Palliative Care Interventions and End-of-Life Care for Patients with Metastatic Breast Cancer: A Multicentre Analysis.

BACKGROUND: The aim of this study was to describe the implementation of integrated palliative care (PC) and the intensity of care in the last 3 months before death for patients with metastatic breast cancer. MATERIALS AND METHODS: We conducted a multicentric study of all adult patients with metastatic breast cancer who died over a 4-month period. Complete data were collected and checked from clinical records, including PC interventions and criteria regarding EOL care aggressiveness. RESULTS: A total of 340 decedent patients from 12 comprehensive cancer centres in France were included in the study. Sixty-five percent met the PC team with a median time of 39 days between the first intervention and death. In the last month before death, 11.5% received chemotherapy, the frequency of admission to intensive care unit was 2.4%, and 83% experienced acute hospitalization. The place of death was home for 16.7%, hospitalization for 63.3%, PC unit for 20%. Univariate and multivariate analyses showed factors independently associated with a higher frequency of chemotherapy in the last month before death: having a dependent person at home, meeting for the first time with a PC team < 30 days before death, and time between the first metastasis and death below the median. CONCLUSION: PC team integration was frequent and late for patients with metastatic breast cancer. However, PC intervention > 30 days is associated with less chemotherapy in the last month before death. Further studies are needed to better understand how to implement a more effective mode of PC integration for patients with metastatic breast cancer.

Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial.

BACKGROUND: In advanced oestrogen receptor-positive, HER2-negative breast cancer, acquired resistance to aromatase inhibitors frequently stems from ESR1-mutated subclones, which might be sensitive to fulvestrant. The PADA-1 trial aimed to show the efficacy of an early change in therapy on the basis of a rising ESR1 mutation in blood (bESR1mut), while assessing the global safety of combination fulvestrant and palbociclib. METHODS: We did a randomised, open-label, phase 3 trial in 83 hospitals in France. Women aged at least 18 years with oestrogen receptor-positive, HER2-negative advanced breast cancer and an Eastern Cooperative Oncology Group performance status of 0-2 were recruited and monitored for rising bESR1mut during first-line aromatase inhibitor (2·5 mg letrozole, 1 mg anastrozole, or 25 mg exemestane, orally once per day, taken continuously) and palbociclib (125 mg orally once per day on days 1-21 of a 28-day cycle) therapy. Patients with newly present or increased bESR1mut in circulating tumour DNA and no synchronous disease progression were randomly assigned (1:1) to continue with the same therapy or to switch to fulvestrant (500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1) and palbociclib (dosing unchanged). The randomisation sequence was generated within an interactive web response system using a minimisation method (with an 80% random factor); patients were stratified according to visceral involvement (present or absent) and the time from inclusion to bESR1mut detection (<12 months or ≥12 months). The co-primary endpoints were investigator-assessed progression-free survival from random assignment, analysed in the intention-to-treat population (ie, all randomly assigned patients), and grade 3 or worse haematological adverse events in all patients. The trial is registered with Clinicaltrials.gov (NCT03079011), and is now complete. FINDINGS: From March 22, 2017, to Jan 31, 2019, 1017 patients were included, of whom 279 (27%) developed a rising bESR1mut and 172 (17%) were randomly assigned to treatment: 88 to switching to fulvestrant and palbociclib and 84 patients to continuing aromatase inhibitor and palbociclib. At database lock on July 31, 2021, randomly assigned patients had a median follow-up of 35·3 months (IQR 29·2-41·4) from inclusion and 26·0 months (13·8-34·3) from random assignment. Median progression-free survival from random assignment was 11·9 months (95% CI 9·1-13·6) in the fulvestrant and palbociclib group versus 5·7 months (3·9-7·5) in the aromatase inhibitor and palbociclib group (stratified HR 0·61, 0·43-0·86; p=0·0040). The most frequent grade 3 or worse haematological adverse events were neutropenia (715 [70·3%] of 1017 patients), lymphopenia (66 [6·5%]), and thrombocytopenia (20 [2·0%]). The most common grade 3 or worse adverse events in step 2 were neutropenia (35 [41·7%] of 84 patients in the aromatase inhibitor and palbociclib group vs 39 [44·3%] of 88 patients in the fulvestrant and palbociclib group) and lymphopenia (three [3·6%] vs four [4·5%]). 31 (3·1%) patients had grade 3 or worse serious adverse events related to treatment in the overall population. Three (1·7%) of 172 patients randomly assigned had one serious adverse event in step 2: one (1·2%) grade 4 neutropenia and one (1·2%) grade 3 fatigue among 84 patients in the aromatase inhibitor and palbociclib group, and one (1·1%) grade 4 neutropenia among 88 patients in the fulvestrant and palbociclib group. One death by pulmonary embolism in step 1 was declared as being treatment related. INTERPRETATION: PADA-1 is the first prospective randomised trial showing that the early therapeutic targeting of bESR1mut results in significant clinical benefit. Additionally, the original design explored in PADA-1 might help with tackling acquired resistance with new drugs in future trials. FUNDING: Pfizer.

