BACKGROUND:The benefit of adjuvant chemotherapy in patients with surgically-resected, stage-I TNBC remains controversial, especially when tumors are smaller than 10 mm in maximum diameter. We conducted a meta-analysis to evaluate the impact of adjuvant chemotherapy on survival outcomes in this setting, with prespecified subgroup analyses by pathological tumor size (pT1a/b/c). METHODS:This study followed PRISMA guidelines and was registered in PROSPERO. Literature search from PubMed, EMBASE, Cochrane (2000-2025) and recent conference proceedings was reviewed for studies comparing overall survival (OS) and/or breast cancer-specific survival (BCSS) in stage I TNBC patients receiving adjuvant chemotherapy versus no chemotherapy. Hazard ratios (HR) were pooled using fixed- or random-effects models according to prespecified heterogeneity criteria (Q statistic, P < 0.10 and/or I2 > 25%). Small-study effects and robustness were evaluated with Egger's test and influence diagnostics. RESULTS:Twenty-seven studies including 98,499 patients were analysed. Adjuvant chemotherapy resulted in significantly improved OS (HR 0.53, 95%CI 0.42-0.68; p < 0.001) and BCSS (HR 0.70, 95%CI 0.62-0.79; p < 0.001). In pT1a tumors, we found no benefit in terms of OS (HR 0.97, p = 0.91) or BCSS (HR 1.49, p = 0.12). In pT1b disease, chemotherapy use was associated with improved OS (HR 0.68, p < 0.0001), while no BCSS benefit was observed (HR 1.01, p = 0.94); this subgroup analysis should be interpreted cautiously. Finally, in pT1c tumors, adjuvant chemotherapy was associated with improved OS (HR 0.46, p < 0.0001) and BCSS (HR 0.68, p < 0.001). CONCLUSIONS:In surgically-resected stage I TNBC, the association between adjuvant chemotherapy and better survival appears to vary according to tumor-size, with more consistent benefit in patients with tumors > 5 mm and no significant survival advantage observed in pT1a disease. These findings support a tailored, size-based approach, although the OS results should be interpreted cautiously given the observational nature of the evidence and the substantial heterogeneity of the pooled OS analysis.

