Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial.

BACKGROUND: Sacituzumab govitecan demonstrated significant progression-free survival benefit over chemotherapy in the phase 3 TROPiCS-02 trial in patients with pretreated, endocrine-resistant hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+ and HER2-) metastatic breast cancer with limited treatment options. Here, we report the protocol-specified final analysis of overall survival and endpoints by trophoblast cell-surface antigen 2 (Trop-2) expression and other variables. METHODS: In this randomised, open-label, multicentre, phase 3 trial, which took place in 91 centres across North America (the USA and Canada) and Europe (Belgium, France, Germany, Italy, the Netherlands, Spain, and the UK), patients were randomly assigned (1:1) to receive sacituzumab govitecan or chemotherapy (eribulin, vinorelbine, capecitabine, or gemcitabine). Patients had confirmed HR+ and HER2- locally recurrent inoperable or metastatic breast cancer and had received at least one previous endocrine therapy, a taxane, and a CDK4/6 inhibitor in any setting and two to four previous chemotherapy regimens for metastatic disease. The primary endpoint was progression-free survival (previously reported and not included in this analysis), and secondary endpoints included overall survival, objective response rate (ORR), and patient-reported outcomes. Overall survival was assessed using stratified log-rank tests and Cox regression. Trop-2 expression was assessed in tumour tissue by immunohistochemistry. In the statistical testing hierarchy, ORR and patient-reported outcomes were tested sequentially if overall survival was significant. This study is registered with ClinicalTrials.gov, NCT03901339. FINDINGS: At the data cutoff date of July 1, 2022, 543 of 776 screened patients were randomly assigned between May 30, 2019, and April 5, 2021, with 272 patients in the sacituzumab govitecan group and 271 patients in the chemotherapy group. With a 12·5-month (IQR 6·4-18·8) median follow-up, 390 deaths occurred among 543 patients. Overall survival was significantly improved with sacituzumab govitecan versus chemotherapy (median 14·4 months [95% CI 13·0-15·7] vs 11·2 months [10·1-12·7]; hazard ratio [HR] 0·79, 95% CI 0·65-0·96; p=0·020); survival benefit was consistent across Trop-2 expression-level subgroups. ORR was significantly improved with sacituzumab govitecan compared with chemotherapy (57 [21%] patients vs 38 [14%]; odds ratio 1·63 [95% CI 1·03-2·56]; p=0·035), as was time to deterioration of global health status and quality of life (median 4·3 months vs 3·0 months; HR 0·75 [0·61-0·92]; p=0·0059) and fatigue (median 2·2 months vs 1·4 months; HR 0·73 [0·60-0·89]; p=0·0021). The safety profile of sacituzumab govitecan was consistent with previous studies (including the TROPiCS-02 primary analysis and the ASCENT trial). One fatal adverse event (septic shock caused by neutropenic colitis) was determined to be related to sacituzumab govitecan treatment. INTERPRETATION: Sacituzumab govitecan demonstrated statistically significant and clinically meaningful benefit over chemotherapy, with a 3·2-month median overall survival improvement and a manageable safety profile. These data support sacituzumab govitecan as a new treatment option for patients with pretreated, endocrine-resistant HR+ and HER2- metastatic breast cancer. FUNDING: Gilead Sciences.

Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer.

BACKGROUND: Patients with metastatic triple-negative breast cancer have a poor prognosis. Sacituzumab govitecan is an antibody-drug conjugate composed of an antibody targeting the human trophoblast cell-surface antigen 2 (Trop-2), which is expressed in the majority of breast cancers, coupled to SN-38 (topoisomerase I inhibitor) through a proprietary hydrolyzable linker. METHODS: In this randomized, phase 3 trial, we evaluated sacituzumab govitecan as compared with single-agent chemotherapy of the physician's choice (eribulin, vinorelbine, capecitabine, or gemcitabine) in patients with relapsed or refractory metastatic triple-negative breast cancer. The primary end point was progression-free survival (as determined by blinded independent central review) among patients without brain metastases. RESULTS: A total of 468 patients without brain metastases were randomly assigned to receive sacituzumab govitecan (235 patients) or chemotherapy (233 patients). The median age was 54 years; all the patients had previous use of taxanes. The median progression-free survival was 5.6 months (95% confidence interval [CI], 4.3 to 6.3; 166 events) with sacituzumab govitecan and 1.7 months (95% CI, 1.5 to 2.6; 150 events) with chemotherapy (hazard ratio for disease progression or death, 0.41; 95% CI, 0.32 to 0.52; P<0.001). The median overall survival was 12.1 months (95% CI, 10.7 to 14.0) with sacituzumab govitecan and 6.7 months (95% CI, 5.8 to 7.7) with chemotherapy (hazard ratio for death, 0.48; 95% CI, 0.38 to 0.59; P<0.001). The percentage of patients with an objective response was 35% with sacituzumab govitecan and 5% with chemotherapy. The incidences of key treatment-related adverse events of grade 3 or higher were neutropenia (51% with sacituzumab govitecan and 33% with chemotherapy), leukopenia (10% and 5%), diarrhea (10% and <1%), anemia (8% and 5%), and febrile neutropenia (6% and 2%). There were three deaths owing to adverse events in each group; no deaths were considered to be related to sacituzumab govitecan treatment. CONCLUSIONS: Progression-free and overall survival were significantly longer with sacituzumab govitecan than with single-agent chemotherapy among patients with metastatic triple-negative breast cancer. Myelosuppression and diarrhea were more frequent with sacituzumab govitecan. (Funded by Immunomedics; ASCENT ClinicalTrials.gov number, NCT02574455; EudraCT number, 2017-003019-21.).

