Mutant p53 stabilized by heat shock protein 90 (HSP90) is a novel target in oncology. The open-label, randomized phase II GANNET53 trial is the first to evaluate the HSP90 inhibitor ganetespib (G) with paclitaxel (P) in platinum-resistant epithelial ovarian cancer (EUDRACT 2013-003868-31; EU FP7 #602602).

Green tea extract was tested for the secondary prevention of colorectal adenoma in the placebo-controlled MIRACLE trial. Genome-wide screening on adenoma recurrence was performed in n = 550 participants 3 years after randomization to green tea or placebo intake.

The prostate-specific membrane antigen (PSMA)-targeted radioligand [¹⁷⁷Lu]Lu-PSMA-617 is a new standard treatment for metastatic castration-resistant prostate cancer (mCRPC), but predictive genomic biomarkers informing its rational use are unknown. We performed detailed dissection of prostate cancer driver genes across 290 serial plasma cell-free DNA samples from 180 molecular imaging-selected patients with mCRPC from the randomized TheraP trial of [¹⁷⁷Lu]Lu-PSMA-617 (n = 97) versus cabazitaxel chemotherapy (n = 83). The primary endpoint was PSA50 biochemical response, with secondary endpoints of progression-free survival (PFS) and overall survival (OS). In this post-hoc biomarker analysis, a low pretreatment circulating tumor DNA (ctDNA) fraction predicted a superior biochemical response (100% versus 58%, P = 0.0067) and PFS (median 14.7 versus 6.0 months; hazard ratio 0.12, P = 2.5 × 10-4) on [¹⁷⁷Lu]Lu-PSMA-617 independent of predictive PSMA-positron emission tomography imaging parameters, although this benefit did not extend to OS. Deleterious PTEN alterations were associated with worse PFS and OS on cabazitaxel, whereas ATM defects were observed in select patients with favorable [¹⁷⁷Lu]Lu-PSMA-617 outcomes. Comparing pretreatment and progression ctDNA revealed population flux but no evidence that alterations in individual mCRPC genes (or FOLH1) are dominant causes of acquired [¹⁷⁷Lu]Lu-PSMA-617 or cabazitaxel resistance. Our results nominate new candidate biomarkers for [¹⁷⁷Lu]Lu-PSMA-617 selection and ultimately expand the mCRPC predictive biomarker repertoire. We anticipate our ctDNA fraction-aware analytical framework will aid future precision management strategies for [¹⁷⁷Lu]Lu-PSMA-617 and other PSMA-targeted therapeutics. ClinicalTrials.gov identifier: NCT03392428 .

Larotrectinib is a first-in-class, highly selective tropomyosin receptor kinase (TRK) inhibitor approved for tumour-agnostic use in patients with TRK fusion cancer. Data on treatment-naïve adult and paediatric patients or the subset of treatment-naïve paediatric patients who discontinued larotrectinib after surgery or achieving durable clinical benefit are unknown.

In the INTRIGUE phase III trial (ClinicalTrials.gov identifier: NCT03673501), adult patients with advanced gastrointestinal stromal tumor previously treated with imatinib were randomly assigned 1:1 to ripretinib 150 mg once daily or sunitinib 50 mg once daily (4 weeks on/2 weeks off). In the primary analysis, overall survival (OS) was immature. In this study, we report the final planned analysis of OS (key secondary end point), progression-free survival (PFS) on third-line therapy (second PFS; prespecified exploratory end point), and long-term safety. Final OS analysis was prespecified to occur with approximately 200 and ≥145 events in the overall and KIT exon 11 intention-to-treat (ITT) populations, respectively. As of March 15, 2023, there were 211 and 151 OS events in the overall ITT and KIT exon 11 ITT populations, respectively. Median OS was similar between second-line ripretinib and sunitinib in both populations (overall, 35.5 v 31.5 months; KIT exon 11, 35.5 v 32.8 months). Median second PFS (on third-line therapy) for the overall ITT population was similar between the ripretinib and sunitinib arms (7.7 v 7.4 months). Safety was consistent with the primary analysis. OS from this analysis was similar between arms, and second PFS suggests that receiving ripretinib did not adversely affect the PFS of third-line therapy.

Ovarian cancer is among the most lethal malignancies in women. The advent of PARP inhibitors (PARPi) has improved outcomes. However, treatment-related toxicity remains a critical challenge, impacting patient quality of life and treatment adherence.

