Tucatinib Combination Treatment After Trastuzumab-Deruxtecan in Patients With ERBB2-Positive Metastatic Breast Cancer.

Importance: Little is known regarding the outcomes associated with tucatinib combined with trastuzumab and capecitabine (TTC) after trastuzumab-deruxtecan exposure among patients with ERBB2 (previously HER2)-positive metastatic breast cancer (MBC). Objective: To investigate outcomes following TTC treatment in patients with ERBB2-positive MBC who had previously received trastuzumab-deruxtecan. Design, Setting, and Participants: This cohort study included all patients with MBC who were treated in 12 French comprehensive cancer centers between August 1, 2020, and December 31, 2022. Exposure: Tucatinib combined with trastuzumab and capecitabine administered at the recommended dose. Main Outcomes and Measures: Clinical end points included progression-free survival (PFS), time to next treatment (TTNT), overall survival (OS), and overall response rate (ORR). Results: A total of 101 patients with MBC were included (median age, 56 [range, 31-85] years). The median number of prior treatment lines for metastatic disease at TTC treatment initiation was 4 (range, 2-15), including 82 patients (81.2%) with previous trastuzumab and/or pertuzumab and 94 (93.1%) with previous ado-trastuzumab-emtansine) exposure. The median duration of trastuzumab-deruxtecan treatment was 8.9 (range, 1.4-25.8) months, and 82 patients (81.2%) had disease progression during trastuzumab-deruxtecan treatment, whereas 18 (17.8%) had stopped trastuzumab-deruxtecan for toxic effects and 1 (1.0%) for other reasons. Tucatinib combined with trastuzumab and capecitabine was provided as a third- or fourth-line treatment in 37 patients (36.6%) and was the immediate treatment after trastuzumab-deruxtecan in 86 (85.1%). With a median follow-up of 11.6 (95% CI, 10.5-13.4) months, 76 of 101 patients (75.2%) stopped TTC treatment due to disease progression. The median PFS was 4.7 (95% CI, 3.9-5.6) months; median TTNT, 5.2 (95% CI, 4.5-7.0) months; and median OS, 13.4 (95% CI, 11.1 to not reached [NR]) months. Patients who received TTC immediately after trastuzumab-deruxtecan had a median PFS of 5.0 (95% CI, 4.2-6.0) months; median TTNT of 5.5 (95% CI, 4.8-7.2) months, and median OS of 13.4 (95% CI, 11.9-NR) months. Those who received TTC due to trastuzumab-deruxtecan toxicity-related discontinuation had a median PFS of 7.3 (95% CI, 3.0-NR) months. Best ORR was 29 of 89 patients (32.6%). Sixteen patients with active brain metastasis had a median PFS of 4.7 (95% CI, 3.0-7.3) months, median TTNT of 5.6 (95% CI, 4.4 to NR), and median OS of 12.4 (95% CI, 8.3-NR) months. Conclusions and Relevance: In this study, TTC therapy was associated with clinically meaningful outcomes in patients with ERBB2-positive MBC after previous trastuzumab-deruxtecan treatment, including those with brain metastases. Prospective data on optimal drug sequencing in this rapidly changing therapeutic landscape are needed.

Plasma-based analysis of ERBB2 mutational status by multiplex digital PCR in a large series of patients with metastatic breast cancer.

Erb-b2 receptor tyrosine kinase 2 (ERBB2)-activating mutations are therapeutically actionable alterations found in various cancers, including metastatic breast cancer (MBC). We developed multiplex digital PCR assays to detect and quantify ERBB2 mutations in circulating tumor DNA from liquid biopsies. We studied the plasma from 272 patients with hormone-receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) MBC to detect 17 ERBB2 mutations using a screening assay. The assay was developed on the three-color Crystal dPCR™ naica® platform with a two-step strategy for precise mutation identification. We found that nine patients (3.3%) harbored at least one ERBB2 mutation. The mutation rate was higher in patients with lobular histology (5.9%) compared to invasive breast carcinoma of no special type (2.6%). A total of 12 mutations were found with the following frequencies: L755S (25.00%), V777L (25.00%), S310Y (16.67%), L869R (16.67%), S310F (8.33%), and D769H (8.33%). Matched tumor samples from six patients identified the same mutations with an 83% concordance rate. In summary, our highly sensitive multiplex digital PCR assays are well suited for plasma-based monitoring of ERBB2 mutational status in patients with MBC.