Real-World Impact of Adjuvant Anti-HER2 Treatment on Characteristics and Outcomes of Women With HER2-Positive Metastatic Breast Cancer in the ESME Program.

BACKGROUND: Although adjuvant cancer treatments increase cure rates, they may induce clonal selection and tumor resistance. Information still lacks as whether (neo)adjuvant anti-HER2 treatments impact the patterns of recurrence and outcomes of HER2-positive (HER2+) metastatic breast cancer (MBC). We aimed to assess this in the large multicenter ESME real-world database. PATIENTS AND METHODS: We examined the characteristics and outcomes (overall survival (OS) and progression-free survival under first-line treatment (PFS1)) of HER2+ patients with MBC from the French ESME program with recurrent disease, as a function of the previous receipt of adjuvant trastuzumab. Multivariable analyses used Cox models adjusted for baseline demographic, prognostic factors, adjuvant treatment received, and disease-free interval. RESULTS: Two thousand one hundred and forty-three patients who entered the ESME cohort between 2008 and 2017 had a recurrent HER2+ MBC. Among them, 56% had received (neo)adjuvant trastuzumab and 2.5% another anti-HER2 in this setting. Patients pre-exposed to trastuzumab were younger, had a lower disease-free interval, more HR-negative disease and more metastatic sites. While the crude median OS appeared inferior in patients exposed to adjuvant trastuzumab, as compared to those who did not (37.2 (95%CI 34.4-40.3) versus 53.5 months (95% CI: 47.6-60.1)), this difference disappeared in the multivariable model (HR = 1.05, 95%CI 0.91-1.22). The same figures were observed for PFS1. CONCLUSIONS: Among patients with relapsed HER2+ MBC, the receipt of adjuvant trastuzumab did not independently predict for worse outcomes when adjusted to other prognostic factors.

Clinical outcomes of curative-intent multimodal management of chemorefractory nonmetastatic inflammatory breast cancer.

INTRODUCTION: Chemorefractory nonmetastatic inflammatory breast cancer (IBC) which progresses under neoadjuvant chemotherapy poses specific therapeutic challenges: either pursuing a curative-intent treatment with a salvage combination of radiotherapy and surgery or switching to second-line systemic treatments despite the absence of metastasis. Due to the rarity of this situation, no specific management guidelines exist and the outcomes of these patients remain uncertain. In this retrospective observational study, we aimed to report the clinical outcomes of patients treated in a curative intent for chemorefractory nonmetastatic IBC, with a multimodal salvage treatment combining radiotherapy and surgery. MATERIALS AND METHODS: This single-center retrospective observational study included all chemorefractory nonmetastatic IBC treated at the Institut Curie (Paris, France). Overall survival (OS), disease-free survival (DFS), and locoregional relapse-free survival (LRRFS) were calculated from the time of diagnosis and from the time of neoadjuvant chemotherapy interruption. RESULTS: Between January 2010 and January 2018, 7 patients presented with chemorefractory nonmetastatic IBC with a progressive disease during neoadjuvant chemotherapy. Overall, chemorefractory IBC patients were young (median age of 50 years), had a good performance status, and usually presented with node-positive tumors characterized by a combination of adverse histological factors such as triple-negative breast cancer (TNBC), grade III, and high proliferation index. From the date of pathological diagnosis, 1­year OS, DFS, and LRRFS were 64.3%, 53.6%, and 71.4%, respectively. From the date of neoadjuvant chemotherapy interruption, 1­year OS, DFS, and LRRFS were 47.6%, 19.0%, and 45.7%, respectively, and median OS, DFS, and LRRFS were 8.3, 5.0, and 5.0 months, respectively. CONCLUSION: The prognosis of chemorefractory nonmetastatic IBC treated with a multimodal approach combining surgery and radiotherapy is particularly reserved, despite the curative intent of the salvage treatment and the lack of distant metastasis at the time of treatment. Optimal treatment modalities are still to be defined in this rare but critical presentation of IBC.

