Prognostic stratification ability of the CPS+EG scoring system in HER2-low and HER2-zero early breast cancer treated with neoadjuvant chemotherapy.

BACKGROUND: The CPS+EG scoring system was initially described in unselected early breast cancer (eBC) patients treated with neoadjuvant chemotherapy (NAC), leading to refined prognostic stratification, and thus helping to select patients for additional post-NAC treatments. It remains unknown whether the performance is the same in new biological breast cancer entities such as the HER2-low subtype. PATIENTS AND METHODS: Outcomes (disease-free (DFS) and overall survival OS)) of 608 patients with HER2-non amplified eBC and treated with NAC were retrospectively analyzed according to CPS-EG score. We compared the prognostic stratification abilities of the CPS+EG in HER2-low and HER2-0 eBC, analyzing ER+ and ER- tumors separately. RESULTS: In ER+ eBC, the CPS+EG scoring system seems to retain a prognostic value, both in HER2-low and HER2-0 tumors, by distinguishing populations with significantly different outcomes (good: score 0-1, poor: score 2-3, and very poor: score 4-5). Using C-indices for DFS and OS, CPS+EG provided the highest prognostic information in ER+ eBC, especially in HER2-0 tumors. In contrast, in ER- eBC, the CPS+EG does not appear to be able to distinguish different outcome groups, either in HER2-low or HER2-0 tumors. In ER- eBC, C-indices for DFS and OS were highest for pathological stage, reflecting the predominant prognostic importance of residual disease in this subtype. CONCLUSIONS: HER2-low status does not influence the prognostic performance of the CPS+EG score. Our results confirm the usefulness of the CPS+EG score in stratifying the prognosis of ER+ eBC after NAC, for both HER2-0 and HER2-low tumors. For ER- eBC, HER2-low status does not influence the performance of the CPS+EG score, which was lower than that of the pathological stage alone.

Palbociclib in Older Patients with Advanced/Metastatic Breast Cancer: A Systematic Review.

BACKGROUND: Palbociclib in combination with endocrine therapy is approved for treatment of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. In addition to clinical trials, several real-world studies have evaluated the effectiveness of palbociclib. With increased life expectancy in the general population, breast cancer in older women is also expected to increase. OBJECTIVE: The aim was to systematically review evidence from both clinical trials and real-world studies for palbociclib treatment outcomes in older patients with HR+/HER2- advanced/metastatic breast cancer (a/mBC). Older patients are often underrepresented in clinical trials, and real-world evidence (RWE) will enrich the analysis of palbociclib outcomes in this subgroup of patients. DESIGN: A systematic literature search in PubMed, EMBASE, and Cochrane Library through May 4, 2023, yielded 2355 unique articles. A total of 52 articles (13 and 39 articles reporting results from seven randomized controlled trials [RCTs] and 37 RWE studies, respectively) were included based on study eligibility criteria. RESULTS: All RCTs used age cutoffs of ≥ 65 years to define older population (n = 722; 437 received palbociclib); all RWE studies, except one with an age cutoff of > 60 years, had age cutoffs of ≥ 65 years or higher to define older population (n = 9840; 7408 received palbociclib). Overall, in studies that compared efficacy (progression-free survival [seven RCTs, 20 RWE studies], overall survival [four RCTs, 11 RWE studies], tumor response [three RWE studies], and clinical benefit rate [one RCT, two RWE studies]) and safety outcomes (three RCTs, three RWE studies) between older and younger patients, palbociclib showed similar benefits, regardless of age. Results from two RCTs and two RWE studies showed that global quality of life (QoL) was maintained in older patients receiving palbociclib. Overall, palbociclib dose modifications (two RWE studies), dose reductions (one RCT, seven RWE studies), and treatment discontinuation rates (three RCTs, three RWE studies) were higher in older patients compared with younger patients; however, these differences did not appear to adversely impact efficacy outcomes. CONCLUSIONS: In this systematic review, data from RCTs showed that palbociclib was effective, well tolerated, and maintained QoL in older patients with HR+/HER2- a/mBC. Palbociclib treatment in older patients in real-world settings was associated with similar clinical benefit as in RCTs. PROSPERO REGISTRATION: CRD42023444195.

