Pattern of practice of re-irradiation for ipsilateral breast tumor recurrence in Italy: a survey by the Italian Association of Radiotherapy and Clinical Oncology (AIRO)

Purpose The Re-irradiation and the Breast Cancer Working Groups of the Italian Association of Radiotherapy and Clinical Oncology (AIRO) conducted a survey to provide an overview of the policies for breast cancer (BC) re-irradiation (re-RT) among the Italian radiotherapy (RT) centers. Methods In October 2021, 183 RT centers were invited to answer a survey: after an initial section about general aspects, the questionnaire focused on radiation oncologists’ (ROs) attitude toward re-RT in three different scenarios: ipsilateral breast tumor recurrence (IBTR) treated with second conservative surgery, IBTR treated with mastectomy and inoperable IBTR. Surveyed ROs were also asked to express their interest in being involved in a prospective trials. Results Seventy-seven/183 (42.0%) centers answered the Survey, only one RO per center was requested to answer. In particular, 86.5% ROs declared to have performed “curative” re-RT for IBTR during the previous two years (2019–2020): 76.7% respondents administered re-RT after second BCS, 50.9% after mastectomy, and 48.1% for inoperable IBTR. Re-RT practice varied widely among centers in terms of treatment volumes, dose and fractionation schedules, techniques and dose-volume constraints for organs at risks (OARs). Forty-six participants (59.7%) expressed their interest in participating in a prospective study investigating BC re-RT. Conclusions About one out of three RT centers in Italy delivered re-RT for IBTR. Nevertheless, practice of re-RT varied widely among centers highlighting the needs for prospective studies to improve knowledge in this field (AU)

A gene expression-based classifier for HER2-low breast cancer.

In clinical trials evaluating antibody-conjugated drugs (ADCs), HER2-low breast cancer is defined through protein immunohistochemistry scoring (IHC) 1+ or 2+ without gene amplification. However, in daily practice, the accuracy of IHC is compromised by inter-observer variability. Herein, we aimed to identify HER2-low breast cancer primary tumors by leveraging gene expression profiling. A discovery approach was applied to gene expression profile of institutional INT1 (n = 125) and INT2 (n = 84) datasets. We identified differentially expressed genes (DEGs) in each specific HER2 IHC category 0, 1+, 2+ and 3+. Principal Component Analysis was used to generate a HER2-low signature whose performance was evaluated in the independent INT3 (n = 95), and in the publicly available TCGA and GSE81538 datasets. The association between the HER2-low signature and HER2 IHC categories was evaluated by Kruskal-Wallis test with post hoc pair-wise comparisons. The HER2-low signature discriminatory capability was assessed by estimating the area under the receiver operating characteristic curve (AUC). Gene Ontology and KEGG analyses were performed to evaluate the HER2-low signature genes functional enrichment. A HER2-low signature was computed based on HER2 IHC category-specific DEGs. The twenty genes included in the signature were significantly enriched with lipid and steroid metabolism pathways, peptidase regulation, and humoral immune response. The HER2-low signature values showed a bell-shaped distribution across IHC categories (low values in 0 and 3+; high values in 1+ and 2+), effectively distinguishing HER2-low from 0 (p < 0.001) to 3+ (p < 0.001). Notably, the signature values were higher in tumors scored with 1+ as compared to 0. The HER2-low signature association with IHC categories and its bell-shaped distribution was confirmed in the independent INT3, TCGA and GSE81538 datasets. In the combined INT1 and INT3 datasets, the HER2-low signature achieved an AUC value of 0.74 (95% confidence interval, CI 0.67-0.81) in distinguishing HER2-low vs. the other categories, outperforming the individual ERBB2 mRNA AUC value of 0.52 (95% CI 0.43-0.60). These results represent a proof-of-concept for an observer-independent gene-expression-based classifier of HER2-low status. The herein identified 20-gene signature shows promise in distinguishing between HER2 0 and HER2-low expressing tumors, including those scored as 1+ at IHC, and in developing a selection approach for ADCs candidates.