The ROSE study (NCT05377684) is an ongoing observational trial evaluating the Quality of Life (QoL) as the primary endpoint in premenopausal patients with Hormone Receptor (HR)+, HER2-negative early Breast Cancer (BC). The trial focuses on patients treated with a Luteinizing Hormone–Releasing Hormone (LHRH) analogue (triptorelin) combined with oral endocrine therapy, with or without chemotherapy depending on the risk of relapse, as determined by multidisciplinary meetings. Since April 2022 and up to October 2023 (18 months), the trial reached 50% enrollment of its target population. At this milestone, a predetermined interim analysis focused on the evaluation of baseline demographic characteristics, tumor features, and BC treatments. Other secondary objectives (e.g. hormonal levels) were not evaluated at this timepoint. Out of the approximately 200 patients initially enrolled, 195 were deemed eligible for the study. All patients had estrogen receptor-positive early BC and, at baseline, were planned to receive adjuvant endocrine therapy with tamoxifen or aromatase inhibitors combined with triptorelin as ovarian function suppression therapy. The median age at BC diagnosis was 45.5 years, ranging from 30 to 56. Tumor characteristics showed that 97.4% of enrolled patients (n=189) had invasive carcinoma, while 2.6% (n=5) had carcinoma in situ. The grading distribution included 10.8% grade 1 lesions, 69.9% grade 2, and 19.4% grade 3. Staging data according to AJCC 2017 criteria were available for 187/195 patients and revealed the following distribution: 44.9% had stage IA BC (stage IB: 5.3%), 27.7% had stage IIA (stage IIB: 16%), and 5.7% had stage IIIA. The Ki-67 proliferation index was available for 193 patients, with a median value of 17% and a mean value of 22.3%. Regarding therapeutic plans, the monthly triptorelin formulation was prescribed to 92.3% of patients (n=180), while the trimestral was prescribed to 7.7% of patients (n=15). The choice between tamoxifen or aromatase inhibitors depended on the relative risk of recurrence based on the aforementioned prognostic factors, with patients receiving the latter in higher-risk cases. Among the 195 patients, 27.2% (n=53) received adjuvant or neoadjuvant chemotherapy, classifying them as high risk for recurrence. Of these patients, nearly all received aromatase inhibitors and triptorelin (n=48). The remaining 72.8% of patients (n=142) were not considered high-risk enough to warrant chemotherapy, placing them in the intermediate-risk category. These patients were planned to receive triptorelin and either tamoxifen (n=28) or aromatase inhibitors (n=114) in chemotherapy-free treatment plans. The majority of intermediate-risk patients received aromatase inhibitors, indicating a higher risk profile, closer to the high-risk category. The ROSE study highlights an Italian best practice approach that tailors therapeutic plans to the individual needs of each patient, allowing for treatments based on personalized risk assessments. This approach aligns with current national oncology guidelines by minimizing chemotherapy use when possible and instead adopting individualized treatment plans based on specific prognostic factors. However, the observational nature of the ROSE trial provides a realistic snapshot of clinical practices, which may differ from the highly-selected populations typical of randomized controlled trials. This observational study of Italian best practices suggests the potential to redefine relapse risk cutoffs based on prognostic factors, providing more accurate and realistic patient-specific therapeutic approaches based on individual risk. The findings of this study, combined with results from ongoing post hoc analyses which aim to identify these new cutoffs, could potentially support the redefinition of relapse risk to better align with clinical practice, thereby fostering patient-specific therapeutic approaches. Citation Format: Alessandra Fabi, Luisa Carbognin, Alessandro Rossi, Ferdinando Riccardi, Carmen Mocerino, Raffaella Ruocco, Giulia Valeria Bianchi, Giuseppe Fotia, Giuseppe Capri, Antonella Palazzo, Elena Di Monte, Valentina Frescura, Michelino De Laurentis, Vincenzo Di Lauro, Valérie Perrot, Giorgio Mauri, Manuelita Mazza, Nadia Bianco, Elisabetta Munzone. Individualized Breast Cancer Treatment Strategies: Real-World Insights from the ROSE Study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-12-11.

Supplementary Tables S1-S6_S17-S18

In preclinical experiments, cyclic fasting-mimicking diets (FMDs) showed broad anticancer effects in combination with chemotherapy. Among different tumor types, triple-negative breast cancer (TNBC) is exquisitely sensitive to FMD. However, the antitumor activity and efficacy of cyclic FMD in TNBC patients remain unclear. Here, we show that a severely calorie-restricted, triweekly, 5-day FMD regimen results in excellent pathologic complete response (pCR) rates (primary endpoint) and long-term clinical outcomes (secondary endpoints) when combined with preoperative chemotherapy in 30 patients with early-stage TNBC enrolled in the phase 2 trial BREAKFAST. Bulk and single-cell RNA sequencing analysis revealed that highly glycolytic cancer cells, myeloid cells, and pericytes from tumors achieving pCR undergo a significant, early downmodulation of pathways related to glycolysis and pyruvate metabolism. Our findings pave the wave for conducting larger clinical trials to investigate the efficacy of cyclic FMD in early-stage TNBC patients and to validate early changes of intratumor glycolysis as a predictor of clinical benefit from nutrient restriction. This study was registered at Clinicaltrials.gov (NCT04248998).