[18F]FDG PET/CT for predicting triple-negative breast cancer outcomes after neoadjuvant chemotherapy with or without pembrolizumab.

PURPOSE: To determine if pretreatment [18F]FDG PET/CT could contribute to predicting complete pathological complete response (pCR) in patients with early-stage triple-negative breast cancer (TNBC) undergoing neoadjuvant chemotherapy with or without pembrolizumab. METHODS: In this retrospective bicentric study, we included TNBC patients who underwent [18F]FDG PET/CT before neoadjuvant chemotherapy (NAC) or chemo-immunotherapy (NACI) between March 2017 and August 2022. Clinical, biological, and pathological data were collected. Tumor SUVmax and total metabolic tumor volume (TMTV) were measured from the PET images. Cut-off values were determined using ROC curves and a multivariable model was developed using logistic regression to predict pCR. RESULTS: N = 191 patients were included. pCR rates were 53 and 70% in patients treated with NAC (N = 91) and NACI (N = 100), respectively (p < 0.01). In univariable analysis, high Ki67, high tumor SUVmax (> 12.3), and low TMTV (≤ 3.0 cm3) were predictors of pCR in the NAC cohort while tumor staging classification (< T3), BRCA1/2 germline mutation, high tumor SUVmax (> 17.2), and low TMTV (≤ 7.3 cm3) correlated with pCR in the NACI cohort. In multivariable analysis, only high tumor SUVmax (NAC: OR 8.8, p < 0.01; NACI: OR 3.7, p = 0.02) and low TMTV (NAC: OR 6.6, p < 0.01; NACI: OR 3.5, p = 0.03) were independent factors for pCR in both cohorts, albeit at different thresholds. CONCLUSION: High tumor metabolism (SUVmax) and low tumor burden (TMTV) could predict pCR after NAC regardless of the addition of pembrolizumab. Further studies are warranted to validate such findings and determine how these biomarkers could be used to guide neoadjuvant therapy in TNBC patients.

Analysis of patients without and with an initial triple-negative breast cancer diagnosis in the phase 3 randomized ASCENT study of sacituzumab govitecan in metastatic triple-negative breast cancer.

PURPOSE: Sacituzumab govitecan (SG) is an antibody-drug conjugate composed of an anti-Trop-2 antibody coupled to SN-38 via a proprietary hydrolyzable linker. In the ASCENT study, SG improved survival versus single-agent treatment of physician's choice (TPC) in pre-treated metastatic triple-negative breast cancer (mTNBC). Hormone/HER2 receptor changes are common, particularly at relapse/metastasis. This subanalysis assessed outcomes in patients who did/did not have TNBC at initial diagnosis, before enrollment. METHODS: TNBC diagnosis was only required at study entry. Patients with mTNBC refractory/relapsing after ≥ 2 prior chemotherapies were randomized 1:1 to receive SG or TPC. Primary endpoint was progression-free survival (PFS) in patients without brain metastases. RESULTS: Overall, 70/235 (30%) and 76/233 (33%) patients who received SG and TPC, respectively, did not have TNBC at initial diagnosis. Clinical benefit with SG versus TPC was observed in this subset. Median PFS was 4.6 versus 2.3 months (HR 0.48; 95% CI 0.32-0.72), median overall survival was 12.4 versus 6.7 months (HR 0.44; 95% CI 0.30-0.64), and objective response rate (ORR) was 31% versus 4%; those who also received prior CDK4/6 inhibitors had ORRs of 21% versus 5%. Efficacy and safety for patients with TNBC at initial diagnosis were generally similar to those who did not present with TNBC at initial diagnosis. CONCLUSION: Patients without TNBC at initial diagnosis had improved clinical outcomes and a manageable safety profile with SG, supporting SG as a treatment option for mTNBC regardless of subtype at initial diagnosis. Subtype reassessment in advanced breast cancer allows for optimal treatment. Clinical trial registration number NCT02574455, registered October 12, 2015.

Characteristics and outcome of breast cancer-related microangiopathic haemolytic anaemia: a multicentre study.