Pattern of practice of re-irradiation for ipsilateral breast tumor recurrence in Italy: a survey by the Italian Association of Radiotherapy and Clinical Oncology (AIRO).

PURPOSE: The Re-irradiation and the Breast Cancer Working Groups of the Italian Association of Radiotherapy and Clinical Oncology (AIRO) conducted a survey to provide an overview of the policies for breast cancer (BC) re-irradiation (re-RT) among the Italian radiotherapy (RT) centers. METHODS: In October 2021, 183 RT centers were invited to answer a survey: after an initial section about general aspects, the questionnaire focused on radiation oncologists' (ROs) attitude toward re-RT in three different scenarios: ipsilateral breast tumor recurrence (IBTR) treated with second conservative surgery, IBTR treated with mastectomy and inoperable IBTR. Surveyed ROs were also asked to express their interest in being involved in a prospective trials. RESULTS: Seventy-seven/183 (42.0%) centers answered the Survey, only one RO per center was requested to answer. In particular, 86.5% ROs declared to have performed "curative" re-RT for IBTR during the previous two years (2019-2020): 76.7% respondents administered re-RT after second BCS, 50.9% after mastectomy, and 48.1% for inoperable IBTR. Re-RT practice varied widely among centers in terms of treatment volumes, dose and fractionation schedules, techniques and dose-volume constraints for organs at risks (OARs). Forty-six participants (59.7%) expressed their interest in participating in a prospective study investigating BC re-RT. CONCLUSIONS: About one out of three RT centers in Italy delivered re-RT for IBTR. Nevertheless, practice of re-RT varied widely among centers highlighting the needs for prospective studies to improve knowledge in this field.

Large-scale meta-genome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types.

BACKGROUND: This study was designed to identify common genetic susceptibility and shared genetic variants associated with acute radiation-induced toxicity across 4 cancer types (prostate, head and neck, breast, and lung). METHODS: A genome-wide association study meta-analysis was performed using 19 cohorts totaling 12 042 patients. Acute standardized total average toxicity (STATacute) was modelled using a generalized linear regression model for additive effect of genetic variants, adjusted for demographic and clinical covariates (rSTATacute). Linkage disequilibrium score regression estimated shared single-nucleotide variation (SNV-formerly SNP)-based heritability of rSTATacute in all patients and for each cancer type. RESULTS: Shared SNV-based heritability of STATacute among all cancer types was estimated at 10% (SE = 0.02) and was higher for prostate (17%, SE = 0.07), head and neck (27%, SE = 0.09), and breast (16%, SE = 0.09) cancers. We identified 130 suggestive associated SNVs with rSTATacute (5.0 × 10‒8 < P < 1.0 × 10‒5) across 25 genomic regions. rs142667902 showed the strongest association (effect allele A; effect size ‒0.17; P = 1.7 × 10‒7), which is located near DPPA4, encoding a protein involved in pluripotency in stem cells, which are essential for repair of radiation-induced tissue injury. Gene-set enrichment analysis identified 'RNA splicing via endonucleolytic cleavage and ligation' (P = 5.1 × 10‒6, P = .079 corrected) as the top gene set associated with rSTATacute among all patients. In silico gene expression analysis showed that the genes associated with rSTATacute were statistically significantly up-regulated in skin (not sun exposed P = .004 corrected; sun exposed P = .026 corrected). CONCLUSIONS: There is shared SNV-based heritability for acute radiation-induced toxicity across and within individual cancer sites. Future meta-genome-wide association studies among large radiation therapy patient cohorts are worthwhile to identify the common causal variants for acute radiotoxicity across cancer types.

Radiomics and artificial intelligence analysis by T2-weighted imaging and dynamic contrast-enhanced magnetic resonance imaging to predict Breast Cancer Histological Outcome.