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.

Comparison of the prognostic value of eight nutrition-related tools in older patients with cancer: A prospective study.

OBJECTIVES: The primary objective of the present study was to evaluate and compare the ability of eight nutrition-related tools to predict 1-year mortality in older patients with cancer. DESIGN, SETTING AND PARTICIPANTS: We studied older patients with cancer from the ELCAPA cohort and who had been referred for a geriatric assessment at one of 14 participating geriatric oncology clinics in the greater Paris area of France between 2007 and 2018. MEASUREMENTS: The studied nutrition-related tools/markers were the body mass index (BMI), weight loss (WL) in the previous 6 months, the Mini Nutritional Assessment, the Geriatric Nutritional Risk Index (GNRI), the Prognostic Nutritional Index, the Glasgow Prognostic Score (GPS), the modified GPS, and the C-reactive protein/albumin ratio. RESULTS: A total of 1361 patients (median age: 81; males: 51%; metastatic cancer: 49%) were included in the analysis. Most of the tools showed a progressively increase in the mortality risk as the nutrition-related risk category worsened (overall p-values <0.02 for all) after adjustment for age, outpatient status, functional status, severe comorbidities, cognition, mood, cancer treatment strategy, tumour site, and tumour metastasis. All the models were discriminant, with a C-index ranging from 0.748 (for the BMI) to 0.762 (for the GPS). The concordance probability estimate ranged from 0.764 (WL) to 0.773 (GNRI and GPS)). CONCLUSION: After adjustment for relevant prognostic factors, all eight nutrition-related tools/markers were independently associated with 1-year mortality in older patients with cancer. Depending on the time or context of the GA, physicians do not always have the time or means to perform and assess all the tools/markers compared here. However, even when some information is missing, each nutritional tool/marker has prognostic value and can be used in the evaluation.

Disentangling the reasons why older adults do not readily participate in cancer trials: a socio-epidemiological mixed methods approach.

BACKGROUND: Few studies of the under-representation of older adults in cancer clinical trials (CTs) have encompassed the entire pathway from a trial being available in a cancer centre to the patient's invitation to participate and then agreement or refusal to participate. OBJECTIVES: The study's primary objective was to evaluate CT non-invitation and refusal rates. The secondary objectives were to identify factors associated with non-invitation and refusal and to assess experiences of CT participation from the patients' and professionals' perspectives. METHODS: Here, we used mixed methods and a socio-epidemiological approach to analyse reasons for the non-participation of eligible older patients with a solid cancer in cancer CTs in France. RESULTS: We found that non-invitation and low CT participation are mainly related to the patients' sociodemographic characteristics and living conditions (such as social isolation, being single, divorced or widowed, not having children and the absence of close family members) and the healthcare professionals' perceptions of insufficient informal support or a high homecare requirement. CONCLUSION: Our results suggest that efforts to increase fair inclusion and the participation of older adults in CTs should target the physician-patient relationship, the medical profession and hospital funding, rather than the patient alone.

Patient-Reported Outcomes in OlympiA: A Phase III, Randomized, Placebo-Controlled Trial of Adjuvant Olaparib in gBRCA1/2 Mutations and High-Risk Human Epidermal Growth Factor Receptor 2-Negative Early Breast Cancer.