Concurrent Olaparib and Radiotherapy in Patients With Triple-Negative Breast Cancer: The Phase 1 Olaparib and Radiation Therapy for Triple-Negative Breast Cancer Trial.

Importance: Triple-negative breast cancer (TNBC) cells are sensitive to poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors used as radiosensitizers. Whether combining PARP inhibitors with radiotherapy in patients with TNBC would enhance the biological effectiveness of the irradiation and improve locoregional control is unclear. Objective: To assess the safety and tolerability of PARP inhibition with olaparib used concurrently with radiotherapy in patients with TNBC with residual disease after neoadjuvant chemotherapy. Design, Setting, and Participants: This phase 1 prospective dose-escalation trial (Olaparib and Radiation Therapy for TNBC [RadioPARP] trial) using a time-to-event continual reassessment method was performed from September 2017 to November 2019, with follow-up until November 2021. Participants had an incomplete pathologic response after neoadjuvant chemotherapy or unresectable TNBC despite previous neoadjuvant chemotherapy, an Eastern Cooperative Oncology Group Performance Status score of 0 or 1, and adequate organ functions. Interventions: Olaparib was administered orally in the form of tablets and given at increasing doses (50 mg, 100 mg, 150 mg, or 200 mg twice daily). Olaparib therapy was started 1 week before radiotherapy and was continued concomitantly with radiotherapy. After breast-conserving surgery, a total dose of 50.4 Gy was delivered to the whole breast, with a 63-Gy simultaneously integrated boost to the tumor bed for patients younger than 60 years. After radical mastectomy or for unresectable tumors despite neoadjuvant chemotherapy, a total dose of 50.0 Gy was delivered to the chest wall (after mastectomy) or to the whole breast (for unresectable tumors). Regional lymph node stations could be treated with a total dose of 50.0 Gy to 50.4 Gy in cases of node-positive disease. Main Outcomes and Measures: Main outcomes were the safety and tolerability of PARP inhibition with radiotherapy for early-stage, high-risk TNBC. Secondary outcomes included overall survival (OS) and event-free survival (EFS). Results: Among the 24 patients included in the trial (100% female; median age, 46 years [range, 25-74 years]), no dose-limiting toxic effects were observed, and olaparib was escalated to 200 mg twice daily without reaching the maximum tolerated dose. No late treatment-related grade 3 or greater toxic effect was observed, and the maximum observed treatment-related toxic effects at the 2-year follow-up were grade 2 breast pain, fibrosis, and deformity in 1 patient (4.2%). Three-year OS and EFS were 83% (95% CI, 70%-100%) and 65% (95% CI, 48%-88%), respectively. Homologous recombination status was not associated with OS or EFS. Conclusions and Relevance: The findings of this phase 1 dose-escalation trial suggest that PARP inhibition with olaparib concurrently with radiotherapy for early-stage, high-risk TNBC is well tolerated and should continue to be evaluated in further clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT03109080.