OBJECTIVE: The objective of the study was to evaluate the accuracy of radiomics features obtained by MR images to predict Breast Cancer Histological Outcome. METHODS: A total of 217 patients with malignant lesions were analysed underwent MRI examinations. Considering histological findings as the ground truth, four different types of findings were used in both univariate and multivariate analyses: (1) G1 + G2 vs G3 classification; (2) presence of human epidermal growth factor receptor 2 (HER2 + vs HER2 -); (3) presence of the hormone receptor (HR + vs HR -); and (4) presence of luminal subtypes of breast cancer. RESULTS: The best accuracy for discriminating HER2 + versus HER2 - breast cancers was obtained considering nine predictors by early phase T1-weighted subtraction images and a decision tree (accuracy of 88% on validation set). The best accuracy for discriminating HR + versus HR - breast cancers was obtained considering nine predictors by T2-weighted subtraction images and a decision tree (accuracy of 90% on validation set). The best accuracy for discriminating G1 + G2 versus G3 breast cancers was obtained considering 16 predictors by early phase T1-weighted subtraction images in a linear regression model with an accuracy of 75%. The best accuracy for discriminating luminal versus non-luminal breast cancers was obtained considering 27 predictors by early phase T1-weighted subtraction images and a decision tree (accuracy of 94% on validation set). CONCLUSIONS: The combination of radiomics analysis and artificial intelligence techniques could be used to support physician decision-making in prediction of Breast Cancer Histological Outcome.

Contouring variation affects estimates of normal tissue complication probability for breast fibrosis after radiotherapy.

BACKGROUND: Normal tissue complication probability (NTCP) models can be useful to estimate the risk of fibrosis after breast-conserving surgery (BCS) and radiotherapy (RT) to the breast. However, they are subject to uncertainties. We present the impact of contouring variation on the prediction of fibrosis. MATERIALS AND METHODS: 280 breast cancer patients treated BCS-RT were included. Nine Clinical Target Volume (CTV) contours were created for each patient: i) CTV_crop (reference), cropped 5 mm from the skin and ii) CTV_skin, uncropped and including the skin, iii) segmenting the 95% isodose (Iso95%) and iv) 3 different auto-contouring atlases generating uncropped and cropped contours (Atlas_skin/Atlas_crop). To illustrate the impact of contour variation on NTCP estimates, we applied two equations predicting fibrosis grade ≥ 2 at 5 years, based on Lyman-Kutcher-Burman (LKB) and Relative Seriality (RS) models, respectively, to each contour. Differences were evaluated using repeated-measures ANOVA. For completeness, the association between observed fibrosis events and NTCP estimates was also evaluated using logistic regression. RESULTS: There were minimal differences between contours when the same contouring approach was followed (cropped and uncropped). CTV_skin and Atlas_skin contours had lower NTCP estimates (-3.92%, IQR 4.00, p < 0.05) compared to CTV_crop. No significant difference was observed for Atlas_crop and Iso95% contours compared to CTV_crop. For the whole cohort, NTCP estimates varied between 5.3% and 49.5% (LKB) or 2.2% and 49.6% (RS) depending on the choice of contours. NTCP estimates for individual patients varied by up to a factor of 4. Estimates from "skin" contours showed higher agreement with observed events. CONCLUSION: Contour variations can lead to significantly different NTCP estimates for breast fibrosis, highlighting the importance of standardising breast contours before developing and/or applying NTCP models.

Axillary Management in Breast Cancer Patients Undergoing Upfront Surgery: Results from a Nationwide Survey on Behalf of the Clinical Oncology Breast Cancer Group (COBCG) and the Breast Cancer Study Group of the Italian Association of Radiotherapy and Clinical Oncology (AIRO).

