherapy group, as compared with 76.8% (95% CI, 72.2 to 80.7) in the placebo-chemotherapy group (hazard ratio for event or death, 0.63; 95% CI, 0.48 to 0.82; P<0.001). Adverse events occurred predominantly during the neoadjuvant phase and were consistent with the established safety profiles of pembrolizumab and chemotherapy. CONCLUSIONS: In patients with early triple-negative breast cancer, neoadjuvant pembrolizumab plus chemotherapy, followed by adjuvant pembrolizumab after surgery, resulted in significantly longer event-free survival than neoadjuvant chemotherapy alone. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-522 ClinicalTrials.gov number, NCT03036488.).

Tailoring neo/adjuvant systemic therapy in breast cancer: "The advent of a personalized approach"-The Breast-Gynecological and Immuno-Oncology International Cancer Conference (BGICC) consensus and recommendations.

BACKGROUND: The management of early breast cancer (BC) has witnessed an uprise in the use of neoadjuvant therapy and a remarkable reshaping of the systemic therapy postneoadjuvant treatment in the last few years, with the evolution of many controversial clinical situations that require consensus. METHODS: During the 14th Breast-Gynecological and Immuno-Oncology International Cancer Conference held in Egypt in 2022, a panel of 44 BC experts from 13 countries voted on statements concerning debatable challenges in the neo/adjuvant treatment setting. The recommendations were subsequently updated based on the most recent data emerging. A modified Delphi approach was used to develop this consensus. A consensus was achieved when ≥75% of voters selected an answer. RESULTS AND CONCLUSIONS: The consensus recommendations addressed different escalation and de-escalation strategies in the setting of neoadjuvant therapy for early BC. The recommendations recapitulate the available clinical evidence and expert opinion to individualize patient management and optimize therapy outcomes. Consensus was reached in 63% of the statements (52/83), and the rationale behind each statement was clarified.

Baseline [18F]FDG PET/CT and MRI first-order breast tumor features do not improve pathological complete response prediction to neoadjuvant chemotherapy.

PURPOSE: To verify the ability of pretreatment [18F]FDG PET/CT and T1-weighed dynamic contrast-enhanced MRI to predict pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) in breast cancer (BC) patients. METHODS: This retrospective study includes patients with BC of no special type submitted to baseline [18F]FDG PET/CT, NAC and surgery. [18F]FDG PET-based features reflecting intensity and heterogeneity of tracer uptake were extracted from the primary BC and suspicious axillary lymph nodes (ALN), for comparative analysis related to NAC response (pCR vs. non-pCR). Multivariate logistic regression was performed for response prediction combining the breast tumor-extracted PET-based features and clinicopathological features. A subanalysis was performed in a patients' subsample by adding breast tumor-extracted first-order MRI-based features to the multivariate logistic regression. RESULTS: A total of 170 tumors from 168 patients were included. pCR was observed in 60/170 tumors (20/107 luminal B-like, 25/45 triple-negative and 15/18 HER2-enriched surrogate molecular subtypes). Higher intensity and higher heterogeneity of [18F]FDG uptake in the primary BC were associated with NAC response in HER2-negative tumors (immunohistochemistry score 0, 1 + or 2 + non-amplified by in situ hybridization). Also, higher intensity of tracer uptake was observed in ALN in the pCR group among HER2-negative tumors. No [18F]FDG PET-based features were associated with pCR in the other subgroup analyses. A subsample of 103 tumors was also submitted to extraction of MRI-based features. When combined with clinicopathological features, neither [18F]FDG PET nor MRI-based features had additional value for pCR prediction. The only significant predictors were estrogen receptor status, HER2 expression and grade. CONCLUSION: Pretreatment [18F]FDG PET-based features from primary BC and ALN are not associated with response to NAC, except in HER2-negative tumors. As compared with pathological features, no breast tumor-extracted PET or MRI-based feature improved response prediction.