PURPOSE: The OlympiA randomized phase III trial compared 1 year of olaparib (OL) or placebo (PL) as adjuvant therapy in patients with germline BRCA1/2, high-risk human epidermal growth factor receptor 2-negative early breast cancer after completing (neo)adjuvant chemotherapy ([N]ACT), surgery, and radiotherapy. The patient-reported outcome primary hypothesis was that OL-treated patients may experience greater fatigue during treatment. METHODS: Data were collected before random assignment, and at 6, 12, 18, and 24 months. The primary end point was fatigue, measured with the Functional Assessment of Chronic Illness Therapy-Fatigue scale. Secondary end points, assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, Core 30 item, included nausea and vomiting (NV), diarrhea, and multiple functional domains. Scores were compared between treatment groups using mixed model for repeated measures. Two-sided P values <.05 were statistically significant for the primary end point. All secondary end points were descriptive. RESULTS: One thousand five hundred and thirty-eight patients (NACT: 746, ACT: 792) contributed to the analysis. Fatigue severity was statistically significantly greater for OL versus PL, but not clinically meaningfully different by prespecified criteria (≥3 points) at 6 months (diff OL v PL: NACT: -1.3 [95% CI, -2.4 to -0.2]; P = .022; ACT: -1.3 [95% CI, -2.3 to -0.2]; P = .017) and 12 months (NACT: -1.6 [95% CI, -2.8 to -0.3]; P = .017; ACT: -1.3 [95% CI, -2.4 to -0.2]; P = .025). There were no significant differences in fatigue severity between treatment groups at 18 and 24 months. NV severity was worse in patients treated with OL compared with PL at 6 months (NACT: 6.0 [95% CI, 4.1 to 8.0]; ACT: 5.3 [95% CI, 3.4 to 7.2]) and 12 months (NACT: 6.4 [95% CI, 4.4 to 8.3]; ACT: 4.5 [95% CI, 2.8 to 6.1]). During treatment, there were some clinically meaningful differences between groups for other symptoms but not for function subscales or global health status. CONCLUSION: Treatment-emergent symptoms from OL were limited, generally resolving after treatment ended. OL- and PL-treated patients had similar functional scores, slowly improving during the 24 months after (N)ACT and there was no clinically meaningful persistence of fatigue severity in OL-treated patients.

First-line real-world treatment patterns and survival outcomes in women younger or older than 40 years with metastatic breast cancer in the real-life multicenter French ESME cohort.

AIM: To describe first-line treatment patterns, overall survival (OS) and real-world progression-free survival (rwPFS) in young women (<40) with metastatic breast cancer (mBC), as compared to women aged 40-69. MATERIALS AND METHODS: Data on adult women diagnosed with mBC (2008-2017) were extracted from the ESME mBC database (NCT03275311) which includes consecutive patients starting first-line metastatic treatment in one of the 18 French Comprehensive cancer centers. We reported first-line therapeutic strategy and prognostic factors of OS and rwPFS for women aged < 40 and 40-69. RESULTS: In total, 14,897 mBC women were included (1512 aged <40). HR+ /HER2- mBC was the most frequent subtype. First-line treatment differed between young patients and older ones for HR+ /HER2- and Triple Negative (TN) mBC. Median OS for women aged < 40 and 40-69, respectively, was 46.9 and 46.2 months for HR+ /HER2- mBC; 13.5 and 15.2 for TN mBC; and, 60.7 and 55.1 for HER2 + mBC. Median rwPFS under first line treatment was 11.6 and 11.9 months for HR+ /HER2- in women aged < 40 and 40-69, respectively; 5.5 and 5.9 for TN, and, 13.3 and 12.9 for HER2 + . Factors associated with shorter OS and rwPFS were similar for both women aged < 40 and 40-69 and included ≥ 3 metastatic sites, visceral metastases, and longer MFI, with time-varying effects observed for several prognostic factors. CONCLUSION: Young women presented more frequently with TN and HER2 + subtypes and aggressive mBC than women aged 40-69 did. Prognostic factors of OS and rwPFS were quite similar between age groups and mBC subtypes.

Assessing patient-reported outcomes (PROs) and patient-related outcomes in randomized cancer clinical trials for older adults: Results of DATECAN-ELDERLY initiative.