Cytidine deaminase activity increases in the blood of breast cancer patients.

Cytidine deaminase (CDA), an enzyme of the pyrimidine salvage pathway, deaminates cytidine, deoxycytidine and analogs, such as gemcitabine. Constitutive low levels of CDA activity have been reported in the blood of patients with hematological malignancies or suffering from gemcitabine toxicity. We previously reported that cellular CDA deficiency leads to genetic instability. We therefore hypothesized that constitutive CDA deficiency might confer a predisposition to cancer. We analyzed CDA activity and expression in blood samples from breast cancer (BC) patients with a suspected predisposition to the disease, and in healthy controls. Contrary to our hypothesis, we found that both CDA activity and mRNA levels were higher in blood samples from BC patients than in those from controls, and that this difference was not due to excess neutrophils. CDA activity levels were significantly higher in the serum samples of BC patients treated by radiotherapy (RT) than in those of untreated healthy controls, and hormone therapy in RT-treated BC patients was associated with significantly lower levels of CDA activity. A preliminary analysis of CDA activity in the serum of the very few BC patients who had undergone no treatment other than surgery suggested that the increase in CDA activity might be due to the breast cancer itself. Our findings raise important questions, which should lead to studies to elucidate the origin and significance of the increase in CDA activity in the serum of BC patients, and the impact of hormone therapy.

Real-Time Detection of ESR1 Mutation in Blood by Droplet Digital PCR in the PADA-1 Trial: Feasibility and Cross-Validation with NGS.

The clinical actionability of circulating tumor DNA requires sensitive detection methods with a short turnaround time. In the PADA-1 phase 3 trial (NCT03079011), metastatic breast cancer patients treated with an aromatase inhibitor and palbociclib were screened every 2 months for activating ESR1 mutations in blood (bESR1mut). We report the feasibility of the droplet digital polymerase chain reaction (ddPCR) and cross-validation with next-generation sequencing (NGS). bESR1mut testing was centralized in two platforms using the same ddPCR assay. Results were reported as copies/mL of plasma and mutant allele frequency (MAF). We analyzed 200 positive ddPCR samples with an NGS assay (0.5-1% sensitivity). Overall, 12,552 blood samples were collected from 1017 patients from 83 centers. Among the 12,525 available samples with ddPCR results, 11,533 (92%) were bESR1mut-negative. A total of 267 patients newly displayed bESR1mut (26% patients/2% samples) with a median copy number of 14/mL (range: 4-1225) and a median MAF of 0.83% (0.11-35), 648 samples (20% patients/5% samples) displayed persistent bESR1mut, and 77 (<1%) samples encountered a technical failure. The median turnaround time from blood drawing to result notification was 13 days (Q1:9; Q3:21 days). Among 200 ddPCR-positive samples tested, NGS detected bESR1mut in 168 (84%); 25 of the 32 cases missed by NGS had low MAF and/or low coverage. In these 200 samples, bESR1mut MAF by both techniques had an excellent intraclass correlation coefficient (ICC = 0.93; 95% CI [0.85; 0.97]). These results from a large-scale trial support the feasibility and accuracy of real-time bESR1mut tracking by ddPCR, opening new opportunities for therapeutic interventions.

Randomised, open-label, multicentric phase III trial to evaluate the safety and efficacy of palbociclib in combination with endocrine therapy, guided by ESR1 mutation monitoring in oestrogen receptor-positive, HER2-negative metastatic breast cancer patients: study design of PADA-1.