After the global approval of atezolizumab plus bevacizumab and chemotherapy as first-line metastatic nonsquamous non-small-cell lung cancer (nsqNSCLC) treatment, the IMpower151 ( NCT04194203 ) trial was conducted in China to address regional differences. Chemotherapy-naive patients with metastatic nsqNSCLC (N = 305) were randomized 1:1 to receive either atezolizumab, bevacizumab, carboplatin and paclitaxel or pemetrexed (ABCPem/Pac; n = 152) or placebo plus bevacizumab, carboplatin and pemetrexed or paclitaxel (BCPem/Pac; n = 153). The primary endpoint was investigator-assessed progression-free survival (INV-PFS); secondary endpoints included subgroup analyses of INV-PFS, independent review facility-assessed PFS, overall survival, and investigator-assessed objective response rate and duration of response per RECIST v.1.1. Most patients (97%) received pemetrexed, and 53% had EGFR+ tumors. Median INV-PFS for ABCPem/Pac versus BCPem/Pac was 9.5 versus 7.1 months (stratified hazard ratio: 0.84; 95% confidence interval: 0.65, 1.09; P = 0.184). INV-PFS across subgroups and independent review facility-assessed PFS were consistent with INV-PFS in the intention-to-treat population. Median overall survival was 20.7 versus 18.7 months in the ABCPem/Pac versus BCPem/Pac arms, respectively (stratified hazard ratio: 0.93; 95% confidence interval: 0.67, 1.28). Confirmed objective response rate with ABCPem/Pac versus BCPem/Pac was 48% versus 50%, respectively; median duration of response was 11.3 versus 8.3 months. Adverse events of special interest for atezolizumab were observed in 68% (grades 3 and 4: 11%) and 71% (grades 3 and 4: 7%) of patients receiving ABCPem/Pac and BCPem/Pac, respectively. The most common adverse events of special interest for atezolizumab in the ABCPem/Pac and BCPem/Pac arms were hepatitis (driven by laboratory abnormalities; mostly low grade), hypothyroidism and rash. Overall, IMpower151 did not meet its primary endpoint (INV-PFS) in metastatic nsqNSCLC. ABCPem/Pac was generally well tolerated, with no new safety signals. Trial registration number: ClinicalTrials.gov, NCT02366143.

To describe PD-L1 expression across tissue types and its associated tumor microenvironment and to investigate how it affects its predictive value for response to pembrolizumab in treatment-naïve patients with ovarian cancer included in the NeoPembrOV phase II trial (NCT03275506).

Although neoadjuvant chemotherapy and immunotherapy show promise in treating oesophageal squamous cell carcinoma (OSCC), long-term survival data are limited. This randomized, multicenter phase 2 study evaluated the efficacy of perioperative Nivolumab with chemotherapy, followed by surgery and adjuvant immunotherapy, in patients with locally advanced resectable OSCC, and explored the prognostic role of circulating tumor DNA (ctDNA) status.

Metformin reduces the incidence of breast cancer in patients with obesity and type 2 diabetes. However, our knowledge of the effects of metformin on breast cancer recurrence is limited. Within the randomized double-blind placebo-controlled phase II trial MetBreCS, we examined changes in breast tissue from breast cancer survivors with BMI > 25 kg/m2 after treatment with metformin. To identify metformin-regulated signaling pathways, we integrated the transcriptomic, metabolomic and steroid hormone profiles using bivariate and functional analyses. We identified MS4A1, HBA2, MT-RNR1, MT-RNR2, EGFL6 and FDCSP expression to be differentially expressed in breast tissues from metformin-treated postmenopausal women. The integration of transcriptomic and metabolomic profiles revealed down-regulation of immune response genes associated with reduced levels of arginine and citrulline in the metformin-treated group. The integration of transcriptomic and steroid hormone profiles showed an enrichment of steroid hormone biosynthesis and metabolism pathways with highly negatively correlated CYP11A1 and CYP1B1 expression in breast tissue from postmenopausal metformin-treated women. Our results indicate that postmenopausal breast cancer survivors treated with metformin have specific changes in breast tissue gene expression that may prevent the development of new tumors.Trial registration: MetBreCs trial is registered at European Union Clinical Trials Register (EudraCT Protocol # 2015-001001-14) on 07/10/2015.