As older adults with cancer are underrepresented in randomized clinical trials (RCT), there is limited evidence on which to rely for treatment decisions for this population. Commonly used RCT endpoints for the assessment of treatment efficacy are more often tumor-centered (e.g., progression-free survival). These endpoints may not be as relevant for the older patients who present more often with comorbidities, non-cancer-related deaths, and treatment toxicity. Moreover, their expectation and preferences are likely to differ from younger adults. The DATECAN-ELDERLY initiative combines a broad expertise, in geriatric oncology and clinical research, with interest in cancer RCT that include older patients with cancer. In order to guide researchers and clinicians coordinating cancer RCT involving older patients with cancer, the experts reviewed the literature on relevant domains to assess using patient-reported outcomes (PRO) and patient-related outcomes, as well as available tools related to these domains. Domains considered relevant by the panel of experts when assessing treatment efficacy in RCT for older patients with cancer included functional autonomy, cognition, depression and nutrition. These were based on published guidelines from international societies and from regulatory authorities as well as minimum datasets recommended to collect in RCT including older adults with cancer. In addition, health-related quality of life, patients' symptoms, and satisfaction were also considered by the panel. With regards to tools for the assessment of these domains, we highlighted that each tool has its own strengths and limitations, and very few had been validated in older adults with cancer. Further studies are thus needed to validate these tools in this specific population and define the minimum clinically important difference to use when developing RCTs in this population. The selection of the most relevant tool should thus be guided by the RCT research question, together with the specific properties of the tool.

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.

Paclitaxel plus Eftilagimod Alpha, a Soluble LAG-3 Protein, in Metastatic, HR+ Breast Cancer: Results from AIPAC, a Randomized, Placebo Controlled Phase IIb Trial.

PURPOSE: Eftilagimod alpha (efti), a soluble lymphocyte activation gene (LAG-3) protein and MHC class II agonist, enhances innate and adaptive immunity. Active Immunotherapy PAClitaxel (AIPAC) evaluated safety and efficacy of efti plus paclitaxel in patients with predominantly endocrine-resistant, hormone receptor-positive, HER2-negative metastatic breast cancer (ET-resistant HR+ HER2- MBC). PATIENTS AND METHODS: Women with HR+ HER2- MBC were randomized 1:1 to weekly intravenous paclitaxel (80 mg/m2) and subcutaneous efti (30 mg) or placebo every 2 weeks for six 4-week cycles, then monthly subcutaneous efti (30 mg) or placebo maintenance. Primary endpoint was progression-free survival (PFS) by blinded independent central review. Secondary endpoints included overall survival (OS), safety/tolerability, pharmacokinetics/pharmacodynamics, and quality of life. Exploratory endpoints included cellular biomarkers. RESULTS: 114 patients received efti and 112 patients received placebo. Median age was 60 years (91.6% visceral disease, 84.1% ET-resistant, 44.2% with previous CDK4/6 inhibitor treatment). Median PFS at 7.3 months was similar for efti and placebo. Median OS was not significantly improved for efti (20.4 vs. 17.5 months; HR, 0.88; P = 0.197) but became significant for predefined exploratory subgroups. EORTC QLQC30-B23 global health status was sustained for efti but deteriorated for placebo. Efti increased absolute lymphocyte, monocyte and secondary target cell (CD4, CD8) counts, plasma IFNγ and CXCL10 levels. CONCLUSIONS: Although the primary endpoint, PFS, was not met, AIPAC confirmed expected pharmacodynamic effects and demonstrated excellent safety profile for efti. OS was not significantly improved globally (2.9-month difference), but was significantly improved in exploratory biomarker subgroups, warranting further studies to clarify efti's role in patients with ET-resistant HER2- MBC.

Impact of guideline adherence and expert center referral on the early management and outcomes of uterine sarcoma patients: A retrospective analysis from the French NETSARC network.