BACKGROUND: Cancer-related microangiopathic haemolytic anaemia (MAHA) is a rare but life-threatening paraneoplastic syndrome. Only single cases or small series have been reported to date. We set up a retrospective multicentre study focusing on breast cancer-related MAHA. METHODS: Main inclusion criteria were known diagnosis of breast cancer, presence of schistocytes and either low haptoglobin or cytopenia and absence of any causes of MAHA other than breast cancer, including gemcitabine- or bevacizumab-based treatment. Patient characteristics, treatments and outcome were retrieved from digital medical records. RESULTS: Individual data from 54 patients with breast cancer-related MAHA were obtained from 7 centres. Twenty-three (44%) patients had a breast tumour with lobular features, and most primary tumours were low grade (grade I/II, N = 39, 75%). ER+/HER2-, HER2+ and triple-negative phenotypes accounted for N = 33 (69%), N = 7 (15%) and N = 8 (17%) cases, respectively. All patients had stage IV cancer at the time of MAHA diagnosis. Median overall survival (OS) was 28 days (range 0-1035; Q1:10, Q3:186). Independent prognostic factors for early death (≤ 28 days) were PS > 2 (OR = 7.0 [1.6; 31.8]), elevated bilirubin (OR = 6.9 [1.1; 42.6]), haemoglobin < 8.0 g/dL (OR = 3.7 [0.9; 16.7]) and prothrombin time < 50% (OR = 9.1 [1.2; 50.0]). A score to predict early death displayed a sensitivity of 86% (95% CI [0.67; 0.96]), a specificity of 73% (95% CI [0.52; 0.88]) and an area under the curve of 0.90 (95% CI [0.83; 0.97]). CONCLUSIONS: Breast cancer-related MAHA appears to be a new feature of invasive lobular breast carcinoma. Prognostic factors and scores may guide clinical decision-making in this serious but not always fatal condition.

Circulating tumor DNA as a dynamic biomarker of response to palbociclib and fulvestrant in metastatic breast cancer patients.

BACKGROUND: Following the PALOMA-3 study results, the combination of palbociclib, a CDK4/6 inhibitor, with fulvestrant, a selective estrogen receptor degrader, has become a standard therapy in women with estrogen receptor-positive (ER+) HER2-negative (HER2-) metastatic breast cancer (MBC). Palbociclib has been shown to increase the progression-free survival (PFS) overall but no predictive biomarker of palbociclib efficacy has been validated so far. We thus evaluated whether early changes of circulating tumor DNA (ctDNA) levels are associated with palbociclib plus fulvestrant efficiency. METHODS: ER+ HER2- MBC patients were included in a prospective observational cohort before treatment initiation. Tumor response was assessed by radiological evaluation (RECIST v1.1) every 3 months. Plasma samples were collected before treatment (baseline), at day 15 (D15), at day 30 (D30), and at disease progression. We searched for somatic mutations from archived tumor tissues by targeted deep sequencing. For patients with somatic mutations identified, circulating tumor DNA (ctDNA) was tracked using digital droplet PCR. Ratios of ctDNA levels ([D15/baseline] and [D30/baseline]) were then correlated with prospectively registered patient characteristics and outcomes. RESULTS: Twenty-five of the 61 patients enrolled had a somatic mutation testable in plasma (NPIK3CA = 21, NTP53 = 2, NAKT1 = 2). At baseline, 84% of patients had detectable ctDNA levels but ctDNA levels had no prognostic impact on PFS (p = 0.10). Among those patients, ctDNA was still detected in 82% at D15 and 68% at D30. ctDNA clearance observed at day 30 was associated with longer PFS (HR = 7.2, 95% CI = 1.5-32.6, p = 0.004). On the contrary, a [D30/baseline] ctDNA ratio > 1 was associated with a shorter PFS (HR = 5.1, 95% CI = 1.4-18.3, p = 0.02) and all 5 patients with increased ctDNA levels at D30 showed disease progression after 3 months under palbociclib-fulvestrant. Finally, at the time of radiological tumor progression, ctDNA was detected in all patients tested. CONCLUSION: Our study demonstrates that the efficiency of palbociclib and fulvestrant can be monitored by serial analyses of ctDNA before radiological evaluation and that early ctDNA variation is a prognostic factor of PFS.

Combination of Olaparib with radiotherapy for triple-negative breast cancers: One-year toxicity report of the RADIOPARP Phase I trial.

Triple-negative breast cancer (TNBC) cells are sensitive to PARP1 inhibitors in vitro. The combination of Olaparib and radiotherapy for TNBC is currently evaluated in the Phase I RADIOPARP trial. RADIOPARP is a monocentric prospective open-label Phase I dose-escalation trial evaluating the combination of breast radiotherapy and Olaparib in TNBC patients with inflammatory, locoregionally advanced or metastatic disease, or with residual disease after neoadjuvant chemotherapy. Olaparib was orally given at increasing dose levels (50, 100, 150 or 200 mg twice a day [BID]); radiotherapy consisted of 50 Gy to the breast or chest wall with or without lymph node irradiation. Twenty-four TNBC patients were enrolled between September 2017 and November 2019. Olaparib was escalated to 200 mg BID without dose-limiting toxicities. At 1-year follow-up, no treatment-related grade ≥3 toxicity was observed. One patient (4.2%) had persistent grade 2 adverse events (breast pain, fibrosis and deformity). There was no cardiac, pulmonary or digestive toxicity related to treatment. The 1-year follow-up report of the RADIOPARP Phase I trial, evaluating Olaparib associated with breast radiotherapy in TNBC patients, consequently demonstrated an excellent toxicity profile of this combination with few low-grade adverse events.