Joint EANM-SNMMI guideline on the role of 2-[18F]FDG PET/CT in no special type breast cancer : (endorsed by the ACR, ESSO, ESTRO, EUSOBI/ESR, and EUSOMA).

INTRODUCTION: There is much literature about the role of 2-[18F]FDG PET/CT in patients with breast cancer (BC). However, there exists no international guideline with involvement of the nuclear medicine societies about this subject. PURPOSE: To provide an organized, international, state-of-the-art, and multidisciplinary guideline, led by experts of two nuclear medicine societies (EANM and SNMMI) and representation of important societies in the field of BC (ACR, ESSO, ESTRO, EUSOBI/ESR, and EUSOMA). METHODS: Literature review and expert discussion were performed with the aim of collecting updated information regarding the role of 2-[18F]FDG PET/CT in patients with no special type (NST) BC and summarizing its indications according to scientific evidence. Recommendations were scored according to the National Institute for Health and Care Excellence (NICE) criteria. RESULTS: Quantitative PET features (SUV, MTV, TLG) are valuable prognostic parameters. In baseline staging, 2-[18F]FDG PET/CT plays a role from stage IIB through stage IV. When assessing response to therapy, 2-[18F]FDG PET/CT should be performed on certified scanners, and reported either according to PERCIST, EORTC PET, or EANM immunotherapy response criteria, as appropriate. 2-[18F]FDG PET/CT may be useful to assess early metabolic response, particularly in non-metastatic triple-negative and HER2+ tumours. 2-[18F]FDG PET/CT is useful to detect the site and extent of recurrence when conventional imaging methods are equivocal and when there is clinical and/or laboratorial suspicion of relapse. Recent developments are promising. CONCLUSION: 2-[18F]FDG PET/CT is extremely useful in BC management, as supported by extensive evidence of its utility compared to other imaging modalities in several clinical scenarios.

Designing clinical trials based on modern imaging and metastasis-directed treatments in patients with oligometastatic breast cancer: a consensus recommendation from the EORTC Imaging and Breast Cancer Groups.

Breast cancer remains the most common cause of cancer death among women. Despite its considerable histological and molecular heterogeneity, those characteristics are not distinguished in most definitions of oligometastatic disease and clinical trials of oligometastatic breast cancer. After an exhaustive review of the literature covering all aspects of oligometastatic breast cancer, 35 experts from the European Organisation for Research and Treatment of Cancer Imaging and Breast Cancer Groups elaborated a Delphi questionnaire aimed at offering consensus recommendations, including oligometastatic breast cancer definition, optimal diagnostic pathways, and clinical trials required to evaluate the effect of diagnostic imaging strategies and metastasis-directed therapies. The main recommendations are the introduction of modern imaging methods in metastatic screening for an earlier diagnosis of oligometastatic breast cancer and the development of prospective trials also considering the histological and molecular complexity of breast cancer. Strategies for the randomisation of imaging methods and therapeutic approaches in different subsets of patients are also addressed.

European Groundshot-addressing Europe's cancer research challenges: a Lancet Oncology Commission.