Poly (ADP-ribose) polymerase inhibitors (PARPi) exploit DNA repair deficiency in germline BRCA1 and BRCA2 pathogenic variant (gBRCAm) cancers. Haematological toxicity limits chemotherapy-PARPi treatment combinations. In preclinical models we identified a schedule combining olaparib and carboplatin that avoids enhanced toxicity but maintains anti-tumour activity. We investigated this schedule in a neoadjuvant, phase II-III, randomised controlled trial for gBRCAm breast cancers (ClinicalTrials.gov ID:NCT03150576; PARTNER). The research arm included carboplatin (Area Under the Curve 5, 3-weekly); paclitaxel (80 mg/m2, weekly) day 1, plus olaparib (150 mg twice daily) day 3-14 (4 cycles), followed by anthracycline-containing chemotherapy (3 cycles); control arm gave chemotherapy alone. The primary endpoint, pathological complete response rate, showed no statistical difference between research 64.1% (25/39); control 69.8% (30/43) (p = 0.59). However, estimated survival outcomes at 36-months demonstrated improved event-free survival: research 96.4%, control 80.1% (p = 0.04); overall survival: research 100%, control 88.2% (p = 0.04) and breast cancer specific survival: research 100%, control 88.2% (p = 0.04). There were no statistical differences in relapse-free survival and distant disease-free survival, both were: research 96.4%, control 87.9% (p = 0.20). Similarly, local recurrence-free survival and time to second cancer were both: research 96.4%, control 87.8% (p = 0.20). The PARTNER trial identified a safe, tolerable schedule combining neoadjuvant chemotherapy with olaparib. This combination demonstrated schedule-dependent overall survival benefit in early-stage gBRCAm breast cancer. This result needs confirmation in larger trials.

Cholangiocarcinoma (CCA) is one of the most aggressive cancers with a poor prognosis. Current treatment strategies involve hepatobiliary surgery, chemotherapy, radiotherapy, and supportive care; however, the success of these treatments remains limited. Therefore, this study investigated the potential of Atractylodes lancea (Thunb) D.C. (AL) in limiting the progress of CCA by targeting the expression of cancer-related genes involved in immune responses and circulating tumor cells. The study was part of Phase 2A clinical trial in advanced-stage intrahepatic iCCA (iCCA) patients: Group 1 (n = 16) received low-dose AL (capsule formulation of the standardized extract of AL: CMC-AL) with standard supportive care, Group 2 (n = 16) received high-dose AL with standard supportive care, and Group 3 (n = 16) received standard supportive care alone. Venous whole blood samples (EDTA, 5 ml) were collected from each patient on Day 1 and Day 90 and the non-CCA subjects (n = 16) on Day 1. Fifty-nine samples (48 and 11 samples for Day 1 and Day 90, respectively) were processed for total RNA isolation. Gene expression was evaluated using reverse transcription followed by a PCR array. Regardless of dosage, gene expression patterns in the AL-treated groups closely resembled those of the healthy subjects. Specifically, cancer-associated genes, including VEGF-A, NR4A3, Ki-67, and EpCAM, were significantly down-regulated. Additionally, the expression levels of immune-related genes were modulated in AL-treated patients. The treatment groups exhibited lower levels of the pro-inflammatory cytokine IL-6, increased expression of the anti-inflammatory cytokine IL-10, and cell-mediated immune-related molecules such as CTLA4 and PFR1. These findings suggest the potential of AL for iCCA treatment. However, additional studies are required to confirm the correlation between gene and protein expression profiles, as well as CTCs profile.

The purpose was to investigate combined PARP and androgen inhibition in primary prostate cancer and understand the biological mechanisms underlying clinical efficacy, especially in the absence of mutations in homologous recombination (HR) repair pathways.

The phase 3 DESTINY-Breast04 trial demonstrated superior efficacy and acceptable safety with trastuzumab deruxtecan (T-DXd) vs physician's choice of chemotherapy in previously treated patients with human epidermal growth factor receptor 2 (HER2)-low metastatic breast cancer (mBC). We report the patient-reported outcomes (PROs), focusing on the hormone receptor-positive cohort.