BACKGROUND: We assessed the current practice concerning the axillary management of breast cancer (BC) patients undergoing upfront surgery among radiation oncologists (ROs) practising in Italy. METHODS: An online survey via SurveyMonkey (including 21 questions) was distributed amongst ROs in Italy through personal contacts and the Italian Association for Radiotherapy and Clinical Oncology (AIRO) network from August to September 2022. We particularly focused on the emerging omission of axillary lymph node dissection (ALND) in the presence of 1-2 sentinel node-positive patients and the consequent change in the role of regional nodal irradiation (RNI). RESULTS: A total of 101/195 (51% response rate) Italian Radiotherapy Cancer Care Centres answered the survey. With respect to patients with 1-2 sentinel node-positive, the relative proportion of respondents that offer patients ALND a) always, b) only in selected cases, and c) never was 37.6%, 60.4%, and 2.0%, respectively, with no significant geographical (North vs. Centre-South Italy; p = 0.92) or institutional (Academic vs. non-Academic; p = 0.49) differences. Radiation therapy indications varied widely in patients who did not undergo ALND. Among these, about a third of the respondents (17/56, 30.4%) stated that RNI was constantly performed. On the other hand, half of the respondents offered RNI in selected cases, stating that an unfavourable biologic tumour profile and extracapsular nodal extension were considered drivers of their decision. CONCLUSIONS: Results of the present survey show the variability of axillary management offered in clinical practice for BC patients undergoing conserving surgery upfront in Italy. Analysis of these attitudes may trigger the modification of some clinical approaches through multidisciplinary collaboration and create the background for future clinical investigations.

Comparison of prone and supine positioning for breast cancer radiotherapy using REQUITE data: dosimetry, acute and two years physician and patient-reported outcomes.

OBJECTIVE: Most patients receive whole breast radiotherapy in a supine position. However, two randomised trials showed lower acute toxicity in prone position. Furthermore, in most patients, prone positioning reduced doses to the organs at risk. To confirm these findings, we compared toxicity outcomes, photographic assessment, and dosimetry between both positions using REQUITE data. METHODS: REQUITE is an international multi-centre prospective observational study that recruited 2069 breast cancer patients receiving radiotherapy. Data on toxicity, health-related quality of life (HRQoL), and dosimetry were collected, as well as a photographic assessment. A matched case control analysis compared patients treated prone (n = 268) versus supine (n = 493). Exact matching was performed for the use of intensity-modulated radiotherapy, boost, lymph node irradiation, chemotherapy and fractionation, and the nearest neighbour for breast volume. Primary endpoints were dermatitis at the end of radiotherapy, and atrophy and cosmetic outcome by photographic assessment at two years. RESULTS: At the last treatment fraction, there was no significant difference in dermatitis (p = .28) or any HRQoL domain, but prone positioning increased the risk of breast oedema (p < .001). At 2 years, patients treated in prone position had less atrophy (p = .01), and higher body image (p < .001), and social functioning (p < .001) scores. The photographic assessment showed no difference in cosmesis at 2 years (p = .22). In prone position, mean heart dose (MHD) was significantly lower for left-sided patients (1.29 Gy vs 2.10 Gy, p < .001) and ipsilateral mean lung dose (MLD) was significantly lower for all patients (2.77 Gy vs 5.89 Gy, p < .001). CONCLUSIONS: Prone radiotherapy showed lower MLD and MHD compared to supine position, although the risk of developing breast oedema during radiotherapy was higher. At 2 years the photographic assessment showed no difference in the cosmetic outcome, but less atrophy was seen in prone-treated patients and this seems to have a positive influence on the HRQoL domain of body image.

Direct and indirect effects of COVID-19 on short-term mortality of breast cancer patients.