Cancer research is a crucial pillar for countries to deliver more affordable, higher quality, and more equitable cancer care. Patients treated in research-active hospitals have better outcomes than patients who are not treated in these settings. However, cancer in Europe is at a crossroads. Cancer was already a leading cause of premature death before the COVID-19 pandemic, and the disastrous effects of the pandemic on early diagnosis and treatment will probably set back cancer outcomes in Europe by almost a decade. Recognising the pivotal importance of research not just to mitigate the pandemic today, but to build better European cancer services and systems for patients tomorrow, the Lancet Oncology European Groundshot Commission on cancer research brings together a wide range of experts, together with detailed new data on cancer research activity across Europe during the past 12 years. We have deployed this knowledge to help inform Europe's Beating Cancer Plan and the EU Cancer Mission, and to set out an evidence-driven, patient-centred cancer research roadmap for Europe. The high-resolution cancer research data we have generated show current activities, captured through different metrics, including by region, disease burden, research domain, and effect on outcomes. We have also included granular data on research collaboration, gender of researchers, and research funding. The inclusion of granular data has facilitated the identification of areas that are perhaps overemphasised in current cancer research in Europe, while also highlighting domains that are underserved. Our detailed data emphasise the need for more information-driven and data-driven cancer research strategies and planning going forward. A particular focus must be on central and eastern Europe, because our findings emphasise the widening gap in cancer research activity, and capacity and outcomes, compared with the rest of Europe. Citizens and patients, no matter where they are, must benefit from advances in cancer research. This Commission also highlights that the narrow focus on discovery science and biopharmaceutical research in Europe needs to be widened to include such areas as prevention and early diagnosis; treatment modalities such as radiotherapy and surgery; and a larger concentration on developing a research and innovation strategy for the 20 million Europeans living beyond a cancer diagnosis. Our data highlight the important role of comprehensive cancer centres in driving the European cancer research agenda. Crucial to a functioning cancer research strategy and its translation into patient benefit is the need for a greater emphasis on health policy and systems research, including implementation science, so that the innovative technological outputs from cancer research have a clear pathway to delivery. This European cancer research Commission has identified 12 key recommendations within a call to action to reimagine cancer research and its implementation in Europe. We hope this call to action will help to achieve our ambitious 70:35 target: 70% average 10-year survival for all European cancer patients by 2035.

Quality of Life and Treatment-Related Side Effects in Patients With HR+/HER2- Advanced Breast Cancer: Findings From a Multicountry Survey.

BACKGROUND: Quality of life (QOL) is a critical factor in decision-making for advanced breast cancer (ABC). There is a need to improve how QOL and treatment-related side effects (SEs) that impact it are clinically assessed. We examined healthcare professionals' (HCPs') and patients' perspectives on the importance of QOL discussions and the impact of SEs on QOL in clinical settings. PATIENTS AND METHODS: A cross-sectional online survey was conducted (7/2020-5/2021) among oncologists, nurses, and patients with HR+/HER2- ABC in 7 countries. RESULTS: The survey was completed by 502 HCPs and 467 patients. Overall, 88% of oncologists and 49% of patients recalled QOL discussions at follow-up. In the first- through fourth-line (1L, 2L, 3L, and 4L) settings, respectively, 48%, 57%, 79%, and 85% of oncologists reported QOL was very important; 73% and 45% of patients receiving 1L and 2L treatment and 40% receiving 3L+ treatment indicated QOL was important. Patients reported that insomnia, anxiety, back pain, fatigue, diarrhea, hot flashes, low sexual interest, and loss of appetite had a moderate/severe impact on QOL. Of patients experiencing certain SEs, ≥64% did not discuss them with HCPs until there was a moderate/severe impact on QOL. In patients receiving a CDK4/6 inhibitor, SEs, including insomnia, diarrhea, back pain, and fatigue, had a moderate/severe impact on QOL. CONCLUSIONS: This survey discovered disconnects between HCPs and patients with ABC on the importance of QOL discussions and the impact of SEs on QOL. These data support the use of ABC-specific QOL questionnaires that closely monitor SEs impacting QOL.

Quality of Life in Male Breast Cancer: Prospective Study of the International Male Breast Cancer Program (EORTC10085/TBCRC029/BIG2-07/NABCG).