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.

Management of trophoblastic tumors : review of evidence, current practice, and future directions.

INTRODUCTION: Gestational trophoblastic neoplasia (GTN) is a group of rare tumors characterized by abnormal trophoblastic proliferation following pregnancy including invasive moles, choriocarcinomas, and intermediate trophoblastic tumors (ITT). Although the treatment and follow-up of GTN has been heterogeneous, globally the emergence of expert networks has helped to harmonize its management. AREAS COVERED: We provide an overview of the current knowledge, diagnosis, and management strategies in GTN and discuss innovative therapeutic options under investigation. While chemotherapy has been the historical backbone of GTN treatment, promising drugs such as immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway and anti-angiogenic tyrosine kinase inhibitors are currently being investigated remodeling the therapeutical landscape of trophoblastic tumors. EXPERT OPINION: Chemotherapy regimens for GTN have potential long-term effects on fertility and quality of life, making innovative and less toxic therapeutic approaches necessary. Immune checkpoint inhibitors have shown promise in reversing immune tolerance in GTN and have been evaluated in several trials. However, immunotherapy is associated with rare but life-threatening adverse events and evidence of immune-related infertility in mice, highlighting the need for further research and careful consideration of its use. Innovative biomarkers could help personalize GTN treatments and reduce chemotherapy burden in some patients.

Development of sensitive and robust multiplex digital PCR assays for the detection of ESR1 mutations in the plasma of metastatic breast cancer patients.

BACKGROUND: Early detection of ESR1 mutations is a key element for better personalization of the management of patients with HR+/HER2- Metastatic Breast Cancer (MBC). Analysis of circulating tumor DNA from liquid biopsies is a particularly well-suited strategy for longitudinal monitoring of such patients. MATERIALS AND METHODS: Using the naica® three-color digital PCR platform, we developed a screening assay allowing the detection of 11 ESR1 mutations and designed a sequential strategy for precise mutation identification. We then applied this strategy in the analysis of plasma circulating cell-free DNA from 109 HR+/HER2- MBC patients and performed a double-blind comparison study on a subset of patients with the multiplex assay used at the Institut Curie (IC) for the PADA-1 study. RESULTS: Thirty-one patients (28.4%) harboured at least one ESR1 mutation, with the following frequencies: D538G (41.03%), Y537S (25.64%), E380Q (10.26%), Y537N (10.26%), "(536-540)" (7.69%), Y537C (2.56%), and L536R (2.56%). The presence of ESR1 mutation(s) was significantly associated with liver metastases (p = 0.0091). A very good agreement (91%) was observed with the IC assay. CONCLUSION: Our assays have proven to be robust and highly sensitive and are very well-suited for monitoring ESR1 mutations in the plasma of MBC patients.

Olaparib First-Line Maintenance Monotherapy in BRCA-Mutated Epithelial Ovarian Cancer: Descriptive Analysis of the First French Real-World Data Study.

BACKGROUND: Olaparib, a poly(ADP-ribose) polymerase inhibitor, was approved by the European Commission in June 2019, following the results of the SOLO-1/GOG 3004 trial as maintenance monotherapy in adult patients with BRCA-mutated epithelial ovarian cancer. OBJECTIVE: This study aimed to provide a descriptive analysis of the first real-world data from patients with BRCA-mutated ovarian cancer who received olaparib as first-line maintenance monotherapy in the French cohort Temporary Authorisation for Use (Autorisation Temporaire d'Utilisation de cohorte, ATUc) programme from 11 March, 2019 to 16 January, 2020. METHODS: Eligible patients were aged 18 years and over with confirmed epithelial ovarian, primary peritoneal or Fallopian tube cancer and a deleterious or suspected deleterious germline or somatic BRCA 1/2 mutation. Patients were in complete or partial clinical response at the end of first-line platinum-based chemotherapy. Olaparib maintenance therapy was initiated within 8 weeks of the patients' last dose of chemotherapy. Real-world data were collected through treatment access request forms completed by physicians. Clinical and safety data were collected monthly until the end of the ATUc programme. RESULTS: A total of 107 centres in metropolitan France and the French Overseas Departments and Territories requested the inclusion for 238 patients, of whom 194 received maintenance olaparib. In total, 87.6% of the primary tumour locations were ovary, the most common histology was high-grade serous (93.0%) and the most common International Federation of Gynaecology and Obstetrics (Fédération Internationale de Gynécologie et d'Obstétrique) stage was IIIC (56.8%). BRCA testing was performed in routine practice, prior to inclusion into the ATUc programme. All patients had a BRCA mutation: 52.5% had a somatic mutation, 38.4% had a germinal mutation and 9.1% had germinal and somatic mutations. Twenty-four (12%) patients experienced serious adverse drug reactions at the last safety follow-up (17 February, 2020). The most common were anaemia (12 [6%] patients), neutropenia (3 [2%] patients) and thrombocytopenia (3 [2%] patients). CONCLUSIONS: The rapid enrolment into the ATUc programme highlighted the strong unmet need for patients with ovarian cancer and a BRCA mutation in first-line maintenance treatment. Olaparib was well tolerated and no new safety signals were observed in this real-world patient population.