Background: Breast surgery may be overtreatment and can potentially be omitted when systemic neoadjuvant treatment (NAT) results in pathological complete response (pCR) in breast cancer (BC) patients. The accuracy of residual disease detection in patients with clinical/radiological response is increased by minimally invasive preoperative image-guided vacuum-assisted biopsy (VAB). Thus, patients with pCR – as indicated by negative VAB – might be spared surgery if pre-operative VAB findings closely correspond with definitive histology after breast surgery. We evaluated the ability of VAB to detect invasive residual disease in patients with cT1-T2-T3 cN0/N1 BC (either HER2-positive, triple-negative, or Luminal B HER2-positive) and complete clinical/radiological remission after NAT. Methods: Patients were enrolled from April 2022 to April 2024 in a single-institute, ongoing, prospective pilot study (NCT 05951699). Patients had either complete clinical/radiological response, or residual breast disease (<1 cm) after NAT at imaging (ultrasound, mammography, contrast-enhanced mammography, and MRI). Breast VAB before surgery consisted of image-guided biopsy on the tumor bed, taking 5-10 cores using a 9G needle. The primary outcome was VAB accuracy, assessed by comparing the VAB findings with definitive histology on the surgical specimen. Cases with negative VAB and invasive residual disease at definitive histology were false negatives. Cases with negative VAB and ductal carcinoma in situ at histology were true negatives since no invasive residual disease was found. Cases with positive VAB (invasive or in situ) and negative histology after surgery were considered true positives (VAB had removed all residual disease). Results: Thirty-nine patients gave their consent and had VAB after NAT. Median age was 53 years (IQR 47-61). Thirteen (33.3%) had HER2-positive disease, 23 (59%) had triple-negative disease, and 3 (7.7%) had Luminal B-HER2-positive disease. VAB failed to identify invasive residual disease in one case (triple-negative). Among true negatives there were 4 cases of ductal carcinoma in situ (3 HER2-positive and 1 triple negative). Furthermore, VAB identified both invasive and in situ residual disease in 3 cases with positive VAB but negative histology after surgery (1 ductal carcinoma in situ in an HER2-positive case, 1 ductal carcinoma in situ in a triple negative case, and 1 invasive disease in a triple negative case). Based on these considerations, VAB accuracy was 97.4% (38/39; 95% CI 92.5-100.0%); specificity was 100% (30/30), and sensitivity was 88.9% (8/9; 95% CI 68.4-100.0%). Conclusion: These preliminary findings indicate that pre-operative VAB has good accuracy in predicting definitive histological findings in cT1-T2-T3 BC patients with HER2-positive, triple-negative, and Luminal B HER2-positive disease, who have a clinical/radiological response after primary chemotherapy. Although these findings require confirmation in larger studies, they suggest the use of VAB to select patients for prospective trials on the omission of surgery in patients who achieve a good clinical/radiological response after primary chemotherapy. Citation Format: Chiara Listorti, Deborah Bonfili, Chiara Osio, Federica Pilotta, Ilaria Maugeri, Virginia Ceccarossi, Cristina Ferraris, Catherine Depretto, Elisa D'Ascoli, Claudio Vernieri, Giuseppe Capri, Giulia Bianchi, Francesco Barretta, Secondo Folli, Giancarlo Pruneri, Rosalba Miceli, Gianfranco Scaperrotta, Gabriele Martelli. Preliminary results of mini-invasive detection of residual disease in breast cancer patients in remission after primary chemotherapy: a further step toward omission of surgery? [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-08-14.

BACKGROUND:The role of axillary surgery in breast cancer has shifted over time from a therapeutic operation to a staging method for subsequent adjuvant therapies, through the introduction of sentinel lymph node biopsy. The discovery of molecular subtypes has since questioned the necessity of axillary staging in breast cancer. METHODS:The INT09/98 randomized trial explored the omission of axillary surgery in early-stage breast cancer in patients under 65 years of age. From June 1998 to June 2003, a total of 565 T1N0 breast cancer patients were enrolled. The trial tested the non-inferiority of quadrantectomy without axillary surgery (QU) compared to quadrantectomy with axillary dissection (QUAD). The primary endpoint was overall survival (OS). Secondary endpoints included disease-free survival (DFS) and incidence/timing of axillary lymph node metastasis in the QU arm. RESULTS:Follow-up at 20 years showed no significant differences between the QU versus the QUAD arm. The adjusted hazard ratio for OS was 1.18 (P = 0.326) and DFS was 1.27 (P = 0.280) respectively, both within the predetermined non-inferiority limit. Axillary relapse rates in the QU arm remained low, indicating that only a subset of metastatic nodes cause recurrences if not removed. In the QU arm, patients with favourable biological features but unknown axillary node involvement did not receive adjuvant chemotherapy, without significant differences in outcomes. The axillary relapse rate with distant metastases was similar in both arms and may reflect aggressive biology of the primary tumour. CONCLUSION:Avoiding axillary surgery and reducing adjuvant treatments in early breast cancer does not increase distant metastases or affect long-term survival. Axillary relapsed patients with distant metastases in both QU and QUAD arms may represent cancers with genomically determined poorer prognosis, independent of surgical intervention and adjuvant therapies. REGISTRATION NUMBER:NCT01508546 (http://www.clinicaltrials.gov).