OBJECTIVE: Uterine sarcomas are rare tumors with a poor prognosis. Their diagnosis is often incidental, following surgery. Our goal was to examine the early management strategies for uterine sarcomas, and to assess the impact of guideline adherence and expert center referral on both the management approaches and the clinical outcomes in patients with uterine sarcomas. METHODS: We retrospectively analyzed medical records from patients with uterine sarcoma referred to the Institut Curie and registered in the database of the French NETSARC network. RESULTS: In total, 100 patients, with a median age of 54 years, were included in the analyses. On MRI scans (n = 36), all patients had at least two signs suggestive of malignancy, and 77.8 % had four or more signs. No preoperative biopsy was performed in 65.6 % of cases. Only 14.1 % of patients underwent initial surgery at an expert center. Surgery performed outside the network was significantly associated with morcellation (32.9 % vs. 0 %; p = 0.036), fewer negative margins (R0 margins 52.4 % vs. 100 %; p = 0.006), and poor adherence to surgical guidelines (28.3 vs. 72.7 %; p = 0.013). Multivariate analysis showed that non-adherence to surgical recommendations was not significantly associated with relapse-free survival (HR = 0.54; 95 % CI [0.21-1.38]), but was an independent predictor of poor overall survival (HR = 0.12; 95 % CI [0.03-0.52]; p = 0.005). CONCLUSION: Despite a high frequency of suspicious clinical and radiological signs, a large proportion of women undergoing sarcoma surgery are treated outside of expert networks. We provide guidelines, integrating the clinical context and radiological signs to encourage early referral to reference centers for sarcoma.

Radium-223 in women with hormone receptor-positive bone-metastatic breast cancer receiving endocrine therapy: pooled analysis of two international, phase 2, randomized, double-blind, placebo-controlled trials.

BACKGROUND: Most women with advanced breast cancer have skeletal metastases. Radium-223 is an alpha-emitting radionuclide that selectively targets areas of bone metastases. METHODS: Two double-blind, placebo-controlled studies of radium-223 were conducted in women with hormone receptor-positive (HR+), bone-predominant metastatic breast cancer. All patients received endocrine therapy (ET), as a single agent of the investigator's choice (Study A) or exemestane + everolimus (Study B). Patients were randomized to receive radium-223 (55 kBq/kg) or placebo intravenously every 4 weeks for six doses. Accrual was halted following unblinded interim analyses per protocol amendments, and both studies were terminated. We report pooled analyses of symptomatic skeletal event-free survival (SSE-FS; primary endpoint), radiologic progression-free survival (rPFS) and overall survival (OS; secondary), and time to bone alkaline phosphatase (ALP) progression (exploratory). RESULTS: In total, 382 patients were enrolled, and 196 SSE-FS events (70% planned total) were recorded. Hazard ratios (95% confidence intervals) and nominal p values for radium-223 + ET versus placebo + ET were: SSE-FS 0.809 (0.610-1.072), p = 0.1389; rPFS 0.956 (0.759-1.205), p = 0.7039; OS 0.889 (0.660-1.199), p = 0.4410; and time to bone ALP progression 0.593 (0.379-0.926), p = 0.0195. Radium-223- or placebo-related treatment-emergent adverse events were reported in 50.3% versus 35.1% of patients (grade 3/4: 25.7% vs. 8.5%), with fractures/bone-associated events in 23.5% versus 23.9%. CONCLUSIONS: In patients with HR+ bone-metastatic breast cancer, numeric differences favoring radium-223 + ET over placebo + ET for the primary SSE-FS endpoint were suggestive of efficacy, in line with the primary outcome measure used in the underlying phase 2 studies. No similar evidence of efficacy was observed for secondary progression or survival endpoints. Adverse events were more frequent with radium-223 + ET versus placebo + ET, but the safety profile of the combination was consistent with the safety profiles of the component drugs. Clinical trial registration numbers Study A: NCT02258464, registered October 7, 2014. Study B: NCT02258451, registered October 7, 2014.

Cancer mortality and competing causes of death in older adults with cancer: A prospective, multicentre cohort study (ELCAPA-19).