Adjuvant Endocrine Therapy in Premenopausal Breast Cancer: 12-Year Results From SOFT.

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.The Suppression of Ovarian Function Trial (SOFT; ClinicalTrials.gov identifier: NCT00066690) randomly assigned premenopausal women with hormone receptor-positive breast cancer to 5 years of adjuvant tamoxifen, tamoxifen plus ovarian function suppression (OFS), or exemestane plus OFS. The primary analysis compared disease-free survival (DFS) between tamoxifen plus OFS versus tamoxifen alone; exemestane plus OFS versus tamoxifen was a secondary objective. After 8 years, SOFT reported a significant reduction in recurrence and improved overall survival (OS) with adjuvant tamoxifen plus OFS versus tamoxifen alone. Here, we report outcomes after median follow-up of 12 years. DFS remained significantly improved with tamoxifen plus OFS versus tamoxifen (hazard ratio, 0.82; 95% CI, 0.69 to 0.98) with a 12-year DFS of 71.9% with tamoxifen, 76.1% with tamoxifen plus OFS, and 79.0% with exemestane plus OFS. OS was improved with tamoxifen plus OFS versus tamoxifen (hazard ratio, 0.78; 95% CI, 0.60 to 1.01) and was 86.8% with tamoxifen, 89.0% with tamoxifen plus OFS, and 89.4% with exemestane plus OFS at 12 years. Among those who received prior chemotherapy for human epidermal growth factor receptor-2-negative tumors, OS was 78.8% with tamoxifen, 81.1% with tamoxifen plus OFS, and 84.4% with exemestane plus OFS. In conclusion, after 12 years, there remains a benefit from including OFS in adjuvant endocrine therapy, with an absolute improvement in OS more apparent with higher baseline risk of recurrence.[Media: see text].

Safety and efficacy of nivolumab, an anti-PD1 immunotherapy, in patients with advanced basal cell carcinoma, after failure or intolerance to sonic Hedgehog inhibitors: UNICANCER AcSé NIVOLUMAB trial.

BACKGROUND: Basal cell carcinoma (BCC) is the most common human malignancy. In most cases, BCC has slow progression and can be definitively cured by surgery or radiotherapy. However, in rare cases, it can become locally advanced or, even more rarely, metastatic. The alternative recommended treatments are Sonic Hedgehog pathway inhibitors; however, the response is often short-lived. METHODS: This was a phase 2 basket study (NCT03012581) evaluating the efficacy and safety of nivolumab in a cohort of 32 advanced BCC patients, enrolled after failure of Sonic Hedgehog inhibitors, including 29 laBCC (91%) and 3 mBCC (9%). RESULTS: Compared to previously published studies, our population consisted of severe patients with a poor prognosis because they had already received multiple lines of treatment: all patients received previous Sonic Hedgehog inhibitors, 53% of patients already had chemotherapy and 75% radiotherapy. At 12 weeks, we reported 3.1% of complete responses, 18.8% of partial responses, and 43.8% of stable diseases. The best response rate to nivolumab reached 12.5% of complete responses (four patients), 18.8% of partial responses (three patients), and 43.8% of stable diseases (14 patients). Adverse events (AE) were mostly grade 2 or 3, slightly different to the adverse events observed in the treatment of metastatic melanoma (higher rate of diabetes, no thyroid dysfunction). CONCLUSION: Nivolumab is a relevant therapeutic option for patients with advanced relapsing/refractory BCC.