PURPOSE:We evaluated the impact of a multidisciplinary clinic model on patient care experience and referral to specialists compared to monodisciplinary visits. METHODS:This convergent parallel mixed-method study was conducted in two outpatient clinics at an Italian cancer center and involved 80 female patients (mean age 67.2) with advanced or metastatic breast cancer. One clinic used a traditional single specialist model, the other offered additional access to multidisciplinary clinic for selected cases. Patient reported data were collected using the ESAS-r, Distress Thermometer, and a customized care experience tool (score range 1-5), developed to assess key domains of patient-centered care, where 1 indicates "not at all" and 5 indicates "very much." Independent t-test compared group differences in care experience scores. Qualitative data were collected through in-depth interviews. RESULTS:Forty patients were enrolled in each group. The multidisciplinary group experienced better care in terms of time to obtain follow-up appointments (1.7 vs 2.8) and more information on psychosocial referrals (2.8 vs 1.8), while patients in the monodisciplinary group reported clearer information about side effects (3.6 vs 2.8) and less doubt about proposed treatments (1.2 vs 1.7). Qualitative interviews revealed high satisfaction with both models and emphasized the role of the nurse case manager in supporting care integration. CONCLUSION:The multidisciplinary model improved psychosocial care referral and perceived time-to-test intervals, but reduced clarity in communication about treatment. Nurse case manager emerged as key figure to facilitate communication and integration of care. Future studies should examine the feasibility and cost-effectiveness of this model.

“Ariadne’s thread” is a psycho-educational intervention designed by the Breast Unit and the Clinical Psychology Unit of an Italian Comprehensive Cancer Center and aims to promote empowerment in patients with metastatic breast cancer. It consists of 8 online meetings led by a psycho-oncologist in which informative sessions by patients’ referring physicians alternate with moments of stress management techniques. This study aims to investigate (1) the feasibility of the “Ariadne’s thread” pilot intervention and (2) the satisfaction and perceived benefits of the pilot intervention. We used a mixed method approach in which (1) it was detected: the number of acceptance to the single session of the intervention by both patients and professionals, the number of help requests by patients, and the number of change of date requests by professionals; (2) semi-structured interviews were conducted with the professionals who participated in the intervention; (3) 2 focus groups were conducted with patients, and (4) a questionnaire was submitted to each of them. The intervention is sustainable from the perspective of the organization, professionals, and patients. In particular, the patients declared perceiving benefits in many aspects: improved relationships with doctors, acceptance of their illness, learning of a relaxation technique, possibility to look at the world with trust and hope, etc. The questionnaires show an improvement in empowerment and satisfaction as a result of the intervention. “Ariadne’s thread” is a psycho-educational intervention that effectively addresses the needs of patients with MBC. It can be applied to other contexts (1) if it has been confirmed that similar needs exist or (2) if it can be modified to accommodate other needs.