In the global CAPItello-291 randomized phase 3 study (NCT04305496) in patients with hormone receptor-positive/HER2-negative advanced breast cancer and progression during/after aromatase inhibitor treatment, capivasertib-fulvestrant significantly improved progression-free survival (PFS) in the overall population and patients with PIK3CA/AKT1/PTEN-altered tumors versus placebo-fulvestrant. We assessed efficacy and safety of capivasertib-fulvestrant in a prespecified exploratory analysis of a Chinese cohort (n = 24) and extended study with the same protocol (n = 110). Clinically meaningful PFS benefit for capivasertib-fulvestrant was observed in the overall population (median PFS: 6.9 [capivasertib-fulvestrant] versus 2.8 [placebo-fulvestrant] months; hazard ratio 0.51, 95% CI 0.34-0.76), patients with PIK3CA/AKT1/PTEN-altered tumors (n = 46; 5.7 versus 1.9 months; hazard ratio 0.41, 95% CI 0.19-0.85) and PIK3CA/AKT1/PTEN-non-altered tumors (patients with confirmed next-generation sequencing results [n = 68]; 9.2 versus 2.7 months; hazard ratio 0.38; 95% CI 0.21-0.68). The most frequent adverse events (AEs) with capivasertib-fulvestrant were diarrhea (60.6% versus 11.3% with placebo-fulvestrant) and hyperglycemia (57.7% versus 17.7%). AEs leading to capivasertib-fulvestrant discontinuation were reported in 11.3% of patients versus 3.2% for placebo-fulvestrant. The benefit-risk profile of capivasertib-fulvestrant in the Chinese cohort was favorable; further exploration in patients with PIK3CA/AKT1/PTEN-non-altered tumors is warranted.

Optimal sequencing of immune checkpoint inhibitors (ICIs) and targeted therapies (TTs) in BRAFV600-positive advanced melanoma should achieve rapid tumour control and durable progression-free survival (PFS), translating into prolonged overall survival (OS).

In updated analyses from the phase III POSEIDON study, after a median follow-up of >5 years, tremelimumab plus durvalumab and chemotherapy (T + D + CT) showed durable long-term overall survival (OS) benefit versus CT alone in first-line metastatic non-small-cell lung cancer (mNSCLC). In this article, we report the associations of tumor mutational burden (TMB) with outcomes of D with or without T in combination with CT versus CT alone.

Cetuximab plus irinotecan, fluorouracil, and leucovorin (FOLFIRI) represents a first-line therapeutic standard for RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients. Despite this established approach, cetuximab β (CMAB009), as a modified antibody of cetuximab, prospectively selected for dual RAS/BRAF wild-type patients, has not yet been validated in the Chinese mCRC patients through phase 3 trial. In this study (ClinicalTrials.gov identifier: NCT03206151), patients with RAS/BRAF wild-type mCRC who were not suitable for radical resection were randomly assigned in a 1:1 ratio to receive cetuximab β plus FOLFIRI or FOLFIRI alone. The primary endpoint was blinded independent review committee-assessed progression-free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), surgery rate for metastasis and R0 resection rate, and safety. From January 4, 2018 to September 2, 2021, a total of 505 eligible patients were enrolled and received study treatment; the median follow-up duration was 8.7 months (95% confidence interval [CI], 7.77 to 9.29) and 5.9 months (95% CI, 5.63 to 6.65) in cetuximab β plus FOLFIRI group and FOLFIRI group, respectively. Compared to FOLFIRI alone, cetuximab β plus FOLFIRI demonstrated statistically significant improvements in median PFS (13.1 vs. 9.6 months, hazard ratio [HR], 0.639; 95% CI, 0.468 to 0.872; P = 0.004), median OS (28.3 vs. 23.1 months, HR, 0.729; 95% CI, 0.551 to 0.965; P = 0.024), and ORR (69.1% vs. 42.3%, odds ratio, 3.090; 95% CI, 2.280 to 4.189; P < 0.001). Cetuximab β plus FOLFIRI exhibited manageable toxicity without novel safety signals. This study demonstrated that cetuximab β plus FOLFIRI provided significant clinical benefits as a first-line treatment for patients with RAS/BRAF wild-type mCRC. Compared to FOLFIRI alone, cetuximab β plus FOLFIRI therapy led to prolonged median PFS and OS while maintaining a manageable safety profile, offering a new treatment option for this patient population.

The phase 3 MAGNITUDE trial previously met its primary endpoint of an improvement in radiographic progression-free survival with niraparib + abiraterone acetate and prednisone (AAP) versus placebo + AAP in patients with metastatic castration-resistant prostate cancer (mCRPC) and alterations in genes involved in DNA homologous recombination repair (HRR+), particularly in BRCA1/2.

Digital health tools, such as websites, now proliferate to assist individuals in managing their health. With user input, we developed the Your Family Connects (YFC) website to promote access to genetic services for survivors of ovarian cancer and their relatives. Although we estimated that half or more would access the website, only 18% of invited survivors did so. We assessed the extent to which perceived relevance of the information provided, trust, and privacy concerns influenced decisions not to access the website.