Selective internal radiation therapy in older patients with hepatocellular carcinoma: a retrospective analysis.

BACKGROUND: Selective internal radiation therapy (SIRT) is applied to hepatocellular carcinoma (HCC), a disease with increased incidence in the elderly. However, SIRT has rarely been specifically studied in elderly population. The aim of this study was to investigate efficacy and safety of SIRT in elderly HCC patients. METHODS: We studied retrospectively data from patients treated with SIRT for HCC. Clinical and laboratory data were retrieved. We used 70-years old as threshold between younger and elderly populations, to compare outcomes. RESULTS: A total of 222 patients treated with SIRT for HCC were studied, of which 134 patients were younger and 88 older. Median overall survival (OS) was not significantly different between younger and elderly group: 15.6 months (95% CI, 11.7-19.5) and 14.8 months (95% CI, 9.4-20.3) (P = 0.86). Age was not associated with OS in multivariable analysis, with a Hazard ratio of 1.09 (95% CI, 0.82-1.45, P = 0.55). Results of progression-free survival and responses were also similar in both groups. Toxicities were similar between the two groups, including the occurrence of radioembolization-induced liver disease (11.5 vs. 11.4%, P = 0.97). CONCLUSION: SIRT appears to be a well-tolerated treatment with the same efficacy in elderly compared to younger patients in HCC. Our study is the first to study its impact with glass microspheres. This warrants confirmation in large prospective studies.

Progression-free survival on endocrine therapy, before or after chemotherapy, in hormone receptor-positive HER2-negative metastatic breast cancer.

PURPOSE: A major question when treating HR+/HER2- metastatic breast cancer (MBC) is whether early introduction of chemotherapy (CT) increases endocrine resistance. We aimed to describe progression-free survival (PFS) under first endocrine therapy (ET) depending on whether given before or after CT in a large nationwide cohort, in the pre-CDK era. METHODS: The real-life retrospective ESME database includes all patients with MBC whose first-line treatment was initiated between 2008 and 2014 in one of the 18 French Comprehensive Cancer Centres. Our primary objective was to compare PFS from start of first ET in patients with HR+/HER2- MBC who received ET or CT first. RESULTS: We identified 6293 patients who received at least one ET line during their first two therapeutic lines for MBC. As first-line therapy, 3832 (60.9%) received ET alone (ET1 1st group), whilst 2461 (39.1%) received CT, including 2024 patients (32.2%) with maintenance ET after CT (ET1 after CT group). Median PFS under first ET was 12.4 months (95% CI 11.9-13.1) in ET 1st group vs. 12.6 months in ET1 after CT group (95% CI 12.1-13.4), HR 0.96 (95% CI 0.90-1.01, P = 0.1277). CONCLUSIONS: PFS under first ET appears identical whether prescribed before or after chemotherapy. These data suggest chemotherapy does not promote endocrine resistance.

Refining Therapy in Patients with HER2-Positive Breast Cancer with Central Nervous System Metastasis.

Background: Brain metastasis (BM) is a major clinical problem in metastatic breast cancer (MBC), occurring in 50% of patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer. Historically omitted from clinical trials, recent studies of novel HER2-targeted agents have focused on HER2+ BM patients, addressing stable but also progressing BM and leptomeningeal carcinomatosis (LMC). Summary: This review aimed to summarize the most relevant data on treating patients with HER2+ BM and LMC. Key Messages: The treatment paradigm for patients with HER2+ MBC has changed. Local therapies play an important role, but accumulating evidence on the intracranial activity and clinical benefit of anti-HER2 targeting therapies might lead to a shift in the paradigm on treating BM in the next few years towards more widespread use of systemic therapy.

Development of multiplex digital PCR assays for the detection of PIK3CA mutations in the plasma of metastatic breast cancer patients.