Clinical utility of circulating tumour cell-based monitoring of late-line chemotherapy for metastatic breast cancer: the randomised CirCe01 trial.

BACKGROUND: CirCe01 trial aimed to assess the clinical utility of circulating tumour cell (CTC)-based monitoring in metastatic breast cancer (MBC) patients beyond the third line of chemotherapy (LC). METHODS: CirCe01 was a prospective, multicentre, randomised trial (NCT01349842) that included patients with MBC after two systemic LC. Patients with ≥5 CTC/7.5 mL (CellSearch®) were randomised between the CTC-driven and the standard arm. In the CTC arm, changes in CTC count were assessed at the first cycle of each LC; patients in whom CTC levels predicted early tumour progression had to switch to a subsequent LC. RESULTS: Greater than or equal to 5 CTC/7.5 mL were observed in N = 101/204 patients. In the CTC arm (N = 51), 43 (83%) and 18 (44%) patients completed CTC monitoring in the third and fourth lines, respectively, and 18 (42%) and 11 (61%) of these patients, respectively, had no CTC response. Thirteen (72%) and 5 (46%) of these patients underwent early switch to the next LC. Overall survival was not different between the two arms (hazard ratio = 0.95, 95% confidence interval = [0.6;1.4], p = 0.8). In subgroup analyses, patients with no CTC response who switched chemotherapy experienced longer survival than patients who did not. CONCLUSIONS: Due to the limited accrual and compliance, this trial failed to demonstrate the clinical utility of CTC monitoring. CLINICAL TRIAL REGISTRATION: NCT, NCT01349842, https://clinicaltrials.gov/ct2/show/NCT01349842 , registered 9 May 2011.

Plasma thymidine kinase 1 activity and outcome of ER+ HER2- metastatic breast cancer patients treated with palbociclib and endocrine therapy.

PURPOSE: Previous cohort studies have reported plasma TK1 activity (pTKa) as a potential prognostic biomarker in estrogen receptor-positive (ER+) HER2-negative (HER2-) metastatic breast cancer (MBC). In this prospective study, we report here the prognostic impact of pTKa in ER+/HER2- MBC patients treated with endocrine therapy and CDK4/6 inhibitor. EXPERIMENTAL DESIGN: Patients were included into the prospective, ethics committee-approved ALCINA study (NCT02866149). Eligibility criteria were patients with ER+/HER2- MBC treated at Institut Curie with endocrine therapy and palbociclib. Plasma samples were obtained at baseline and after 4 weeks of treatment. pTKa was quantified by the DiviTum® assay (Biovica, Sweden). RESULTS: From May 2016 to August 2018, 103 patients treated with endocrine therapy and palbociclib were included. Patients had received a median of two prior systemic therapies for MBC (range 0-14). Median follow-up was 13.8 months (range 6-31), with median PFS and OS of 9.6 months (95%CI [7.0-11.3]) and 28 months (95%CI [23-not reached]), respectively. Median baseline pTKa was 292 Du/L (range 20-27,312 Du/L, IQR [89-853]). After adjusting for other prognostic factors, baseline pTKa remained an independent prognostic factor for both PFS (HR = 1.3 95%CI [1.1-1.4], p = 0.0005) and OS (HR = 1.3 95%CI [1.2-1.6], p < 0.0001), and 4-week pTKa was associated with OS (HR = 1.6 95%CI [1.3-2], p < 0.0001). That survival prediction was significantly improved by the addition of baseline pTKa to clinicopathological characteristics. Adding pTKa changes at 4 weeks to baseline pTKa did not further increase survival prediction. CONCLUSION: This study demonstrates the clinical validity of pTKa as a new circulating prognostic marker in ER+/HER2- MBC patients treated with endocrine therapy and palbociclib.

The fully synthetic glycopeptide MAG-Tn3 therapeutic vaccine induces tumor-specific cytotoxic antibodies in breast cancer patients.

Cancer is one of the main causes of mortality worldwide and a major public health concern. Among various strategies, therapeutic vaccines have been developed to stimulate anti-tumoral immune responses. However, in spite of extensive studies, this approach suffers from a lack of efficacy. Recently, we designed the MAG-Tn3 vaccine, aiming to induce antibody responses against Tn, a tumor-associated carbohydrate antigen. The Tn antigen is of interest because it is expressed by several adenocarcinomas, but not normal cells. The fully synthetic glycopeptide vaccine MAG-Tn3 is composed of four arms built on three adjacent Tn moieties associated with the tetanus toxin-derived peptide TT830-844 CD4+ T-cell epitope. This promiscuous CD4+ T-cell epitope can bind to a wide range of HLA-DRB molecules and is thus expected to activate CD4+ T-cell responses in a large part of the human population. The MAG-Tn3 vaccine was formulated with the GSK-proprietary immunostimulant AS15, composed of CpG7909, MPL, and QS21, which has been shown to stimulate both innate and humoral responses, in addition to being well tolerated. Here, seven patients with localized breast cancer with a high-risk of relapse were immunized with the MAG-Tn3 vaccine formulated with AS15. The first results of phase I clinical trial demonstrated that all vaccinated patients developed high levels of Tn-specific antibodies. Moreover, these antibodies specifically recognized Tn-expressing human tumor cells and killed them through a complement-dependent cytotoxicity mechanism. Overall, this study establishes, for the first time, the capacity of a fully synthetic glycopeptide cancer vaccine to induce specific immune responses in humans.