Abstract Background: Preclinical studies showed that severely calorie restricted fasting-mimicking diets (FMDs) enhance the antitumor efficacy of chemotherapy (CT) or immunotherapy (IO) in murine triple negative breast cancer (TNBC) models. These effects are mediated by a combination of blood glucose reduction and positive immunomodulatory effects. Moreover, combining fasting and metformin produced synergistic anticancer effects in a broad range of tumor models. The BREAKFAST trial was designed to investigate if FMD, plus/minus metformin, could increase the antitumor activity of neoadjuvant CT in patients with stage I-III TNBC. Methods: BREAKFAST (NCT04248998) is a randomized, non-comparative, phase II, pilot trial that enrolled stage I-III (cT>1 cm) TNBC patients (pts) candidate to receive 4 cycles of neoadjuvant CT with doxorubicin-cyclophosphamide every 3 weeks, followed by 12 cycles of weekly paclitaxel. Pts were randomized 1:1 to receive: CT plus 5-day FMD every 3 weeks, up to 8 cycles (arm A); CT plus FMD plus daily metformin (1700 mg) (arm B). The primary study endpoint was the rate of pCR in either experimental arm. Secondary/exploratory endpoints included safety, compliance, and biomarker analyses based on blood metabolomics and tumor transcriptomics analyses at different timepoints. Results: Between June 2020 and February 2022 we enrolled 30 pts. Then, the study was interrupted after the introduction of chemo-immunotherapy (CT-IO) as a standard neoadjuvant therapy for early stage TNBC pts. Among 30 pts, 13 were treated with CT plus FMD, while 17 pts received CT plus FMD plus metformin. Overall, pCR rate was 56.6%, i.e., significantly higher than pCR rates reported with anthracycline-taxane CT alone in previous phase II/III trials (26-39%), with no significant differences among treatment arms (p=0.49). The FMD acutely reduced blood glucose, insulin and LDH levels, which reflects a reduction in systemic and/or tumor glucose metabolism. Of note, precocious LDH reduction was more pronounced in patients undergoing pCR. RNA-seq analysis of tumor samples revealed a significant downmodulation of glycolysis and TCA cycle pathways after one treatment cycle, paralleled by an increase of intratumor activated T cells, memory T cells and NK cells, as estimated by deconvolution analyses of tumor transcriptomic data. Of note, these changes were observed only in patients achieving pCR. While intratumor metabolic changes were similar in the two treatment arms, the modulation of intratumor immunity was more pronounced in patients not receiving metformin. Conclusion: Preoperative CT plus cyclic FMD (plus/minus metformin) results in excellent pCR rates in localized TNBC patients. Early on-treatment downregulation of systemic and intratumor metabolic parameters related to glucose metabolism predicts pCR, and this is independent of metformin use. Based on results of this study, we recently initiated a large, multicentric trial, namely the BREAKFAST-2 (NCT05763992) study, which will investigate if adding cyclic FMD to neoadjuvant CT-IO increases pCR rates in ~ 145 pts with stage II-III TNBC. Citation Format: Francesca Ligorio, Giovanni Fucà, Andrea Vingiani, Fabio Iannelli, Riccardo Lobefaro, Leonardo Provenzano, Lucrezia Zanenga, Cristina Ferraris, Antonino Belfiore, Silvia Brich, Alessia Bertolotti, Gianfranco Scaperrotta, Catherine Depretto, Antonia Martinetti, Elisa Sottotetti, Paola Antonia Corsetto, Giulia Valeria Bianchi, Giuseppe Capri, Secondo Folli, Saverio Minucci, Marco Foiani, Massimiliano Pagani, Giancarlo Pruneri, Filippo De Braud, Claudio Vernieri. Precocious modulation of metabolic and immunological parameters predicts tumor response to fasting-mimicking diet plus chemotherapy in patients with early stage TNBC [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr RF02-07.

Background: Patients under antiestrogen hormonal treatment as adjuvant therapy after breast surgery may usually experience significant adverse events, which often negatively impact patient's Quality of Life. As a result of treatment-related adverse events, failure to adhere to adjuvant therapies or discontinuation of treatment has been reported to be high in pre-menopausal and post-menopausal women.