We studied the COVID-19 impact in newly-diagnosed breast cancer (7,349 patients in 2019, and 5,563 in 2020). In 2020 there were two diagnostic drops: -37.2% (March-May), -15.8% (October-December). Early-stage at presentation (76.4% vs. 74.4%, p = 0.0013), conserving surgery (71.0% vs. 67.0%, p < 0.0001), chemotherapy (86.2% vs. 53.4%, p < 0.0001), and radiotherapy (65.7% vs. 42.1%, p < 0.0001) decreased in 2020 compared to 2019. COVID-19 occurred in 250 patients (4.49%). The time-dependent COVID-19 effect was associated with mortality (multivariable Cox analysis HR [95% CI] 2.26 [1.35-3.74]; p = 0.0018). Survival within the year of diagnosis was 97.6% in 2020 and 98.3% in 2019; 30-day mortality was 1.13% in 2020 (1.07 in uninfected patients), and 0.61% in 2019. The year of diagnosis lost its prognostic relevance after adjusting for stage and treatment. These findings emphasize the critical role of continuity of care, which was disrupted during the pandemic, and underscore the need for policies minimizing treatment initiation delay in newly diagnosed breast cancer patients.

One-week external beam partial breast irradiation: survival and toxicity outcomes.

PURPOSE: According to ASTRO and ESTRO guidelines, external beam Partial Breast Irradiation (PBI) is a valid option for early-stage breast cancer patients. Nevertheless, there is lack of consensus about the best treatment schedule. METHODS: We retrospectively analysed data of female patients treated at our institution from 2013 to 2022 with adjuvant "one-week" partial breast irradiation. Clinical Target Volume (CTV) was an isotropic expansion of 15 mm from the tumour bed (identified as the breast tissue between surgical clips). The treatment schedule was 30 Gy delivered with Volumetric Modulated Arc Therapy in 5 daily fractions. The primary endpoint was Local Control (LC). Disease-Free Survival (DFS), Overall Survival (OS) and safety were secondary endpoints. RESULTS: Three hundred and forty-four patients with a median age of 69 (33-87) years were included in the study. After a median follow-up of 34 (7-105) months, 7 patients (2.0%) developed a local recurrence. Three-year LC, DFS and OS actuarial rates were 97.5% (95% CI 96.2%-98.8%), 95.7% (95% CI 94.2%-97.2%), and 96.9% (95% CI 95.7%-98.1%), respectively. Ten (2.9%) patients experienced grade 2 late toxicities. Five (1.5%) patients reported late cardiac major events. Three (0.9%) late pulmonary toxicities were detected. One hundred and five (30.5%) patients reported fat necrosis. Good or excellent cosmetic evaluation following the Harvard Scale was reported in 252 (96.9%) cases by the physicians, while in 241 (89.2%) cases by the patients. CONCLUSION: "One-week" PBI is effective and safe, and this schedule is a valid option for highly selected early breast cancer patients.

Image-guided radiotherapy (IGRT) in Lombardy, Italy: a survey by the Lombardy section of the Italian Association of Radiotherapy and Clinical Oncology (AIRO-Lombardy).

BACKGROUND: Image-guided radiation therapy (IGRT) has changed clinical practice. We proposed a survey to radiotherapy centers in Lombardy to picture the current clinical practice of its use. RESEARCH DESIGN AND METHODS: The survey consisted of 32 multiple-choice questions, divided into five topics: type of hospital, patients treated in 2019, number of LINACs; presence of protocols and staff involved in IGRT; IGRT in stereotaxis; IGRT in non-stereotactic treatments; availability of medical and technical staff. RESULTS: Twenty-seven directors answered (77%). Most centers (74%) have produced protocols to ensure uniformity in the IGRT process. The most widely used IGRT modality (92%) is cone-beam CT. Daily IGRT control is favored for prostate (100%), head and neck (87%), and lung (78%) neoplasms. The resident doctors can always perform supervised IGRT matching in only six centers. Radiation therapists perform IGRT controls only for some sites in 12 cases (44%) and always in 9 cases (33%). Radiation oncologists are present in real time, in most cases. CONCLUSIONS: Today, IGRT can be considered standard practice but at the price of more time-consuming procedures. A balance between a fully physician-controlled process and an increased role for specifically trained RTTs is actively being sought.

