Intense neoadjuvant androgen deprivation therapy (ADT) before radical prostatectomy (RP) is an investigational approach to reduce recurrence rates in men with high-risk localized prostate cancer ...(PCa). The impact of germline DNA damage repair (gDDR) gene alterations on response to intense neoadjuvant ADT is not known.
To evaluate the prevalence of gDDR alterations among men with localized PCa at high risk of recurrence and evaluate their impact on response to intense neoadjuvant ADT.
We performed germline panel sequencing for 201 men with intermediate- and high-risk localized PCa from five randomized multicenter clinical trials of intense neoadjuvant ADT before RP.
Intense neoadjuvant ADT followed by RP.
The prevalence of pathogenic gDDR alterations and their association with exceptional pathologic response (complete response or minimal residual disease, defined as residual tumor with the largest cross-section dimension ≤5 mm) to intense neoadjuvant ADT and rates of post-RP biochemical recurrence.
Pathogenic gDDR alterations were detected in 19 (9.5%) of the 201 PCa patients. The most frequently altered genes were BRCA2 (n = 6; 3.0%) and ATM (n = 4; 2.0%). Patients with gDDR alterations exhibited similar rates of exceptional pathologic response (26% vs 22%), pT3 disease (42% vs 53%), lymph node involvement (5.3% vs 10%), extraprostatic extension (35% vs 54%), and positive margins (5.3% vs 13%) to patients without gDDR alterations (all p > 0.05). The 3-yr biochemical recurrence–free survival was also similar at 45% (95% confidence interval 7.9–78%) for men with gDDR alterations and 55% (95% confidence interval 44–64%) for men without gDDR alterations.
gDDR alterations are common among men with intermediate- and high-risk localized PCa. Men with gDDR alterations appear to have a comparable response to intense neoadjuvant ADT to that among men without gDDR alterations and should not be excluded from consideration for this treatment approach.
Intense therapy to inhibit the production of androgen hormones (eg, testosterone) before surgery may minimize the risk of cancer recurrence for men with high-risk localized prostate cancer. Inherited mutations in certain DNA repair genes are associated with particularly high rates of recurrence. We found that men with these mutations respond equally well to this intense androgen inhibition before surgery as men without the mutations.
We identified pathogenic germline DNA damage repair (gDDR) alterations in 10% of men with localized high-risk prostate cancer. Despite their association with aggressive disease, we observed comparable pathologic response rates to intense neoadjuvant androgen deprivation therapy before prostatectomy for men with versus without gDDR alterations.
•HRR testing is key to informed treatment decisions for patients and clinicians.•For BRCA- and HRR-altered mCRPC, PARPi + ARSI is a new standard-of-care option.•Final OS data will further inform the ...long-term benefits of PARPi + ARSI for mCRPC.
Metastatic castration-resistant prostate cancer (mCRPC) remains incurable and develops from biochemically recurrent PC treated with androgen deprivation therapy (ADT) following definitive therapy for localized PC, or from metastatic castration-sensitive PC (mCSPC). In the mCSPC setting, treatment intensification of ADT plus androgen receptor (AR)–signaling inhibitors (ARSIs), with or without chemotherapy, improves outcomes vs ADT alone. Despite multiple phase 3 trials demonstrating a survival benefit of treatment intensification in PC, there remains high use of ADT monotherapy in real-world clinical practice. Prior studies indicate that co-inhibition of AR and poly(ADP-ribose) polymerase (PARP) may result in enhanced benefit in treating tumors regardless of alterations in DNA damage response genes involved either directly or indirectly in homologous recombination repair (HRR). Three recent phase 3 studies evaluated the combination of a PARP inhibitor (PARPi) with an ARSI as first-line treatment for mCRPC: TALAPRO-2, talazoparib plus enzalutamide; PROpel, olaparib plus abiraterone acetate and prednisone (AAP); and MAGNITUDE, niraparib plus AAP. Results from these studies have led to the recent approval in the United States of talazoparib plus enzalutamide for the treatment of mCRPC with any HRR alteration, and of both olaparib and niraparib indicated in combination with AAP for the treatment of mCRPC with BRCA alterations.
Here, we review the newly approved PARPi plus ARSI treatments within the context of the mCRPC treatment landscape, provide an overview of practical considerations for the combinations in clinical practice, highlight the importance of HRR testing, and discuss the benefits of treatment intensification for patients with mCRPC.
Surfactant flooding was identified as a possible addition to water-based enhanced oil recovery techniques. In the past few years, core displacement research on carbonate rock samples using ...low-salinity brine as the injection fluid has shown to improve crude oil recovery moderate. This study presents a unique hybrid enhanced oil recovery (EOR) technique that combines the effects of low-salinity brine injection and surfactant flooding. When the surfactant was utilized in tertiary mode, i.e. after secondary water flooding, the results indicated a higher oil percentage recovery over 75% of original oil in place (OOIP). The first step of the investigation was to evaluate interfacial tension and wettability by screening IL, namely C12PyCl, using the pendant drop and contact angle experimentally. The result shows that this surfactant alters wettability from 98° to 28° and interfacial tension (IFT) from 3.13 to 1.25 dynes/cm at 250 ppm. Following this, the impact of ionic liquid concentration on ultimate oil recovery in the core plug from the carbonate oil reservoir was investigated using a core-flooding test. This hybrid EOR technology may be more economically feasible than low-salinity water flooding or surfactant flooding alone in certain circumstances due to poor surfactant preservation.