BACKGROUND: In older patients with cancer, comorbidities compete with cancer for cause of death. The objectives were to evaluate cancer mortality and factors associated, according to metastatic status. METHODS: Between 2007 and 2014, patients with cancer aged ≥70 referred for pre-therapeutic geriatric assessment (GA) were included through the ELCAPA prospective cohort study. The underlying cause of death was defined according to the International Classification of Diseases, 10th Revision. The World Health Organisation definition was used to categorise the cause of death as cancer versus another disease (e.g. cardiovascular disease, infectious disease, etc.) Competing risk models were used. RESULTS: Mean (SD) age of the 1445 included patients was 80.2 (5.8) and 48% were women. Most common tumour sites were colorectal (19%), breast (17%) and urinary (15%); 773 patients (49%) had metastases. After a 34-month median follow-up, 706 cancer deaths were observed among 843 deaths. The 6-month and 3-year cancer mortality rates (95% CI) were 12% (9-15) and 34% (29-38) for non-metastatic patients and 43% (39-47) and 79% (75-82) for metastatic patients, respectively. Dependency in activities of daily living and comorbidities were associated with 6-month and 3-year cancer mortality in non-metastatic (adjusted subhazard ratio [aSHR] = 1.68 [0.99-2.85] and 1.69 [1.16-2.45]; and 1.98 [1.08-3.63] and 3.38 [1.47-7.76], respectively) and metastatic patients (aSHR = 2.81 [2.01-3.93] and 2.95 [2.14-4.07]; and 1.63 [1.18-2.25] and 2.06 [1.39-3.05], respectively). Impaired Timed-Get-Up-and-Go test was associated with 6-month and 3-year cancer mortality in metastatic patients (aSHR = 1.5 [1.06-2.12] and 1.38 [1.06-1.81], respectively). Obesity was negatively associated with 3-year cancer death in non-metastatic (aSHR = 0.53 [0.29-0.97]) and metastatic patients (aSHR = 0.71 [0.51-1.00]). CONCLUSIONS: The majority of older adults with cancer referred for pre-therapeutic GA die from cancer. Geriatric parameters are independently associated with cancer mortality and should be considered for prognosis assessment, decision-making and care.

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.

Pertuzumab Plus Trastuzumab With or Without Chemotherapy Followed by Emtansine in ERBB2-Positive Metastatic Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial.

Importance: In ERBB2 (formerly HER2)-positive metastatic breast cancer (MBC), combining trastuzumab and pertuzumab with taxane-based chemotherapy is the first line of standard care. Given that trastuzumab plus pertuzumab was proven effective in ERBB2-positive MBC, even without chemotherapy, whether the optimal first-line strategy could be trastuzumab plus pertuzumab alone instead of with chemotherapy is unresolved. Objective: To assess overall survival (OS) at 2 years and progression-free survival (PFS) for patients randomly assigned to receive first-line pertuzumab plus trastuzumab alone or with chemotherapy followed by trastuzumab and emtansine at progression; PFS of second-line trastuzumab and emtansine treatment following trastuzumab plus pertuzumab; and OS and PFS in the ERBB2-enriched and ERBB2-nonenriched subtypes. Design, Setting, and Participants: This was a secondary analysis of a multicenter, open-label, phase 2 randomized clinical trial conducted at 27 sites in France, 20 sites in Switzerland, 9 sites in the Netherlands, and 1 site in Germany. Overall, 210 patients with centrally confirmed ERBB2-positive MBC were randomized between May 3, 2013, and January 4, 2016, with termination of the trial May 26, 2020. Data were analyzed from December 18, 2020, to May 10, 2022. Interventions: Patients randomly received pertuzumab (840 mg intravenously [IV], then 420 mg IV every 3 weeks) plus trastuzumab (8 mg/kg IV, then 6 mg/kg IV every 3 weeks) without chemotherapy (group A) or pertuzumab plus trastuzumab (same doses) with either paclitaxel (90 mg/m2 for days 1, 8, and 15, then every 4 weeks for ≥4 months) or vinorelbine tartrate (25 mg/m2 for first administration followed by 30 mg/m2 on days 1 and 8 and every 3 weeks for ≥4 months) followed by pertuzumab plus trastuzumab maintenance after chemotherapy discontinuation (group B). Main Outcomes and Measures: Overall survival at 24 months by treatment group, PFS for first-line treatment, PFS for second-line treatment, and patient-reported quality of life (QOL). Results: A total of 210 patients were included in the analysis, with a median age of 58 (range, 26-85) years. For group A, 24-month OS was 79.0% (90% CI, 71.4%-85.4%); for group B, 78.1% (90% CI, 70.4%-84.5%). Median PFS with first-line treatment was 8.4 (95% CI, 7.9-12.0) months in group A and 23.3 (95% CI, 18.9-33.1) months in group B. Unlike expectations, OS and PFS did not markedly differ between populations with ERBB2-enriched and ERBB2-nonenriched cancer. Adverse events were less common without chemotherapy, with small QOL improvements from baseline in group A and stable QOL in group B. Conclusions and Relevance: The findings of this secondary analysis of a randomized clinical trial suggest that the chemotherapy-free anti-ERBB2 strategy is feasible without being detrimental in terms of OS. The 50-gene prediction analysis of microarray signature could not help to identify the most appropriate patient population for this approach. Trial Registration: ClinicalTrials.gov Identifier: NCT01835236.