Technological advancements and future perspectives in breast cancer radiation therapy.

INTRODUCTION: Breast cancer is still one of the most common tumors worldwide and radiation therapy has a central role in the oncological pathway. Several technological options are now available with the aim to improve therapeutic index, target definition, and patient selection. AREAS COVERED: In this review, we summarize current available technologies in the management of breast cancer. These advances can support the prescription of postoperative partial breast cancer treatment and preoperative stereotactic partial breast irradiation. Moreover, image-guided radiotherapy is crucial for high-quality radiation treatments. Additionally, the recent development of hybrid magnetic resonance linear accelerator can impact target volume outline procedure, adaptive planning and radiomics. Finally, artificial intelligence represents the new frontier in medicine, supporting clinicians in target definition, patient selection, and treatment planning. EXPERT OPINION: In patients with breast cancer the overall level of evidence about new technologies is still low even if some advances are potentially very interesting to further development.

Overview of the synergistic use of radiotherapy and immunotherapy in cancer treatment: current challenges and scopes of improvement.

INTRODUCTION: Oncological treatments are changing rapidly due to the advent of several targeted anticancer drugs and regimens. The primary new area of research in oncological medicine is the implementation of a combination of novel therapies and standard care. In this scenario, radioimmunotherapy is one of the most promising fields, as proven by the exponential growth of publications in this context during the last decade. AREAS COVERED: This review provides an overview of the synergistic use of radiotherapy and immunotherapy and addresses questions like the importance of this subject, aspects clinicians look for in patients to administer this combined therapy, individuals who would benefit the most from this treatment, how to achieve abscopal effect and when does radio-immunotherapy become standard clinical practice. EXPERT OPINION: Answers to these queries generate further issues that need to be addressed and solved. The abscopal and bystander effects are not utopia, rather physiological phenomena that occur in our bodies. Nevertheless, substantial evidence regarding the combination of radioimmunotherapy is lacking. In conclusion, joining forces and finding answers to all these open questions is of paramount importance.

Moving HER2-low breast cancer predictive and prognostic data from clinical trials into the real world.

Background: Previous data, mostly from clinical trials, reported that HER2-low status is associated with low pathological complete response (pCR), and favourable prognosis. Since these findings suggest the existence of an additional breast cancer subtype, we questioned if the predictive/prognostic value of HER2-low was also relevant in the real world. Methods: Data from non-metastatic breast cancer patients treated with neoadjuvant chemotherapy and surgery (2009-2020) were retrieved from our institutional prospectively-maintained registry. Univariable and multivariable logistic models were implemented to study the association between pCR and baseline HER2 status. Univariable analysis of disease-free survival (DFS) was performed through Kaplan-Meier survival curves and log-rank tests. Results: Starting from a total of 790 consecutive cases, we identified 444 newly-diagnosed breast cancer patients featuring HER2 immunohistochemistry (IHC) 0 (HER2-0, n = 109), and 1 + or IHC 2+/in situ hybridization negative (HER2-low, n = 335) receiving anthracycline and taxane-based regimens in 88.9% of cases. Most of the patients were diagnosed with stage II (67.3%) and there was no difference of disease presentation according to HER2-status. pCR was attained by 71 (16.0%) patients and was significantly associated with increased DFS (p = 0.031). Compared to HER2-0, HER2-low cases were more likely hormone receptor-positive (81.2% vs. 43.1%, p < 0.001), well-differentiated (47.5% vs. 26.6%, p = 0.001), less proliferative (21.5% vs. 8.3%, p = 0.001) and less responsive to treatment (pCR 11.6% vs. 29.4%, p < 0.0001). There was no difference in DFS according to HER2 status, though hormone-receptor (HR) negative/HER2-low cases tended to have a worse prognosis compared to HR-negative/HER2-0. By pCR achievement, 3-years DFS was 87.5.% (75.1-100%) vs. 71.6% (65.9-77.8%) (p = 0.161) in HER2-low and 89.1% (75.8-100%) vs. 72.1% (59.7-87.0%) (p = 0.092) in HER2-0. Conclusion: Our real-world data show that HER2-low breast cancer patients represent roughly a half of the cases treated with neoadjuvant therapy, and have poor treatment response. In absence of pCR, HER2-low breast cancer patients have a dismal prognosis, especially when primary tumor hormone receptor status is negative. Studies are therefore needed to define the biology of these tumors for new therapeutic targets and to incorporate HER2-targeting agents in early-stage treatment.