: Reversion mutations in
, resulting in restoration of the open reading frame, have been identified as a mechanism of resistance to platinum-based chemotherapy or PARP inhibition. We sought to ...explore the incidence of
reversion mutations in different tumor types.
: We retrospectively analyzed molecular profiling results from primary and/or metastatic tumor samples submitted by multiple institutions. The samples underwent DNA and RNA sequencing at a CLIA/CAP-certified clinical lab. Reversion mutations were called only in patients whose available clinical records showed the use of PARP inhibitors or platinum agents prior to tumor profiling.
: Reversion mutations were identified in 75 of 247,926 samples profiled across all tumor types. Among patients carrying pathogenic or likely pathogenic
mutations, reversion mutations in
genes were seen in ovarian cancer (OC) (30/3424), breast cancer (BC) (27/1460), endometrial cancer (4/564), pancreatic cancer (2/340), cholangiocarcinoma (2/178), prostate cancer (5/461), cervical cancer (1/117), cancer of unknown primary (1/244), bladder cancer (1/300), malignant pleural mesothelioma (1/10), and a neuroendocrine tumor of the prostate. We identified 22 reversion mutations in
and 8 in
in OC. In BC, we detected 6 reversion mutations in
and 21 in
We compared molecular profile results of 14 high-grade serous ovarian cancers (HGSOC) with reversion mutations against 87 control HGSOC with pathogenic
mutations without reversion mutations. Tumors with reversion mutations trended to have had lower ER expression (25% vs. 64%,
= 0.024, q = 0.82) and higher
mutation rate (15% vs. 0,
= 0.016, q = 0.82).
: We present one of the largest datasets reporting reversion mutations in
genes across various tumor types. These reversion mutations were rare; this may be because some patients may not have had repeat profiling post-treatment. Repeat tumor profiling at times of treatment resistance can help inform therapy selection in the refractory disease setting.
TFE3-rearranged renal cell carcinoma (rRCC) is a rare subtype of renal cell carcinomas belonging to the MiT family translocation RCC. To further elucidate the co-alterations that occur along with ...TFE3 fusions in rRCC, we characterized the genomic, transcriptional, and immune landscapes in comparison to clear cell (ccRCC) and papillary renal cell carcinoma (pRCC). Next-generation sequencing of RNA (whole transcriptome) and DNA (592-gene panel or whole exome) for rRCC (N = 20), pRCC (N = 20), and ccRCC samples (N = 392) was performed. Patients with rRCC were significantly younger and more frequently female (median 44.5 years, 75.0% female) as compared with patients with pRCC (68.5 years, 25.0% female; P < .05) and ccRCC (62.0 years, 27.8% female; P < .05). A total of 8 unique fusion partners were observed, including a novel fusion with SRRM2::TFE3 in 2 patients. ccRCC exhibited significantly higher mutation rates of VHL (0% rRCC, 0% pRCC, 78.7% ccRCC; P < .05) and PBMR1 (0% rRCC, 5.0% pRCC, 49.4% ccRCC; P < .05). The genomic landscapes of rRCC were sparse with no mutations occurring with a prevalence higher than 10% other than pTERT (18.2% rRCC, 0% pRCC, 9.2% ccRCC). rRCC were associated with significantly less M1 macrophages (0.8%) as compared with pRCC (1.4%) and ccRCC (2.7%) (P < .05), suggesting a cold tumor-immune microenvironment. However, rRCC were more commonly PD-L1+ (rRCC 50%, pRCC 19.0%, ccRCC 12.2%; P < .05). Gene set enrichment analysis showed that rRCC are enriched in genes related to oxidative phosphorylation when compared with both ccRCC and pRCC. Despite having a colder tumor-immune microenvironment than pRCC and ccRCC, increased PDL1+ rates in rRCC suggest a potential benefit from immune checkpoint inhibitor therapy.
Patients with metastatic castration-resistant prostate cancer have few treatment options after novel hormonal therapy (eg, abiraterone or enzalutamide). We aimed to evaluate cabozantinib, a tyrosine ...kinase inhibitor with immunomodulatory properties, in combination with the PD-L1 inhibitor atezolizumab in metastatic castration-resistant prostate cancer.