Modernizing adverse events analysis in oncology clinical trials using alternative approaches: rationale and design of the MOTIVATE trial.

In oncology clinical research, the analysis and reporting of adverse events is of major interest. A consistent depiction of the safety profile of a new treatment is as crucial in establishing how to use it as its antitumor activity. The advent of new therapeutics has led to major changes in the management of patients and targeted therapies or immune checkpoint inhibitors are administered continuously for months or even years. However, the classical methods of adverse events analysis are no longer adequate to properly assess their safety profile. Indeed, the worst grade method and time-to-event analysis cannot capture the duration or the evolution of adverse events induced by extended treatment durations. Many authors have highlighted this issue and argue that the analysis of safety data from clinical trials should be modernized by considering the dimension of time and the recurrent nature of adverse events. This paper aims to illustrate the limitations of current methods and discusses the value of alternative approaches such as the prevalence function, Q-TWiST, the ToxT and the recurrent event approaches. The rationale and design of the MOTIVATE trial, which aims to model the evolution of toxicities over time using the prevalence function in patients treated by immunotherapy, is also presented ( ClinicalTrials.gov Identifier: NCT03447483; Date of registration: 27 February 2018).

Circulating tumor cells: clinical validity and utility.

Circulating tumor cells (CTCs) are rare tumor cells and have been investigated as diagnostic, prognostic and predictive biomarkers in many types of cancer. Although CTCs are not currently used in clinical practice, CTC studies have accumulated a high level of clinical validity, especially in breast, lung, prostate and colorectal cancers. In this review, we present an overview of the current clinical validity of CTCs in metastatic and non-metastatic disease, and the main concepts and studies investigating the clinical utility of CTCs. In particular, this review will focus on breast, lung, colorectal and prostate cancer. Three major topics concerning the clinical utility of CTC are discussed-(1) treatment based on CTCs used as liquid biopsy, (2) treatment based on CTC count or CTC variations, and (3) treatment based on CTC biomarker expression. A summary of published or ongoing phase II and III trials is also presented.

Tolerance of Concurrent Adjuvant Radiation Therapy and Pembrolizumab for Triple Negative Breast Cancer: Real Life Experience.

Purpose: The current standard-of-care management of locally advanced triple negative breast cancer (TNBC) is based on neoadjuvant chemo-immunotherapy with pembrolizumab, surgery, radiation therapy (RT), and adjuvant pembrolizumab. However, the safety of combining pembrolizumab with adjuvant breast RT has never been evaluated. This study evaluated the tolerance profile of concurrent pembrolizumab with adjuvant RT in patients with locally advanced TNBC. Methods and Materials: This bicentric ambispective study included all the patients with early and locally advanced TNBC who received neoadjuvant chemo-immunotherapy with pembrolizumab and adjuvant RT as part of their treatment. The tolerance profile of adjuvant RT was evaluated and compared in patients who received concurrent pembrolizumab and in patients for whom pembrolizumab was withheld. Results: Fifty-five patients were included between July 2021 and March 2023. Twenty-eight patients received adjuvant RT with concurrent pembrolizumab (RT+P group), and 27 patients had pembrolizumab withheld while receiving adjuvant RT (RT-only group). Two patients developed grade ≥3 toxicity (1 grade 3 pain in the RT+P group and 1 grade 3 radiodermatitis in the RT-only group), and there were no differences in terms of toxicity between the RT-only and the RT+P groups. No cardiac or pulmonary adverse event was reported during RT. With a median follow-up of 12 months (10-26), no patient relapsed. Conclusions: In this study of limited size, the authors did not find a difference between the RT-only and RT+P groups in terms of toxicity. More studies and longer follow-up may add to the strength of this evidence.

Fulvestrant and everolimus efficacy after CDK4/6 inhibitor: a prospective study with circulating tumor DNA analysis.