With the approval of new therapies targeting the PI3K pathway, the detection of PIK3CA mutations has become a key factor in treatment management for HR+/HER2- metastatic breast cancer (MBC). We developed multiplex digital PCR (dPCR) assays to detect and quantify PIK3CA mutations. A first screening assay allows the detection of 21 mutations, with a drop-off system targeting the 542-546 hotspot mutations combined with the simultaneous detection of N345K, C420R, H1047L and H1047R mutations. In the case of a positive result, a sequential strategy based on other assays that we have developped allows for precise mutation identification. Clinical validity was determined by analyzing plasma circulating free DNA (cfDNA) from 213 HR+/HER2- MBC samples, as well as DNA extracted from 97 available matched tumors from 89 patients. Our assays have shown reliable specificity, accuracy and reproducibility, with limits of blank of three and four droplets for the screening assay. Sixty-eight patients (32%) had at least one PIK3CA mutation detectable in their plasma, and we obtained 83.1% agreement between the cfDNA analysis and the corresponding tumors. The high sensitivity and robustness of these new dPCR assays make them well-suited for rapid and cost-effective detection of PIK3CA mutations in the plasma of MBC patients.

The role of tyrosine kinase inhibitors in the treatment of HER2+ metastatic breast cancer.

The introduction of trastuzumab and other subsequent human epidermal growth factor receptor 2 (HER2)-targeted therapies dramatically shifted the treatment landscape of HER2+ breast cancer, changing the natural history of the disease. There is no standard-of-care for patients with HER2+ metastatic breast cancer (MBC) in third and later lines of treatment; however, continued use of anti-HER2 therapies is recommended. Small-molecule tyrosine kinase inhibitors (TKIs) that target HER2 and other HER family receptors play a central role in this setting. TKIs have demonstrated various degrees of efficacy against central nervous system (CNS) metastases, which are a major clinical challenge for patients with HER2+ MBC. The TKIs lapatinib, neratinib, and tucatinib have received regulatory approval for the treatment of HER2+ MBC, while pyrotinib and afatinib have been evaluated in this setting. These TKIs vary by molecular weight, HER protein specificity and reversibility of binding and in turn have unique safety profiles. Toxicities reported in clinical trials of TKIs in HER2+ MBC that may require specific management strategies include diarrhoea, palmar-plantar erythrodysesthesia syndrome and rash. Here, we review the efficacy data, including CNS activity, and the safety profiles of the TKIs, and we provide guidance on adverse event management. Finally, we discuss how to incorporate the TKIs into the HER2+ MBC treatment algorithm.

Impact of EPclin on adjuvant therapeutic decision making and comparison of EPclin to the PREDICT tool.

PURPOSE: Genomic signatures, such as EndoPredict®, may help clinicians to decide which adjuvant treatment is the most appropriate. METHODS: We propose the EndoPredict® assay for unclear cases of adjuvant treatment in patients treated in our comprehensive cancer center. We prospectively and retrospectively report the decision of adjuvant treatment before and after the EndoPredict® assay, respectively, compared to the PREDICT's tool scores. RESULTS: From November 2016 to March 2019, 159 breast cancer tumors were analyzed and presented before and after the EndoPredict® assay. Before the EndoPredict® results, clinicians recommended chemotherapy for 57 patients (57/159, 36%). A total of 108 patients (108/159, 68%) were classified as EPclin high-risk score. There was only a slight agreement between clinicians' decisions and EPclin risk score. The EPclin score led to 37% changes in treatment (59/159); chemotherapy was favored in 80% of cases (47/59). The PREDICT tool recommended chemotherapy for 16 high-risk patients (16/159, 10%). CONCLUSION: Although genomic tests were developed in order to de-escalate adjuvant treatment, in our comprehensive cancer center the use of the EndoPredict® assay led to an increase in prescribed chemotherapy.

EpCAM-independent isolation of circulating tumor cells with epithelial-to-mesenchymal transition and cancer stem cell phenotypes using ApoStream® in patients with breast cancer treated with primary systemic therapy.