Systemic Therapy in Older Patients With High-Risk Disease.

Adjuvant systemic treatments for older patients with breast cancer require constant dose or schedule adjustments of standards established for younger ones. This is mainly due to frailty that increases according to age (40%-50% of signals in all comers after age 70 years) and remains difficult to spot or diagnose accurately and therefore is often overlooked. Older patients are at higher risk to develop side effects whether under chemotherapy, optimized endocrine treatment, or targeted therapies. Pharmacokinetic reflects poorly functional reserves that reduce with aging and is therefore misleading. The demonstration of significant long-term benefits provided by adjuvant treatments is challenged by life expectancy, driven by multimorbidity status that increases with age, competing with cancer outcome. When geriatric assessment is incorporated into the multidisciplinary team, treatment decision process shows 30%-50% changes, de-escalating initial age-agnostic treatment choices in two of three cases. Finally, expectations from treatment vary over the years: In older ones, although not being exclusive, there is a general shift of preference for protecting functionality, cognitive functions, and independence, as summarized in quality of life that many systemic adjuvant treatment may jeopardize. These provocative considerations show importance to pay more attention to expectations expressed by older patients to limit gaps between what is thought by health care professionals as right, often on the basis of dose intensity models strongly engrained in oncology and that older patients may assess counterintuitively differently. The most achieved molecular testing to identify high-risk luminal tumors should be combined with determinant geriatric factors to bring relevant global information in the adjuvant setting for older patients.

Real-world clinical and survival outcomes of patients with early relapsed triple-negative breast cancer from the ESME national cohort.

BACKGROUND: Early metastatic relapse of triple-negative breast cancer (mTNBC) after anthracyclins and/or taxanes based (A/T) primary treatment represents a highly aggressive cancer situation requiring urgent characterisation and handling. Epidemio-Strategy-Medico-Economical-Metastatic Breast Cancer (ESME-MBC) database, a multicenter, national, observational cohort (NCT03275311) provides recent data on this entity. METHODS: All ESME patients diagnosed between 2008 and 2020 with mTNBC occurring as a relapse after a systemic neoadjuvant/adjuvant taxane and/or anthracycline-based chemotherapy were included. Early relapses were defined by a metastatic diagnosis up to 12 months of the end of neo/adjuvant A/T chemotherapy. We assessed overall survival (OS) and progression-free-survival under first-line treatment (PFS1) by early versus late relapse (≥12 months). RESULTS: Patients with early relapse (N = 881, 46%) were younger and had a larger tumour burden at primary diagnosis than those with late relapses (N = 1045). Early relapse rates appeared stable over time. Median OS was 10.1 months (95% CI 9.3-10.9) in patients with early relapse versus 17.1 months (95% CI 15.7-18.2) in those with late relapse (adjusted hazard-ratio (aHR): 1.92 (95% CI 1.73-2.13); p < 0.001). The median PFS1 was respectively 3.1 months (95% CI 2.9-3.4) and 5.3 months (95% CI 5.1-5.8); (aHR: 1.66; [95% CI 1.50-1.83]; p < 0.001). Among early relapsed patients, a higher number of metastatic sites, visceral disease but not treatment types, were independently associated with a poorer OS. CONCLUSION: These real-world data provide strong evidence on the dismal prognosis, higher treatment resistance and major unmet medical need associated with early relapsed mTNBC. Database registration: clinicaltrials.gov Identifier NCT032753.