INTRODUCTION: The combination of a CDK4/6 inhibitor with an aromatase inhibitor (AI) has recently become the gold standard for AI-sensitive first line treatment of oestrogen receptor-positive (ER+) HER2-negative (HER2-) advanced breast cancer. However, most patients receiving this combination will ultimately progress and require further therapies.Several studies have demonstrated that the onset of a ESR1 gene mutation lead to AIs resistance in the advanced setting. ESR1 mutations can be detected in circulating tumour DNA (ctDNA) using a digital PCR assay. Our study aims to prove the clinical efficacy of periodic monitoring for emerging or rise of ESR1 mutations in ctDNA to trigger an early change from AI plus palbociclib to fulvestrant plus palbociclib treatment while assessing global safety. METHODS: PADA-1 is a randomised, open-label, multicentric, phase III trial conducted in patients receiving AI and palbociclib as first line therapy for metastatic ER +HER2- breast cancer. 1000 patients will be included and treated with palbociclib in combination with an AI. Patients will be screened for circulating blood ESR1 mutation detection at regular intervals. Patients for whom a rising circulating ESR1 mutation is detected without tumour progression (up to N=200) will be randomised (1:1) between (1) Arm A: no modification of therapy; and (2) Arm B: palbociclib in combination with fulvestrant, a selective ER down-regulator. At tumour progression, an optional crossover will be offered to patients randomised in arm A. The coprimary endpoints are (1) Grade ≥3 haematological toxicities and their associations with baseline characteristics and (2) progression-free survival in randomised patients. ETHICS AND DISSEMINATION: The study has been approved by the French medicines agency (ANSM) and by an ethics committee (ref 01/17_1 CPP Ouest-IV Nantes) in January 2017. The trial results will be published in academic conference presentations and international peer-reviewed journals. TRIAL REGISTRATION NUMBERS: EudraCT: 2016-004360-18; NCT03079011.

Multimodal liquid biopsy for early monitoring and outcome prediction of chemotherapy in metastatic breast cancer.

Circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) are two cancer-derived blood biomarkers that inform on patient prognosis and treatment efficacy in breast cancer. We prospectively evaluated the clinical validity of quantifying both CTCs (CellSearch) and ctDNA (targeted next-generation sequencing). Their combined value as prognostic and early monitoring markers was assessed in 198 HER2-negative metastatic breast cancer patients. All patients were included in the prospective multicenter UCBG study COMET (NCT01745757) and treated by first-line chemotherapy with weekly paclitaxel and bevacizumab. Blood samples were obtained at baseline and before the second cycle of chemotherapy. At baseline, CTCs and ctDNA were respectively detected in 72 and 74% of patients and were moderately correlated (Kendall's τ = 0.3). Only 26 (13%) patients had neither detectable ctDNA nor CTCs. Variants were most frequently observed in TP53 and PIK3CA genes. KMT2C/MLL3 variants detected in ctDNA were significantly associated with a lower CTC count, while the opposite trend was seen with GATA3 alterations. Both CTC and ctDNA levels at baseline and after four weeks of treatment were correlated with survival. For progression-free and overall survival, the best multivariate prognostic model included tumor subtype (triple negative vs other), grade (grade 3 vs other), ctDNA variant allele frequency (VAF) at baseline (per 10% increase), and CTC count at four weeks (≥5CTC/7.5 mL). Overall, this study demonstrates that CTCs and ctDNA have nonoverlapping detection profiles and complementary prognostic values in metastatic breast cancer patients. A comprehensive liquid-biopsy approach may involve simultaneous detection of ctDNA and CTCs.

CENP-A Subnuclear Localization Pattern as Marker Predicting Curability by Chemoradiation Therapy for Locally Advanced Head and Neck Cancer Patients.

Effective biomarkers predictive of the response to treatments are key for precision medicine. This study identifies the staining pattern of the centromeric histone 3 variant, CENP-A, as a predictive biomarker of locoregional disease curability by chemoradiation therapy. We compared by imaging the subnuclear distribution of CENP-A in normal and tumoral tissues, and in a retrospective study in biopsies of 62 locally advanced head and neck squamous cell carcinoma (HNSCC) patients treated by chemoradiation therapy. We looked for predictive factors of locoregional disease control and patient's survival, including CENP-A patterns, Ki67, HPV status and anisokaryosis. In different normal tissues, we reproducibly found a CENP-A subnuclear pattern characterized by CENP-A clusters both localized at the nuclear periphery and regularly spaced. In corresponding tumors, both features are lost. In locally advanced HNSCC, a specific CENP-A pattern identified in pretreatment biopsies predicts definitive locoregional disease control after chemoradiation treatment in 96% (24/25) of patients (OR = 17.6 CI 95% [2.6; 362.8], p = 0.002), independently of anisokaryosis, Ki67 labeling or HPV status. The characteristics of the subnuclear pattern of CENP-A in cell nuclei revealed by immunohistochemistry could provide an easy to use a reliable marker of disease curability by chemoradiation therapy in locally advanced HNSCC patients.