INTRODUCTION: Prospective data about quality of life (QoL) in men with breast cancer (BC) are lacking. A prospective registry (EORTC10085) of men with all BC stages, including a QoL correlative study, was performed as part of the International Male Breast Cancer Program. METHODS: Questionnaires at BC diagnosis included the EORTC QLQ-C30 and BR23 (BC specific module), adapted for men. High functioning and global health/QoL scores indicate high functioning levels/high QoL; high symptom-focused measures scores indicate high symptoms/problems levels. EORTC reference data for healthy men and women with BC were used for comparisons. RESULTS: Of 422 men consenting to participate, 363 were evaluable. Median age was 67 years, and median time between diagnosis and survey was 1.1 months. A total of 114 men (45%) had node-positive early disease, and 28 (8%) had advanced disease. Baseline mean global health status score was 73 (SD: 21), better than in female BC reference data (62, SD: 25). Common symptoms in male BC were fatigue (22, SD: 24), insomnia (21, SD: 28), and pain (16, SD: 23), for which women's mean scores indicated more burdensome symptoms at 33 (SD: 26), 30 (SD: 32), and 29 (SD: 29). Men's mean sexual activity score was 31 (SD: 26), with less sexual activity in older patients or advanced disease. CONCLUSIONS: QoL and symptom burden in male BC patients appears no worse (and possibly better) than that in female patients. Future analyses on impact of treatment on symptoms and QoL over time, may support tailoring of male BC management.

Pembrolizumab for Early Triple-Negative Breast Cancer.

BACKGROUND: Previous trials showed promising antitumor activity and an acceptable safety profile associated with pembrolizumab in patients with early triple-negative breast cancer. Whether the addition of pembrolizumab to neoadjuvant chemotherapy would significantly increase the percentage of patients with early triple-negative breast cancer who have a pathological complete response (defined as no invasive cancer in the breast and negative nodes) at definitive surgery is unclear. METHODS: In this phase 3 trial, we randomly assigned (in a 2:1 ratio) patients with previously untreated stage II or stage III triple-negative breast cancer to receive neoadjuvant therapy with four cycles of pembrolizumab (at a dose of 200 mg) every 3 weeks plus paclitaxel and carboplatin (784 patients; the pembrolizumab-chemotherapy group) or placebo every 3 weeks plus paclitaxel and carboplatin (390 patients; the placebo-chemotherapy group); the two groups then received an additional four cycles of pembrolizumab or placebo, and both groups received doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide. After definitive surgery, the patients received adjuvant pembrolizumab or placebo every 3 weeks for up to nine cycles. The primary end points were a pathological complete response at the time of definitive surgery and event-free survival in the intention-to-treat population. RESULTS: At the first interim analysis, among the first 602 patients who underwent randomization, the percentage of patients with a pathological complete response was 64.8% (95% confidence interval [CI], 59.9 to 69.5) in the pembrolizumab-chemotherapy group and 51.2% (95% CI, 44.1 to 58.3) in the placebo-chemotherapy group (estimated treatment difference, 13.6 percentage points; 95% CI, 5.4 to 21.8; P<0.001). After a median follow-up of 15.5 months (range, 2.7 to 25.0), 58 of 784 patients (7.4%) in the pembrolizumab-chemotherapy group and 46 of 390 patients (11.8%) in the placebo-chemotherapy group had disease progression that precluded definitive surgery, had local or distant recurrence or a second primary tumor, or died from any cause (hazard ratio, 0.63; 95% CI, 0.43 to 0.93). Across all treatment phases, the incidence of treatment-related adverse events of grade 3 or higher was 78.0% in the pembrolizumab-chemotherapy group and 73.0% in the placebo-chemotherapy group, including death in 0.4% (3 patients) and 0.3% (1 patient), respectively. CONCLUSIONS: Among patients with early triple-negative breast cancer, the percentage with a pathological complete response was significantly higher among those who received pembrolizumab plus neoadjuvant chemotherapy than among those who received placebo plus neoadjuvant chemotherapy. (Funded by Merck Sharp & Dohme [a subsidiary of Merck]; KEYNOTE-522 ClinicalTrials.gov number, NCT03036488.).

Well-being trajectories in breast cancer and their predictors: A machine-learning approach.