In a prospective study (NCT02866149), we assessed the efficacy of fulvestrant and everolimus in CDK4/6i pre-treated mBC patients and circulating tumor DNA (ctDNA) changes throughout therapy. Patients treated with fulvestrant and everolimus had their ctDNA assessed at baseline, after 3-5 weeks and at disease progression. Somatic mutations were identified in archived tumor tissues by targeted NGS and tracked in cell-free DNA by droplet digital PCR. ctDNA detection was then associated with clinicopathological characteristics and patients' progression-free survival (PFS), overall survival (OS) and best overall response (BOR). In the 57 included patients, median PFS and OS were 6.8 (95%CI [5.03-11.5]) and 38.2 (95%CI [30.0-not reached]) months, respectively. In 47 response-evaluable patients, BOR was a partial response or stable disease in 15 (31.9%) and 11 (23.4%) patients, respectively. Among patients with trackable somatic mutation and available plasma sample, N = 33/47 (70.2%) and N = 19/36 (52.8%) had ctDNA detected at baseline and at 3 weeks, respectively. ctDNA detection at baseline and PIK3CA mutation had an adverse prognostic impact on PFS and OS in multivariate analysis. This prospective cohort study documents the efficacy of fulvestrant and everolimus in CDK4/6i-pretreated ER + /HER2- mBC and highlights the clinical validity of early ctDNA changes as pharmacodynamic biomarker.

TROPION-Breast03: a randomized phase III global trial of datopotamab deruxtecan ± durvalumab in patients with triple-negative breast cancer and residual invasive disease at surgical resection after neoadjuvant therapy.

Background: Despite advances in the treatment of early triple-negative breast cancer (TNBC), patients with residual invasive disease after neoadjuvant therapy have a high risk of disease recurrence and worse survival outcomes than those who have pathological complete response (pCR). Improving outcomes in early TNBC remains an unmet need requiring new adjuvant treatment approaches. Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate comprising a humanized anti-trophoblast cell-surface antigen 2 immunoglobulin G1 (IgG1) monoclonal antibody attached via a plasma-stable, cleavable linker to a potent topoisomerase I inhibitor payload, with activity observed in advanced TNBC. Objectives: TROPION-Breast03 is an ongoing phase III study evaluating the efficacy and safety of Dato-DXd alone or combined with durvalumab versus standard-of-care therapy as adjuvant treatment in patients with stage I-III TNBC with residual invasive disease at surgical resection following neoadjuvant treatment. Methods and design: Eligible patients, aged ⩾18 years, will be randomized in a 2:1:2 ratio to receive Dato-DXd [6 mg/kg intravenously (IV) every 3 weeks (Q3W); eight cycles] and durvalumab (1120 mg IV Q3W; nine cycles), Dato-DXd monotherapy (6 mg/kg IV Q3W), or investigator's choice of therapy (ICT; capecitabine, pembrolizumab, or capecitabine and pembrolizumab). The primary endpoint is invasive disease-free survival (iDFS) for Dato-DXd and durvalumab versus ICT. Key secondary endpoints include safety, distant disease-free survival, and overall survival for Dato-DXd and durvalumab versus ICT and iDFS for Dato-DXd monotherapy versus ICT. Ethics: TROPION-Breast03 will be approved by the independent ethics committees or institutional review boards at each study site. All study participants will provide written informed consent. Discussion: TROPION-Breast03 will help define the potential role of Dato-DXd in the treatment of patients with early-stage TNBC who do not have pCR after neoadjuvant therapy. Trial registration: ClinicalTrials.gov identifier: NCT05629585 (registration date: 29 November 2022).

TROPION-Breast03: a clinical trial designed to assess the effectiveness and safety of Dato-DXd, alone or in combination with durvalumab, in patients with triple-negative breast cancer who have cancer cells remaining at the time of surgery after initial systemic therapy Triple-negative breast cancer (TNBC), in which cells do not have estrogen or progesterone receptors or high levels of human epidermal growth factor receptor 2, is the most aggressive breast cancer subtype. TNBC is difficult to treat and associated with high risk of recurrence despite standard systemic therapy (treatment targeting the entire body), which can include chemotherapy alone or in combination with immunotherapy (treatment targeting the immune system). To reduce the risk of recurrence, standard systemic treatment is often followed by surgical removal of the patient's tumors and additional systemic treatment. Dato-DXd is an antibody-drug conjugate, which is an anticancer drug (DXd) connected to an antibody (datopotamab) by a stable linker. Datopotamab binds to TROP2, a protein found on breast cancer cells, and is taken into the tumor cell where the linker breaks, releasing DXd to kill the cell. By delivering DXd directly to cancer cells, Dato-DXd reduces exposure in the rest of the body, reducing the risk of side effects. Since Dato-DXd can recruit immune cells to cancer sites, it may work better combined with durvalumab, a drug that blocks the activity of a protein called PD-L1, making cancer cells more susceptible to being killed by immune cells. The TROPION-Breast03 study will compare Dato-DXd, alone or combined with durvalumab, with standard-of-care therapy in patients with TNBC that has not spread to parts of the body away from the original tumor site(s), but with cancer cells remaining at the time of surgery after initial systemic therapy. It will assess how well each treatment works and describe any side effects. We plan to recruit 1,075 eligible adults who will be randomly assigned in a 2:1:2 ratio to: • Dato-DXd + durvalumab • Dato-DXd alone • Standard-of-care therapy • Patients will receive treatment until they complete the planned course of therapy (8 or 9 cycles), their cancer returns, side effects become unacceptable, or they choose to stop.