AIRO Breast Cancer Group Best Clinical Practice 2022 Update.

INTRODUCTION: Breast cancer is the most common tumor in women and represents the leading cause of cancer death. Radiation therapy plays a key-role in the treatment of all breast cancer stages. Therefore, the adoption of evidence-based treatments is warranted, to ensure equity of access and standardization of care in clinical practice. METHOD: This national document on the highest evidence-based available data was developed and endorsed by the Italian Association of Radiation and Clinical Oncology (AIRO) Breast Cancer Group.We analyzed literature data regarding breast radiation therapy, using the SIGN (Scottish Intercollegiate Guidelines Network) methodology (www.sign.ac.uk). Updated findings from the literature were examined, including the highest levels of evidence (meta-analyses, randomized trials, and international guidelines) with a significant impact on clinical practice. The document deals with the role of radiation therapy in the treatment of primary breast cancer, local relapse, and metastatic disease, with focus on diagnosis, staging, local and systemic therapies, and follow up. Information is given on indications, techniques, total doses, and fractionations. RESULTS: An extensive literature review from 2013 to 2021 was performed. The work was organized according to a general index of different topics and most chapters included individual questions and, when possible, synoptic and summary tables. Indications for radiation therapy in breast cancer were examined and integrated with other oncological treatments. A total of 50 questions were analyzed and answered.Four large areas of interest were investigated: (1) general strategy (multidisciplinary approach, contraindications, preliminary assessments, staging and management of patients with electronic devices); (2) systemic therapy (primary, adjuvant, in metastatic setting); (3) clinical aspects (invasive, non-invasive and micro-invasive carcinoma; particular situations such as young and elderly patients, breast cancer in males and cancer during pregnancy; follow up with possible acute and late toxicities; loco-regional relapse and metastatic disease); (4) technical aspects (radiation after conservative surgery or mastectomy, indications for boost, lymph node radiotherapy and partial breast irradiation).Appendixes about tumor bed boost and breast and lymph nodes contouring were implemented, including a dedicated web application. The scientific work was reviewed and validated by an expert group of breast cancer key-opinion leaders. CONCLUSIONS: Optimal breast cancer management requires a multidisciplinary approach sharing therapeutic strategies with the other involved specialists and the patient, within a coordinated and dedicated clinical path. In recent years, the high-level quality radiation therapy has shown a significant impact on local control and survival of breast cancer patients. Therefore, it is necessary to offer and guarantee accurate treatments according to the best standards of evidence-based medicine.

Treatment time and circadian genotype interact to influence radiotherapy side-effects. A prospective European validation study using the REQUITE cohort.