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.

Molecular features of untreated breast cancer and initial metastatic event inform clinical decision-making and predict outcome: long-term results of ESOPE, a single-arm prospective multicenter study.

BACKGROUND: Prognosis evaluation of advanced breast cancer and therapeutic strategy are mostly based on clinical features of advanced disease and molecular profiling of the primary tumor. Very few studies have evaluated the impact of metastatic subtyping during the initial metastatic event in a prospective study. The genomic landscape of metastatic breast cancer has mostly been described in very advanced, pretreated disease, limiting the findings transferability to clinical use. METHODS: We developed a multicenter, single-arm, prospective clinical trial in order to address these issues. Between November 2010 and September 2013, 123 eligible patients were included. Patients at the first, untreated metastatic event were eligible. All matched primary tumors and metastatic samples were centrally reviewed for pathological typing. Targeted and whole-exome sequencing was applied to matched pairs of frozen tissue. A multivariate overall survival analysis was performed (median follow-up 64 months). RESULTS: Per central review in 84 patients (out of 130), we show that luminal A breast tumors are more prone to subtype switching. By combining targeted sequencing of a 91 gene panel (n = 67) and whole-exome sequencing (n = 30), a slight excess of mutations is observed in the metastases. Luminal A breast cancer has the most heterogeneous mutational profile and the highest number of mutational signatures, when comparing primary tumor and the matched metastatic tissue. Tumors with a subtype change have more mutations that are private. The metastasis-specific mutation load is significantly higher in late than in de novo metastases. The most frequently mutated genes were TP53 and PIK3CA. The most frequent metastasis-specific druggable genes were PIK3CA, PTEN, KDR, ALK, CDKN2A, NOTCH4, POLE, SETD2, SF3B1, and TSC2. Long-term outcome is driven by a combination of tumor load and metastasis biology. CONCLUSIONS: Profiling of the first, untreated, metastatic event of breast cancer reveals a profound heterogeneity mostly in luminal A tumors and in late metastases. Based on this profiling, we can derive information relevant to prognosis and therapeutic intervention, which support current guidelines recommending a biopsy at the first metastatic relapse. TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov ( NCT01956552 ).

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.

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.

Efficacy of Circulating Tumor Cell Count-Driven vs Clinician-Driven First-line Therapy Choice in Hormone Receptor-Positive, ERBB2-Negative Metastatic Breast Cancer: The STIC CTC Randomized Clinical Trial.