Diagnostic effectiveness of [18F]Fluoroestradiol PET/CT in oestrogen receptor-positive breast cancer: the key role of histopathology. Evidence from an international multicentre prospective study.

INTRODUCTION: [18F]Fluoroestradiol ([18F]FES) PET/CT has been proposed as a tool for detecting the oestrogen receptor density in patients with metastatic breast cancer (BC) non-invasively across all disease localizations. However, its diagnostic potential in terms of the detection rate (DR) of metastases is unclear. In this study, we pitted this method against [18F]FDG PET/CT and tried to identify predictors of the diagnostic superiority of the [18F] FES-based method. MATERIALS AND METHODS: From a multicentre database, we enrolled all patients with metastatic BC who had undergone both [18F]FES PET/CT and [18F]FDG PET/CT. Two readers assessed both images independently and used a patient-based (PBA) and lesion-based analysis (LBA) to calculate the DR. Pathology-related and clinical factors were tested as predictors of [18F]FES PET/CT superiority using a multivariate model. RESULTS: 92 patients, bearing a total of 2678 metastases, were enrolled. On PBA, the DR of [18F]FDG and [18F]FES PET/CT was 97% and 86%, respectively (p = 0.018). On LBA, the [18F]FES method proved more sensitive than [18F]FDG PET/CT in lymph nodes, bone, lung and soft tissue (p < 0.01). This greater sensitivity was associated with lobular histology, both on PBA (Odds Ratio (OR) 3.4, 95%CI 1.0-12.3) and on LBA (OR 4.4, 95%CI 1.2-16.1 for lymph node metastases and OR 3.29, 95%CI 1.1-10.2 for bone localizations). CONCLUSIONS: The overall DR of [18F]FES PET/CT appears to be lower than that of [18F]FDG PET/CT on PBA. However, the [18F]FES method, if positive, can identify more lesions than [18F]FDG at most sites. The higher sensitivity of [18F]FES PET/CT was associated with lobular histology.

Evolution of synchronous female bilateral breast cancers and response to treatment.

Synchronous bilateral breast cancer (sBBC) occurs after both breasts have been affected by the same germline genetics and environmental exposures. Little evidence exists regarding immune infiltration and response to treatment in sBBCs. Here we show that the impact of the subtype of breast cancer on levels of tumor infiltrating lymphocytes (TILs, n = 277) and on pathologic complete response (pCR) rates (n = 140) differed according to the concordant or discordant subtype of breast cancer of the contralateral tumor: luminal breast tumors with a discordant contralateral tumor had higher TIL levels and higher pCR rates than those with a concordant contralateral tumor. Tumor sequencing revealed that left and right tumors (n = 20) were independent regarding somatic mutations, copy number alterations and clonal phylogeny, whereas primary tumor and residual disease were closely related both from the somatic mutation and from the transcriptomic point of view. Our study indicates that tumor-intrinsic characteristics may have a role in the association of tumor immunity and pCR and demonstrates that the characteristics of the contralateral tumor are also associated with immune infiltration and response to treatment.