BACKGROUND: Tumor cells with a mesenchymal phenotype and/or cancer stem-like cells (CSCs) are known to contribute to metastasis and drug resistance. Circulating tumor cells (CTCs) undergoing epithelial-mesenchymal transition (EMT) and CTCs reflecting a dedifferentiated CSC phenotype may not be detected using only an anti-EpCAM antibody to capture them. We used an antibody-independent CTC enrichment platform, ApoStream®, which does not rely on any antibody, including anti-EpCAM, to capture EMT- and CSC-CTCs in breast cancer patients who received neoadjuvant chemotherapy and correlated them to pathological complete response (pCR). METHODS: Blood samples from newly diagnosed breast cancer patients were prospectively collected before neoadjuvant chemotherapy (T0), after chemotherapy but before surgery (T1), and after surgery (T2) and processed using ApoStream. CTCs detected were stained with additional markers to define 3 CTC subsets with the following phenotypes: epithelial CTCs (CK+, EpCAM+ or E-cadherin+), EMT-CTCs (ß-catenin+ or vimentin+), and CSC-CTCs (CD44+ and CD24low). RESULTS: We enrolled 55 patients, 47 of which had data for analysis. EMT-CTCs were detected in 57%, 62%, and 72% and CSC-CTCs in 9%, 22%, and 19% at the T0, T1, and T2 time points, respectively. Counts of epithelial (P = 0.225) and EMT (P = 0.522) phenotypes of CTCs at T0 did not significantly predict pCR. Moreover, no correlation between CTC count change and pCR was demonstrated. CONCLUSIONS: ApoStream was successful in detecting EMT-CTCs among patients after neoadjuvant chemotherapy. However, EMT-/CSC-CTC counts did not correlate with pCR. Due to the small sample size and heterogeneity of this patient population, further study in a larger cohort of molecularly homogeneous patients is warranted.

UCBG 2-04: Long-term results of the PACS 04 trial evaluating adjuvant epirubicin plus docetaxel in node-positive breast cancer and trastuzumab in the human epidermal growth factor receptor 2-positive subgroup.

PURPOSE: We conducted a double-randomised phase III trial to evaluate a concomitant taxane-anthracycline regimen in node-positive breast cancer and the efficacy of trastuzumab in the human epidermal growth factor receptor 2 (HER2)-positive subpopulation. METHODS: A total of 3010 patients with node-positive breast cancer were randomly assigned to receive 6 cycles of 500 mg/m2 of fluorouracil, 100 mg/m2 of epirubicin and 500 mg/m2 of cyclophosphamide (FEC) or 75 mg/m2 of epirubicin and 75 mg/m2 of docetaxel (ED). Patients with HER2-positive tumours were secondary randomly assigned to either trastuzumab or observation. The primary end-point was disease-free survival (DFS) in the two chemotherapy arms. RESULTS: After a 115-month median follow-up, DFS was not significantly better in the ED arm (DFS: 70%, 95% confidence interval [CI]: 67-72) than in the FEC arm (DFS: 68%, 95% CI: 65-70; hazard ratio [HR] = 0.88, 95% CI: 0.77-1.01; p = 0.064). The OS was not different between FEC (OS: 80%, 95% CI: 78-83) and ED (OS: 81%, 95% CI: 79-83); HR = 0.97, 95% CI: 0.81-1.16; p = 0.729). ED appeared more toxic. In the 528 HER2-positive subset, there was trend for a higher DFS, in the intention-to-treat population, in the trastuzumab arm (DFS: 68%, 95% CI: 61-74) than in the observation arm (DFS: 60%, 95% CI: 54-66; HR = 0.77, 95% CI: 0.57-1.03; p = 0.079). In the per-protocol population, DFS was significantly higher in the trastuzumab arm (DFS: 70%, 95% CI: 63-76) than in the observation arm (DFS: 59%, 95% CI: 53-65; HR = 0.69, 95% CI: 0.51-0.94; p = 0.0156). The OS was not different between these 2 arms. CONCLUSION: This study did not show superiority of the concomitant anthracycline-taxane arm which was more toxic in high-risk node-positive breast cancer patients. Long-term results of the HER2-positive subpopulation are in line with those of the other adjuvant trastuzumab trials but quantitatively less pronounced mostly because of lack of power.

Therapeutic innovations in breast cancer.

Managing endocrine resistance and resistance to endocrine therapy for ER+ HER2- breast cancer with the CDK 4/6 inhibitors in the metastatic setting. New antibodies drug conjugates for HER2+ and TNBC. Targeting DNA damage and synthetic lethality strategies with PARP inhibitors for breast cancer patients harboring BRCA mutation. Immunotherapies in 1st line metastatic setting of TNBC.