OBJECTIVE: This study aimed to describe distinct trajectories of anxiety/depression symptoms and overall health status/quality of life over a period of 18 months following a breast cancer diagnosis, and identify the medical, socio-demographic, lifestyle, and psychological factors that predict these trajectories. METHODS: 474 females (mean age = 55.79 years) were enrolled in the first weeks after surgery or biopsy. Data from seven assessment points over 18 months, at 3-month intervals, were used. The two outcomes were assessed at all points. Potential predictors were assessed at baseline and the first follow-up. Machine-Learning techniques were used to detect latent patterns of change and identify the most important predictors. RESULTS: Five trajectories were identified for each outcome: stably high, high with fluctuations, recovery, deteriorating/delayed response, and stably poor well-being (chronic distress). Psychological factors (i.e., negative affect, coping, sense of control, social support), age, and a few medical variables (e.g., symptoms, immune-related inflammation) predicted patients' participation in the delayed response and the chronic distress trajectories versus all other trajectories. CONCLUSIONS: There is a strong possibility that resilience does not always reflect a stable response pattern, as there might be some interim fluctuations. The use of machine-learning techniques provides a unique opportunity for the identification of illness trajectories and a shortlist of major bio/behavioral predictors. This will facilitate the development of early interventions to prevent a significant deterioration in patient well-being.

Associations between Physical Exercise, Quality of Life, Psychological Symptoms and Treatment Side Effects in Early Breast Cancer.

Background: Identifying and understanding modifiable factors for the well-being of cancer patients is critical in survivorship research. We studied variables associated with the exercise habits of breast cancer patients and investigated if the achievement of exercise recommendations was associated with enhanced quality of life and/or psychological well-being. Material and Methods. 311 women from Finland, Portugal, Israel, and Italy receiving adjuvant therapy for stage I-III breast cancer answered questions about sociodemographic factors and physical exercise. Quality of life was assessed by the EORTC C30 and BR23 questionnaires. Anxiety and depression were evaluated using the HADS scale. Results: At the beginning of adjuvant therapy and after twelve months, 32% and 26% of participants were physically inactive, 27% and 30% exercised between 30 and 150 minutes per week, while 41% and 45% exercised the recommended 150 minutes or more per week. Relative to other countries, Finnish participants were more likely to be active at baseline and at twelve months (89% vs. 50%, p < 0.001 and 87% vs. 64%, p < 0.001). Participants with stage I cancer were more likely to be active at twelve months than those with a higher stage (80% vs. 70%,p < 0.05). The inactive participants reported more anxiety (p < 0.05) and depression (p < 0.001), lower global quality of life (p < 0.001), and more side effects (p < 0.05) than the others at twelve months. Accordingly, those who remained inactive or decreased their level of exercise from baseline to twelve months reported more anxiety (p < 0.01) and depression (p < 0.001), lower global quality of life (p < 0.001), and more side effects (p < 0.05) than those with the same or increased level of exercise. Conclusion: For women with early breast cancer, exercise was associated with a better quality of life, less depression and anxiety, and fewer adverse events of adjuvant therapy. Trial registration number: NCT05095675. Paula Poikonen-Saksela on behalf of Bounce consortium (https://www.bounce-project.eu/).

3D Breast Volume Estimation.