IMPORTANCE: The choice between chemotherapy and endocrine therapy as first-line treatment for hormone receptor-positive, ERBB2 (also known as HER2)-negative metastatic breast cancer is usually based on the presence of clinical features associated with a poor prognosis. In this setting, a high circulating tumor cell (CTC) count (≥5 CTCs/7.5 mL) is a strong adverse prognostic factor for overall survival and progression-free survival (PFS). OBJECTIVE: To compare the efficacy of a clinician-driven treatment choice vs a CTC-driven choice for first-line treatment. INTERVENTIONS: In the CTC arm, patients received chemotherapy or endocrine therapy according to the CTC count (chemotherapy if ≥5 CTCs/7.5 mL; endocrine therapy if <5 CTCs/7.5 mL), whereas in the control arm, the choice was left to the investigator. DESIGN, SETTING, AND PARTICIPANTS: In the STIC CTC randomized, open-label, noninferiority phase 3 trial, participants were randomized to a clinician-driven choice of first-line treatment or a CTC count-driven first-line treatment choice. Eligible participants were premenopausal and postmenopausal women 18 years or older diagnosed with hormone receptor-positive, ERBB2-negative metastatic breast cancer. Data were collected at 17 French cancer centers from February 1, 2012, to July 28, 2016, and analyzed June 2019 to October 2019. MAIN OUTCOME AND MEASURES: The primary end point was the investigator-assessed PFS in the per-protocol population, with a noninferiority margin of 1.25 for the 90% CI of the hazard ratio. RESULTS: Among the 755 women in the per-protocol population, the median (range) age was 63 (30-88) years [64 (30-88) years for the 377 patients allocated to the CTC arm and 63 (31-87) years for the 378 patients allocated to the standard arm]; 138 (37%) and 103 (27%) received chemotherapy, respectively. Median PFS was 15.5 months (95% CI, 12.7-17.3) in the CTC arm and 13.9 months (95% CI, 12.2-16.3) in the standard arm. The primary end point was met, with a hazard ratio of 0.94 (90% CI, 0.81-1.09). CONCLUSIONS AND RELEVANCE: This randomized clinical trial found that the CTC count may be a reliable biomarker method for guiding the choice between chemotherapy and endocrine therapy as the first-line treatment in hormone receptor-positive, ERBB2-negative metastatic breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01710605.

Combination of Olaparib and Radiation Therapy for Triple Negative Breast Cancer: Preliminary Results of the RADIOPARP Phase 1 Trial.

PURPOSE: Preclinical studies have evidenced that triple-negative breast cancer (TNBC) cell lines are more sensitive to poly (ADP-ribose) polymerase inhibitors. This provides a strong rationale for developing a new therapeutic approach for TNBC management based on poly (ADP-ribose) polymerase inhibition. The primary goal of the RADIOPARP phase 1 trial was to evaluate the dose-limiting toxicities (DLT) and the maximum tolerated dose of olaparib combined with locoregional radiation therapy. METHODS AND MATERIALS: RADIOPARP was a single institutional phase 1 trial which evaluated olaparib-radiation therapy combination in patients with inflammatory, locoregionally advanced or metastatic TNBC who received neoadjuvant chemotherapy. Radiation therapy delivered 50 Gy to the breast or to the chest wall. Lymph nodes could be included in target volumes according to local guidelines. The dose-finding toxicity-based study was conducted in sequential and adaptive Bayesian scheme using the time-to-event continual reassessment method, with 4 olaparib dose levels (50 mg, 100 mg, 150 mg, and 200 mg twice per day). RESULTS: Twenty-four patients with Eastern Cooperative Oncology Group Performance Status of 0 or 1 were enrolled from September 2017 to November 2019. Twenty-one patients (87.5%) received the olaparib-radiation therapy combination after breast surgery owing to residual disease after neoadjuvant chemotherapy, and the 3 other patients (12.5%) had unresectable tumors which were refractory to neoadjuvant chemotherapy. All patients received full course combination treatment as follows: 4 patients (pts) at 50 mg twice a day, 8 pts at 100 mg twice a day, 7 pts at 150 mg twice a day, and 5 pts at 200 mg twice a day. No DLT was observed. CONCLUSIONS: Olaparib was escalated to the maximum target dose of 200 mg twice a day without DLT. Further follow-up is needed to evaluate the late toxicities. Pending the long-term results of the RADIOPARP trial, we suggest using 200 mg of olaparib twice per day for future trials.

Biomarkers of cetuximab resistance in patients with head and neck squamous cell carcinoma.