Despite remarkable improvements in early-stage Triple-Negative Breast Cancer (TNBC) treatment with neoadjuvant chemoimmunotherapy (CT-IO), a considerable proportion of TNBC patients (pts) still experience tumor relapse after surgery. Preclinical studies indicate that TNBC is exquisitely sensitive to fasting-like approaches (FLAs), and we have recently shown that cyclic FLA boosts systemic and intratumor immunity in cancer patients. We hypothesize that combining FLA with preoperative CT-IO can increase pathologic complete response (pCR) rates in pts with stage II-III TNBC. BREAKFAST-2 (NCT05763992) is an open-label, multicentric, randomized, phase 2 trial aimed at investigating the antitumor activity of experimental FLA in combination with standard preoperative CT-IO in pts with treatment-naïve, localized (T1c and N1-2, or T2-4 and N0-2) TNBC. Pts will be randomized in a 1:1 ratio to: a) control arm (standard CT-IO), consisting of 12 administrations of weekly paclitaxel + carboplatin concomitant with 4 triweekly cycles of Pembrolizumab, followed by 4 triweekly cycles of doxorubicin/epirubicin + cyclophosphamide + Pembrolizumab every three weeks; b) experimental arm, consisting of CT-IO + 5-day FLA every three weeks, up to 8 FLA cycles. Then pts will undergo surgery. Key eligibility criteria are: age of 18-75 years, ECOG PS 0-1, BMI > 19 kg/m2, absence of malnutrition, diabetes, uncontrolled autoimmune disorders, or severe comorbidities. The primary study endpoint is pCR. Hypothesizing that the experimental treatment is able to increase the pCR rate from 65% (historical data with CT-IO alone) to 85%, and assuming an α error of 5% and a power of 85%, a total of 145 patients will be enrolled. Secondary endpoints include: safety and tolerability, compliance, Event-Free Survival (EFS) and Overall Survival (OS). We will combine plasma metabolomics and bulk/single cell RNA-seq analyses to explore the impact of the experimental treatment on systemic and intratumor immunometabolic pathways, as well as to assess the association between immunometabolic changes and clinical outcomes. The trial has started to enroll pts on May 2nd, 2023. NCT05763992. Fondazione IRCCS Istituto Nazionale dei Tumori, Milan. Giuliani Foundation – Fondazione Gianmaria e Sabrina Giuliani; Fondazione IRCCS Istituto Nazionale dei Tumori; AIRC.

BACKGROUND:Platinum-based chemotherapy is widely used in patients with advanced triple-negative breast cancer (TNBC). However, the most effective platinum-based combination in the first-line treatment setting remains unclear.MATERIALS AND METHODS:We evaluated the efficacy of first-line carboplatin-paclitaxel (CP) or carboplatin-gemcitabine (CG) combinations in advanced TNBC patients treated between April 2007 and April 2021. CP and CG were compared in terms of progression-free survival (PFS), overall survival (OS), and incidence of adverse events (AEs). Multivariable Cox Models were used to adjust the efficacy of CP versus CG for clinically relevant covariates.RESULTS:Of 88 consecutive advanced TNBC patients receiving first-line carboplatin-based doublets, 56 (63.6%) received CP and 32 (36.4%) CG. After adjusting for clinically relevant variables, patients receiving CG had significantly better PFS when compared to CP-treated patients (HR: 0.49 (95% CI, 0.27-0.87), P value 0.014). Of note, CG was associated with better PFS only among patients previously treated with taxanes in the (neo)adjuvant setting (HR: 0.39; 95% CI, 0.21-0.75), but not in patients not exposed to taxanes (HR: 1.20; 95% CI, 0.37-3.88). CG was also independently associated with better OS when compared to CP (HR: 0.31 (95% CI: 0.15-0.64), P value 0.002). Overall, grade 3-4 AEs were more common in patients treated with CG than in patients treated with CP (68.8% vs. 21.4%, P value .009).CONCLUSION:CG and CP are effective and well tolerated first-line platinum doublets in advanced TNBC patients. CG could be more effective than CP in patients previous exposed to taxanes despite worse toxicity profile.