INTRODUCTION: Breast volume estimation is considered crucial for breast cancer surgery planning. A single, easy, and reproducible method to estimate breast volume is not available. This study aims to evaluate, in patients proposed for mastectomy, the accuracy of the calculation of breast volume from a low-cost 3D surface scan (Microsoft Kinect) compared to the breast MRI and water displacement technique. MATERIAL AND METHODS: Patients with a Tis/T1-T3 breast cancer proposed for mastectomy between July 2015 and March 2017 were assessed for inclusion in the study. Breast volume calculations were performed using a 3D surface scan and the breast MRI and water displacement technique. Agreement between volumes obtained with both methods was assessed with the Spearman and Pearson correlation coefficients. RESULTS: Eighteen patients with invasive breast cancer were included in the study and submitted to mastectomy. The level of agreement of the 3D breast volume compared to surgical specimens and breast MRI volumes was evaluated. For mastectomy specimen volume, an average (standard deviation) of 0.823 (0.027) and 0.875 (0.026) was obtained for the Pearson and Spearman correlations, respectively. With respect to MRI annotation, we obtained 0.828 (0.038) and 0.715 (0.018). DISCUSSION: Although values obtained by both methodologies still differ, the strong linear correlation coefficient suggests that 3D breast volume measurement using a low-cost surface scan device is feasible and can approximate both the MRI breast volume and mastectomy specimen with sufficient accuracy. CONCLUSION: 3D breast volume measurement using a depth-sensor low-cost surface scan device is feasible and can parallel MRI breast and mastectomy specimen volumes with enough accuracy. Differences between methods need further development to reach clinical applicability. A possible approach could be the fusion of breast MRI and the 3D surface scan to harmonize anatomic limits and improve volume delimitation.

Breast conservation and axillary management after primary systemic therapy in patients with early-stage breast cancer: the Lucerne toolbox.

Primary systemic therapy is increasingly used in the treatment of patients with early-stage breast cancer, but few guidelines specifically address optimal locoregional therapies. Therefore, we established an international consortium to discuss clinical evidence and to provide expert advice on technical management of patients with early-stage breast cancer. The steering committee prepared six working packages to address all major clinical questions from diagnosis to surgery. During a consensus meeting that included members from European scientific oncology societies, clinical trial groups, and patient advocates, statements were discussed and voted on. A consensus was reached in 42% of statements, a majority in 38%, and no decision in 21%. Based on these findings, the panel developed clinical guidance recommendations and a toolbox to overcome many clinical and technical requirements associated with the diagnosis, response assessment, surgical planning, and surgery of patients with early-stage breast cancer. This guidance could convince clinicians and patients of the major clinical advancements purported by primary systemic therapy, the use of less extensive and more targeted surgery to improve the lives of patients with breast cancer.

70-gene signature as an aid for treatment decisions in early breast cancer: updated results of the phase 3 randomised MINDACT trial with an exploratory analysis by age.