Objective: In patients with head and neck squamous cell carcinoma (HNSCC), cetuximab [a monoclonal antibody targeting epidermal growth factor receptor (EGFR)] has been shown to improve overall survival when combined with radiotherapy in the locally advanced setting or with chemotherapy in first-line recurrent and/or metastatic (R/M) setting, respectively. While biomarkers of resistance to cetuximab have been identified in metastatic colorectal cancer, no biomarkers of efficacy have been identified in HNSCC. Here, we aimed to identify biomarkers of cetuximab sensitivity/resistance in HNSCC. Methods: HNSCC patients treated with cetuximab at the Curie Institute, for whom complete clinicopathological data and formalin-fixed paraffin-embedded (FFPE) tumor tissue collected before cetuximab treatment were available, were included. Immunohistochemistry analyses of PTEN and EGFR were performed to assess protein expression levels. PIK3CA and H/N/KRAS mutations were analyzed using high-resolution melting (HRM) and Sanger sequencing. We evaluated the predictive value of these alterations in terms of progression-free survival (PFS). Results: Hot spot activating PIK3CA and KRAS/HRAS mutations were associated with poor PFS among HNSCC patients treated with cetuximab in the first-line R/M setting, but not among HNSCC patients treated with cetuximab in combination with radiotherapy. Loss of PTEN protein expression had a negative predictive value among HNSCC patients treated with cetuximab and radiotherapy. High EGFR expression did not predict cetuximab sensitivity in our patient population. Conclusions: Hot spot activating PIK3CA and RAS mutations predicted cetuximab resistance among HNSCC patients in the first-line R/M setting, whereas loss of PTEN protein expression predicted resistance to cetuximab when combined to radiotherapy.

Actionability of HER2-amplified circulating tumor cells in HER2-negative metastatic breast cancer: the CirCe T-DM1 trial.

BACKGROUND: In this prospective phase 2 trial, we assessed the efficacy of trastuzumab-emtansine (T-DM1) in HER2-negative metastatic breast cancer (MBC) patients with HER2-positive CTC. METHODS: Main inclusion criteria for screening were as follows: women with HER2-negative MBC treated with ≥ 2 prior lines of chemotherapy and measurable disease. CTC with a HER2/CEP17 ratio of ≥ 2.2 by fluorescent in situ hybridization (CellSearch) were considered to be HER2-amplified (HER2amp). Patients with ≥ 1 HER2amp CTC were eligible for the treatment phase (T-DM1 monotherapy). The primary endpoint was the overall response rate. RESULTS: In 154 screened patients, ≥ 1 and ≥ 5 CTC/7.5 ml of blood were detected in N = 118 (78.7%) and N = 86 (57.3%) patients, respectively. ≥1 HER2amp CTC was found in 14 patients (9.1% of patients with ≥ 1 CTC/7.5 ml). Among 11 patients treated with T-DM1, one achieved a confirmed partial response. Four patients had a stable disease as best response. Median PFS was 4.8 months while median OS was 9.5 months. CONCLUSIONS: CTC with HER2 amplification can be detected in a limited subset of HER2-negative MBC patients. Treatment with T-DM1 achieved a partial response in only one patient. TRIAL REGISTRATION: NCT01975142, Registered 03 November 2013.

A Quantitative Multivariate Model of Human Dendritic Cell-T Helper Cell Communication.

Cell-cell communication involves a large number of molecular signals that function as words of a complex language whose grammar remains mostly unknown. Here, we describe an integrative approach involving (1) protein-level measurement of multiple communication signals coupled to output responses in receiving cells and (2) mathematical modeling to uncover input-output relationships and interactions between signals. Using human dendritic cell (DC)-T helper (Th) cell communication as a model, we measured 36 DC-derived signals and 17 Th cytokines broadly covering Th diversity in 428 observations. We developed a data-driven, computationally validated model capturing 56 already described and 290 potentially novel mechanisms of Th cell specification. By predicting context-dependent behaviors, we demonstrate a new function for IL-12p70 as an inducer of Th17 in an IL-1 signaling context. This work provides a unique resource to decipher the complex combinatorial rules governing DC-Th cell communication and guide their manipulation for vaccine design and immunotherapies.

Photons Without Bolus Versus Electrons With Bolus After Upfront Mastectomy Without Immediate Reconstruction in Breast Cancer Patients.