Preclinical studies showed that nutrient starvation, in the form of cyclic fasting or fasting-mimicking diet (FMD), sensitizes cancer cells to the antitumor effect of cytotoxic agents and boosts antitumor immunity. These effects are in part mediated by the reduction of blood glucose, insulin and IGF-1 concentration, and by the inhibition of the IGF1-IGF1R axis in tumor cells. We conducted a prospective phase Ib clinical trial (NCT03340935) to assess the safety, feasibility and biological effects of a cyclic, 5-day, calorie-restricted, low-carbohydrate, low-protein FMD regimen in a heterogeneous population of cancer patients (pts), and a window-of-opportunity trial (DigesT trial, NCT03454282), in pts with early-stage breast cancer (BC) or melanoma to investigate the immunological effects of a single FMD cycle before surgery. In 101 pts enrolled in the NCT03340935 trial, and in 22 BC pts included in an interim analysis of the DigesT trial, cyclic FMD was safe, and feasible, and patient compliance was excellent. In addition, the FMD reduced plasma glucose, insulin and IGF-1 concentration and lowered expression/activation of IGF1R in tumor cells. These changes were paralleld by desirable immunologic modifications, including a reduction of circulating immunosuppressive myeloid cells and an increase in activated/cytotoxic T cells and memory T cells at both peripheral blood and tumor levels. Five complete and long-lasting tumor responses were observed in pts with extensive-stage small cell lung cancer (ES-SCLC), advanced pancreatic cancer, metastatic triple-negative BC (TNBC) and metastatic colorectal cancer. Cyclic FMD may increase the efficacy of standard anticancer therapies. Based on these results we are going to present our next 2 prospective studies: 1) a monocentric, single-arm, phase 2 trial "FASTIMMUNE" to investigate the antitumor efficacy of maintenance atezolizumab plus cyclic FMD in pts with ES-SCLC after 4 cycles of induction chemo-immunotherapy, and 2) the multicentric, open-label, randomized, phase 2 trial "BREAKFAST-2" to investigate if cyclic FMD improves the antitumor activity of neoadjuvant chemoimmunotherapy in patients with stage II/III TNBC.

Cyclic fasting or fasting-mimicking diets (FMDs) enhanced the antitumor activity of chemotherapy (CT) in TNBC mouse models, while the combination of fasting and metformin resulted in impressive antitumor activity in several preclinical tumor models. The BREAKFAST study was designed to investigate if cyclic FMD, plus/minus metformin, improves the antitumor activity of neoadjuvant CT in patients (pts) with localized TNBC. BREAKFAST is a randomized, non-comparative, phase II trial originally designed to enrol 90 stage I-III (cT>1cm) TNBC pts candidate to receive neoadjuvant doxorubicin-cyclophosphamide q3w for 4 cycles, followed by weekly paclitaxel for 12 cycles. Pts were randomized 1:1 to receive: CT + triweekly 5-day FMD cycles (arm A), or CT + FMD + daily metformin (1700 mg) (arm B). The primary study objective was to investigate if one or both experimental treatments were able to increase pCR rates when compared to anthracycline-taxane CT alone according to historical data. We enrolled 30 pts between June 2020 and February 2022, when the study was prematurely interrupted after the introduction of chemo-immunotherapy (CT-IO) as a standard neoadjuvant therapy for early stage TNBC. Of these pts, 13 were randomized to arm A and 17 to arm B; 73.3% of enrolled pts completed the maximum of 8 FMD cycles, with an average number of 6.9 completed FMD cycles. The observed pCR rate was 56.6%, i.e., significantly higher than pCR rates previously reported with CT alone in phase II/III trials (26-39%), and with no significant differences among treatment arms (OR 1.67, 95% CI 0.39-7.43; p=0.49). RNA-seq analysis in tumor specimens revealed higher pCR probability in pts undergoing precocious enhancement of tumor infiltration by activated T and NK cells, as well as precocious downmodulation of glycolysis and oxidative mitochondrial metabolism pathways. Preoperative CT plus cyclic FMD (plus/minus metformin) results in excellent pCR rates in early TNBC pts. Based on these findings, we recently initiated a phase II, randomized, multicentric trial, namely BREAKFAST-2, to investigate if adding cyclic FMD to neoadjuvant CT-IO increases pCR rates in stage II-III TNBC pts.

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. 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. 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