BACKGROUND: The MINDACT trial showed excellent 5-year distant metastasis-free survival of 94·7% (95% CI 92·5-96·2) in patients with breast cancer of high clinical and low genomic risk who did not receive chemotherapy. We present long-term follow-up results together with an exploratory analysis by age. METHODS: MINDACT was a multicentre, randomised, phase 3 trial done in 112 academic and community hospitals in nine European countries. Patients aged 18-70 years, with histologically confirmed primary invasive breast cancer (stage T1, T2, or operable T3) with up to three positive lymph nodes, no distant metastases, and a WHO performance status of 0-1 were enrolled and their genomic risk (using the MammaPrint 70-gene signature) and clinical risk (using a modified version of Adjuvant! Online) were determined. Patients with low clinical and low genomic risk results did not receive chemotherapy, and patients with high clinical and high genomic risk did receive chemotherapy (mostly anthracycline-based or taxane-based, or a combination thereof). Patients with discordant risk results (ie, patients with high clinical risk but low genomic risk, and those with low clinical risk but high genomic risk) were randomly assigned (1:1) to receive chemotherapy or not based on either the clinical risk or the genomic risk. Randomisation was done centrally and used a minimisation technique that was stratified by institution, risk group, and clinical-pathological characteristics. Treatment allocation was not masked. The primary endpoint was to test whether the distant metastasis-free survival rate at 5 years in patients with high clinical risk and low genomic risk not receiving chemotherapy had a lower boundary of the 95% CI above the predefined non-inferiority boundary of 92%. In the primary test population of patients with high clinical risk and low genomic risk who adhered to the treatment allocation of no chemotherapy and had no change in risk post-enrolment. Here, we present updated follow-up as well as an exploratory analysis of a potential age effect (≤50 years vs >50 years) and an analysis by nodal status for patients with hormone receptor-positive and HER2-negative disease. These analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT00433589, and the European Clinical Trials database, EudraCT2005-002625-31. Recruitment is complete and further long-term follow-up is ongoing. FINDINGS: Between Feb 8, 2007, and July 11, 2011, 6693 patients were enrolled. On Feb 26, 2020, median follow-up was 8·7 years (IQR 7·8-9·7). The updated 5-year distant metastasis-free survival rate for patients with high clinical risk and low genomic risk receiving no chemotherapy (primary test population, n=644) was 95·1% (95% CI 93·1-96·6), which is above the predefined non-inferiority boundary of 92%, supporting the previous analysis and proving MINDACT as a positive de-escalation trial. Patients with high clinical risk and low genomic risk were randomly assigned to receive chemotherapy (n=749) or not (n=748); this was the intention-to-treat population. The 8-year estimates for distant metastasis-free survival in the intention-to-treat population were 92·0% (95% CI 89·6-93·8) for chemotherapy versus 89·4% (86·8-91·5) for no chemotherapy (hazard ratio 0·66; 95% CI 0·48-0·92). An exploratory analysis confined to the subset of patients with hormone receptor-positive, HER2-negative disease (1358 [90.7%] of 1497 randomly assigned patients, of whom 676 received chemotherapy and 682 did not) shows different effects of chemotherapy administration on 8-year distant metastasis-free survival according to age: 93·6% (95% CI 89·3-96·3) with chemotherapy versus 88·6% (83·5-92·3) without chemotherapy in 464 women aged 50 years or younger (absolute difference 5·0 percentage points [SE 2·8, 95% CI -0·5 to 10·4]) and 90·2% (86·8-92·7) versus 90·0% (86·6-92·6) in 894 women older than 50 years (absolute difference 0·2 percentage points [2·1, -4·0 to 4·4]). The 8-year distant metastasis-free survival in the exploratory analysis by nodal status in these patients was 91·7% (95% CI 88·1-94·3) with chemotherapy and 89·2% (85·2-92·2) without chemotherapy in 699 node-negative patients (absolute difference 2·5 percentage points [SE 2·3, 95% CI -2·1 to 7·2]) and 91·2% (87·2-94·0) versus 89·9% (85·8-92·8) for 658 patients with one to three positive nodes (absolute difference 1·3 percentage points [2·4, -3·5 to 6·1]). INTERPRETATION: With a more mature follow-up approaching 9 years, the 70-gene signature shows an intact ability of identifying among women with high clinical risk, a subgroup, namely patients with a low genomic risk, with an excellent distant metastasis-free survival when treated with endocrine therapy alone. For these women the magnitude of the benefit from adding chemotherapy to endocrine therapy remains small (2·6 percentage points) and is not enhanced by nodal positivity. However, in an underpowered exploratory analysis this benefit appears to be age-dependent, as it is only seen in women younger than 50 years where it reaches a clinically relevant threshold of 5 percentage points. Although, possibly due to chemotherapy-induced ovarian function suppression, it should be part of informed, shared decision making. Further study is needed in younger women, who might need reinforced endocrine therapy to forego chemotherapy. FUNDING: European Commission Sixth Framework Programme.

Cognitive, emotional, and behavioral mediators of the impact of coping self-efficacy on adaptation to breast cancer: An international prospective study.

OBJECTIVE: The main objective of this prospective multicenter study was to examine whether illness representations of control, affect, and coping behaviors mediate the effects of self-efficacy to cope with cancer on psychological symptoms and overall quality of life, in breast cancer patients. METHOD: Data from 413 women (Mean age = 54.87; SD = 8.01), coming from four countries (i.e., Finland, Israel, Italy, Portugal), who received medical therapy for their early breast cancer, were analyzed. Coping self-efficacy was assessed at baseline. Potential mediators were assessed three months later, and outcomes after six months. RESULTS: Coping self-efficacy was related to all mediators and outcomes. Illness representations of treatment control, positive and negative affect, and certain coping behaviors (mostly, anxiety preoccupation) mediated the effects of coping self-efficacy. Coping self-efficacy was related to each outcome through a different combination of mediators. CONCLUSIONS: Coping self-efficacy is a major self-regulation factor which is linked to well-being through multiple cognitive, emotional, and behavioral pathways. Enhancement of coping self-efficacy should be a central intervention goal for patients with breast cancer, towards promotion of their well-being.