Sacituzumab govitecan in metastatic triple-negative breast cancer patients treated at Institut Curie Hospitals: efficacy, safety, and impact of brain metastases.

BACKGROUND: Sacituzumab govitecan (SG) has been approved by FDA in April 2021 for pre-treated metastatic triple-negative breast cancer (mTNBC), following the ASCENT trial results. METHODS: We set up an ambispective bicentric cohort study to assess the real-world effectiveness and safety of SG in patients with mTNBC treated at Institut Curie Hospitals, with a focus on patients with brain metastases. RESULTS: This study included 99 patients treated through the French Early Access Program to SG from May 2021 to January 2023. Median age was 55 years [26-89], N = 8 patients (8%) had BRCA1/2 mutation, N = 12 (12%) de novo stage IV disease and N = 31 (31%) brain metastases. Patients had previously received a median of two [1-10] lines of treatment in advanced setting. After a median follow-up of 9.7 months, the median progression-free survival (PFS) and overall survival (OS) were 3.9 months (95%CI[3.4-5.0]) and 8.6 months (95%CI[7.1-11.9]), respectively, while objective response rate was 29% (95%CI[21-39]). Among patients with brain metastases, median PFS and OS were 3.7 months (95%CI[2.6-6.2]) and 6.7 months (95%CI[6.3-NR]), respectively, with intracranial tumor responses. Dose reductions were required in N = 17 patients (17%) within a median of three [2-11] cycles, due to gastrointestinal toxicity (N = 6; 6%), hematological toxicity (N = 9; 9%) including febrile neutropenia (N = 2; 2%), liver enzyme elevation (N = 1; 1%), and physical deterioration (N = 1; 1%). There was no related death to SG. CONCLUSIONS: The observed response rate and safety of SG are consistent with the results of the ASCENT trial, with efficacy observed in patients with brain metastases, but observed PFS and OS are numerically shorter.

Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer (BROCADE3): Final overall survival results from a randomized phase 3 trial.

BACKGROUND: In the BROCADE3 study, the addition of veliparib to carboplatin plus paclitaxel resulted in a significant improvement in progression-free survival (PFS) compared with placebo plus carboplatin and paclitaxel, in patients with germline BRCA1 or BRCA2 (BRCA1/2)-mutated, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. We now report final overall survival (OS) data. METHODS: BROCADE3 is a randomized phase 3 study that enrolled patients with BRCA1/2-mutated, HER2-negative advanced breast cancer who received ≤ 2 prior lines of chemotherapy for metastatic disease. Patients were randomized 2:1 to carboplatin and paclitaxel, dosed with either veliparib or matching placebo. OS was a secondary endpoint. RESULTS: In the intention-to-treat population (N = 509), 337 patients were randomized to receive veliparib and 172 to placebo. Median OS was 32.4 months vs 28.2 months (hazard ratio, 0.916; 95% CI, 0.736-1.140; P = .434). The updated safety data for veliparib are consistent with those reported in the primary analysis; the addition of veliparib was generally well tolerated. CONCLUSIONS: Final OS data indicate that the PFS improvement shown in the primary analysis did not translate into an OS benefit. The long survival times observed in both arms suggest that combination therapy with paclitaxel and carboplatin provides clinical benefit in the population of patients with BRCA1/2-mutated metastatic breast cancer.

Overall Survival With Circulating Tumor Cell Count-Driven Choice of Therapy in Advanced Breast Cancer: A Randomized Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer, the STIC CTC trial established that, for choosing between endocrine therapy (ET) or chemotherapy, the use of circulating tumor cell (CTC) count is noninferior to the investigator's choice in terms of progression-free survival. Here, we report overall survival (OS) results, a secondary end point. Patients were randomly assigned in a 1:1 ratio to have their first-line treatment (ET or chemotherapy) determined by investigators or CTC count (chemotherapy if ≥ 5 CTCs/7.5 mL; ET if low CTC count; CellSearch). OS was assessed at the discontinuation of follow-up. After a median follow-up of 4.7 years, 382 deaths (50.6%) had occurred among 755 patients. Median OS was 51.3 months (95% CI, 46.8 to 55.1) in the CTC arm and 45.5 months (95% CI, 40.9 to 51.1) in the standard arm (hazard ratio [HR] for death, 0.85; 95% CI, 0.69 to 1.03; P = .11). Among 189 patients (25.0%) with ET recommended by clinicians and high CTC count, chemotherapy was superior to ET (HR for death, 0.53; 95% CI, 0.36 to 0.78; P = .001). In case of a discordant estimate, OS data demonstrate the clinical utility of CTC count.