BACKGROUND: Circadian rhythm impacts broad biological processes, including response to cancer treatment. Evidence conflicts on whether treatment time affects risk of radiotherapy side-effects, likely because of differing time analyses and target tissues. We previously showed interactive effects of time and genotypes of circadian genes on late toxicity after breast radiotherapy and aimed to validate those results in a multi-centre cohort. METHODS: Clinical and genotype data from 1690 REQUITE breast cancer patients were used with erythema (acute; n=340) and breast atrophy (two years post-radiotherapy; n=514) as primary endpoints. Local datetimes per fraction were converted into solar times as predictors. Genetic chronotype markers were included in logistic regressions to identify primary endpoint predictors. FINDINGS: Significant predictors for erythema included BMI, radiation dose and PER3 genotype (OR 1.27(95%CI 1.03-1.56); P < 0.03). Effect of treatment time effect on acute toxicity was inconclusive, with no interaction between time and genotype. For late toxicity (breast atrophy), predictors included BMI, radiation dose, surgery type, treatment time and SNPs in CLOCK (OR 0.62 (95%CI 0.4-0.9); P < 0.01), PER3 (OR 0.65 (95%CI 0.44-0.97); P < 0.04) and RASD1 (OR 0.56 (95%CI 0.35-0.89); P < 0.02). There was a statistically significant interaction between time and genotypes of circadian rhythm genes (CLOCK OR 1.13 (95%CI 1.03-1.23), P < 0.01; PER3 OR 1.1 (95%CI 1.01-1.2), P < 0.04; RASD1 OR 1.15 (95%CI 1.04-1.28), P < 0.008), with peak time for toxicity determined by genotype. INTERPRETATION: Late atrophy can be mitigated by selecting optimal treatment time according to circadian genotypes (e.g. treat PER3 rs2087947C/C genotypes in mornings; T/T in afternoons). We predict triple-homozygous patients (14%) reduce chance of atrophy from 70% to 33% by treating in mornings as opposed to mid-afternoon. Future clinical trials could stratify patients treated at optimal times compared to those scheduled normally. FUNDING: EU-FP7.

Rethinking breast cancer follow-up based on individual risk and recurrence management.

Current follow-up policies for early breast cancer aim to detect loco-regional recurrences and manage treatment-related adverse effects. Their "one size fits all" approach does not take into account differences in subtypes at initial diagnosis, individual prognosis and treatments received. They are derived from clinical trials conducted when early detection means - other than mammography - and treatment options were limited. Herein, we address the arguments for re-evaluating current breast cancer follow-up strategies starting from recent advances in breast cancer local and systemic treatments and discussing individual risk of recurrence prediction models, time-adapted imaging and biomarker assessment for disease diagnostic anticipation. This change in perspective would transform breast cancer follow-up into an integrated, multidisciplinary team medical practice. Hence we discuss the important role of patient-centered approaches, but also of general practitioners and other health professionals, in the final promotion of personalized surveillance programs and patient education.

Copy number alterations analysis of primary tumor tissue and circulating tumor cells from patients with early-stage triple negative breast cancer.

Triple negative breast cancer (TNBC) is characterized by clinical aggressiveness, lack of recognized target therapy, and a dismal patient prognosis. Several studies addressed genomic changes occurring during neoadjuvant chemotherapy (NAC) focusing on somatic variants, but without including copy number alterations (CNAs). We analyzed CNA profiles of 31 TNBC primary tumor samples before and after NAC and of 35 single circulating tumor cells (CTCs) collected prior, during and after treatment by using next-generation sequencing targeted profile and low-pass whole genome sequencing, respectively. In pre-treatment tissue samples, the most common gains occurred on chromosomes 1, 2 and 8, and SOX11 and MYC resulted the most altered genes. Notably, amplification of MSH2 (4/4 versus 0/12, p < 0.01) and PRDM1 and deletion of PAX3 (4/4 versus 1/12, p < 0.01) significantly characterized primary tumors of patients with pathological complete response. All patients with paired pre- and post-NAC samples reported a change in post-treatment CNAs compared to baseline, despite they showed at least one common alteration. CNAs detected after treatment involved genes within druggable pathways such as EGFR, cell cycle process and Ras signaling. In two patients, CTCs shared more alterations with residual rather than primary tumor involving genes such as MYC, BCL6, SOX2, FGFR4. The phylogenetic analysis of CTCs within a single patient revealed NAC impact on tumor evolution, suggesting a selection of driver events under treatment pressure. In conclusion, our data showed how chemoresistance might arise early from treatment-induced selection of clones already present in the primary tumor, and that the characterization of CNAs on single CTCs informs on cancer evolution and potential druggable targets.