70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer.

BACKGROUND: The 70-gene signature test (MammaPrint) has been shown to improve prediction of clinical outcome in women with early-stage breast cancer. We sought to provide prospective evidence of the clinical utility of the addition of the 70-gene signature to standard clinical-pathological criteria in selecting patients for adjuvant chemotherapy. METHODS: In this randomized, phase 3 study, we enrolled 6693 women with early-stage breast cancer and determined their genomic risk (using the 70-gene signature) and their clinical risk (using a modified version of Adjuvant! Online). Women at low clinical and genomic risk did not receive chemotherapy, whereas those at high clinical and genomic risk did receive such therapy. In patients with discordant risk results, either the genomic risk or the clinical risk was used to determine the use of chemotherapy. The primary goal was to assess whether, among patients with high-risk clinical features and a low-risk gene-expression profile who did not receive chemotherapy, the lower boundary of the 95% confidence interval for the rate of 5-year survival without distant metastasis would be 92% (i.e., the noninferiority boundary) or higher. RESULTS: A total of 1550 patients (23.2%) were deemed to be at high clinical risk and low genomic risk. At 5 years, the rate of survival without distant metastasis in this group was 94.7% (95% confidence interval, 92.5 to 96.2) among those not receiving chemotherapy. The absolute difference in this survival rate between these patients and those who received chemotherapy was 1.5 percentage points, with the rate being lower without chemotherapy. Similar rates of survival without distant metastasis were reported in the subgroup of patients who had estrogen-receptor-positive, human epidermal growth factor receptor 2-negative, and either node-negative or node-positive disease. CONCLUSIONS: Among women with early-stage breast cancer who were at high clinical risk and low genomic risk for recurrence, the receipt of no chemotherapy on the basis of the 70-gene signature led to a 5-year rate of survival without distant metastasis that was 1.5 percentage points lower than the rate with chemotherapy. Given these findings, approximately 46% of women with breast cancer who are at high clinical risk might not require chemotherapy. (Funded by the European Commission Sixth Framework Program and others; ClinicalTrials.gov number, NCT00433589; EudraCT number, 2005-002625-31.).

Male breast cancer: a disease distinct from female breast cancer.

PURPOSE: Male breast cancer (BC) is rare, representing approximately 1% of cancers that occur in men and approximately 1% of all BCs worldwide. Because male BC is rare, not much is known about the disease, and treatment recommendations are typically extrapolated from data available from clinical trials enrolling female BC patients. METHODS: We review the epidemiology, risk factors, prognosis, and the varied molecular and clinicopathologic features that characterize male BC. In addition, we summarize the available data for the use of systemic therapy in the treatment of male BC and explore the ongoing development of targeted therapeutic agents for the treatment of this subgroup of BCs. RESULTS: There are important biological differences between male and female BC. Male BC is almost exclusively hormone receptor positive (+), including the androgen receptor (AR), and is associated with an increased prevalence of BRCA2 germline mutations, especially in men with increased risk for developing high-risk BC. Additional research is warranted to better characterize male BC. To accomplish this, a multi-national consortium approach, such as the International Male Breast Cancer Program, is needed in response to the scarcity of patients. This approach allows the pooling of information from a large number of men with BC and the creation of registries for future therapeutic-focused clinical trials. CONCLUSIONS: Given the unique biology of BC in men, promising new therapeutic targets are currently under investigation, including the use of poly-ADP-ribose polymerase inhibitors or AR-targeted agents either as monotherapy or in combination with other agents.