PURPOSE: To evaluate locoregional control and outcome after mastectomy in patients treated with postmastectomy highly conformal electron radiation therapy (PMERT) with bolus compared with patients treated by highly conformal photon radiation therapy (PMPhRT) without bolus in the adjuvant setting of nonmetastatic breast cancer. METHODS AND MATERIALS: We studied women undergoing PMRT without immediate reconstruction for breast cancer before 2012 in 2 sites of our hospital using 2 different techniques. All patients received 50 Gy in 25 fractions. Patients previously treated by neoadjuvant chemotherapy were excluded. RESULTS: Among the 807 patients, 583 received PMERT and 224 received PMPhRT. The median follow-up was 64 months. Patients in the PMERT group had a median age of 52.7 years (range, 26-91 years), 6.9% were triple-negative, 16.3% were HER2-positive, and 58.6% had multifocal lesions. Patients in the PMPhRT group had a median age of 56.4 years (28-89), 8.5% were triple negative, 12.9% were HER2-positive, and 55.8% had multifocal lesions. Lymph node involvement was observed in 66% and 72.8% of cases (P = .07) treated with PMERT and PMPhRT, respectively. No significant difference in overall survival was observed between the 2 groups (hazard ratio [HR], 1.2; 95% CI, 0.67-2.13; P = .54). The risk of locoregional recurrence, estimated using the Fine-Gray method, was significantly higher with PMPhRT than with PMERT (subdistribution HR, 3.62; 95% CI, 1.07-12.3; P = .04), corresponding to a 5-year LRR rate of 0.53% (95% CI, 0-1.12%) for PMERT and 2.52% (95% CI, 0.05%-4.6%) for PMPhRT. CONCLUSIONS: A higher risk of local recurrence was observed in the PMPhRT without bolus group compared with the PMERT with bolus group. Prospective randomized trials are needed to confirm these findings.

Disseminated Tumor Cells Predict Efficacy of Regional Nodal Irradiation in Early Stage Breast Cancer.

PURPOSE: Disseminated tumor cells (DTCs) collect in the bone marrow and indicate micrometastatic spread. We previously reported that DTCs could be a predictive factor for the efficacy of regional node irradiation (internal mammary nodes [IMNs]/supra- and infraclavicular nodes [SCNs]). In this article, we report the long-term results (>10 years) on the impact of DTC status in early stage breast cancer. METHODS AND MATERIALS: Patients with localized breast cancer were eligible for inclusion in this prospective cohort. DTCs were obtained from a medullary iliac crest sample performed before any primary therapy. DTC status was prospectively assessed by pathologists. Irradiation volumes were defined per standard of care. Cumulative incidence rates and hazard ratios were obtained using both Cox and Fine-Gray models. Interaction tests were performed to confirm the predictive value of DTC status in a multivariate analysis. RESULTS: Six hundred twenty patients with localized breast cancer were included. Overall, 94 patients (15.2%) were DTC-positive. After a median follow-up of 11.7 years, 47 patients (7.6%) experienced locoregional relapse. DTC detection was associated with a higher risk of locoregional relapse in univariate and multivariate analyses (Cox hazard ratio, 3.26; 95% confidence interval, 1.6-5.7; P = .001). In the multivariate subgroup analysis, IMN/SCN irradiation significantly reduced locoregional relapse among DTC-positive patients compared with DTC-negative patients (interaction test: hazard ratio, 0.3; 95% confidence interval, 0.1-0.9; P = .02). IMN/SCN was the only irradiation volume with an impact on locoregional relapse in patients according to DTC status, and the predictive value of DTC status for the benefit of locoregional irradiation was independent of locoregional nodal status. CONCLUSIONS: This long-term analysis confirms the predictive impact of DTC status on the efficacy of regional radiation therapy for locoregional relapse in early breast cancer. After further studies, DTC status could be used as a decision tool to better tailor adjuvant radiation therapy in patients with early stage breast cancer.