COSMIC-021 is an ongoing, multicentre, open-label, phase 1b study with a dose-escalation stage followed by tumour-specific expansion stages. Expansion cohort 6 in metastatic castration-resistant prostate cancer was enrolled at 42 cancer research centres in France, Italy, the Netherlands, Spain, and the USA. Eligible patients were aged 18 years or older and had metastatic castration-resistant prostate cancer with radiographic soft tissue progression following treatment with either enzalutamide or abiraterone, or both; measurable soft tissue disease per Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1; and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received oral cabozantinib 40 mg per day and intravenous atezolizumab 1200 mg once every 3 weeks. Study treatment continued until progressive disease or unacceptable toxicity. All enrolled patients were assessed for efficacy and safety. The primary endpoint was objective response rate per RECIST version 1.1 as assessed by the investigator. This study is registered with ClinicalTrials.gov, NCT03170960.
Between April 24, 2018, and Aug 31, 2020, 132 patients were enrolled and received at least one dose of study treatment. At data cutoff (Feb 19, 2021), median duration of follow-up was 15·2 months (IQR 9·6–21·7). Objective response rate was 23% (95% CI 17–32; 31 of 132 patients), with three (2%) confirmed complete responses and 28 (21%) confirmed partial responses. 72 (55%) of 132 patients had grade 3–4 treatment-related adverse events, with the most common being pulmonary embolism (11 8% patients), diarrhoea (nine 7%), fatigue (nine 7%), and hypertension (nine 7%). There was one grade 5 treatment-related adverse event (dehydration). 74 (56%) of 132 patients had serious adverse events of any causality. 28 (21%) of 132 patients had treatment-related adverse events leading to discontinuation of either study drug.
Cabozantinib plus atezolizumab showed promising antitumour activity in patients with metastatic castration-resistant prostate cancer after novel hormonal therapy with an acceptable safety profile, supporting further evaluation of this combination.
Exelixis.
The rapid-charge carrier recombination and low conductivity are critical in devising an efficient photoelectrochemical (PEC) sensor. Herein, we propose partial oxidation of few-layered MXene ...(Ti3C2Tx) to construct a photo-active TiO2/Ti3C2Tx platform that could be configured for PEC sensing of folate receptors (FR), particularly, FR-expressing breast cancer cells (MDA-MB-231). MXene-Ti3C2Tx dispersion was oxidized in natural-open air conditions, where continuous exposure for six (06) days allowed for homogeneous in-situ growth of TiO2 over MXenes nanosheets (MX-06). This exposure enabled partial oxidation of MXene-sheets with a balanced TiO2 to MXene content that could exhibit improved photoresponsive characteristics owing to the synergism of redox-active TiO2 and highly conductive underlying Ti3C2Tx. The photoelectrode was then adapted for biorecognition by conjugating chitosan and folic acid (FA) networks, which permitted selective detection of FR-expressed cells with significant antifouling capabilities against common proteins such as bovine serum album (BSA), hemoglobin, and immunoglobulin G. (Ig G). The detection mechanism relies on FA's strong affinity for cancer cell folate receptors, which proportionally inhibited the photoelectrodes PEC oxidation response to ascorbic acid (AA)(mediator). The proposed inhibition strategy enabled sensitive detection of FR-expressed MDA-MB-231 cells in the concentration range of 1 × 102 to 2 × 107 cells/mL with a detection limit of 1.01 cells/mL (S/N = 3).
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•Natural oxidation of Ti3C2Tx to construct a photo-active TiO2/Ti3C2Tx platform.•Folic acid biorecognition platform for PEC sensing of FR-expression.•Photoactive biosensor for direct detection of FR-expressing breast cancer cells.
Systemic therapy strategies in the setting of localized and locally advanced renal cell carcinoma have continued to evolve in two directions: (i) as adjuvant therapy (to reduce the risk of recurrence ...or progression in high‐risk localized groups); or (ii) as neoadjuvant therapy as a strategy to render primary renal tumors amenable to planned surgical resection in settings where radical resection or nephron‐sparing surgery was not thought to be safe or feasible. In the realm of adjuvant therapy, the results of adjuvant therapy phase III randomized clinical trials have been mixed and contradictory; nevertheless, the findings of the landmark Sunitinib Treatment of Renal Adjuvant Cancer study have led to approval of sunitinib as an adjuvant agent in the USA. In the realm of neoadjuvant therapy, presurgical tumor reduction has been shown in a number of phase II studies utilizing targeted molecular agents and in a recently published small randomized double‐blind placebo‐controlled study, and an expanding body of literature suggests benefit in select patients. Thus, large randomized clinical trial data are not present to support this approach, and guidelines for use of presurgical therapy have not been promulgated. The advent of immunomodulation through checkpoint inhibition represents an exciting horizon for adjuvant and neoadjuvant strategies. The present article reviews the current status and future prospects of adjuvant and neoadjuvant therapy in localized and locally advanced renal cell carcinoma.
In patients with colorectal cancer (CRC) that metastasizes to the liver, there are several key goals for improving outcomes including early detection, effective prognostic indicators of treatment ...response, and accurate identification of patients at high risk for recurrence. Although new therapeutic regimens developed over the past decade have increased survival, there is substantial room for improvement in selecting targeted treatment regimens for the patients who will derive the most benefit. Recently, there have been exciting developments in identifying high-risk patient cohorts, refinements in the understanding of systemic vs localized drug delivery to metastatic niches, liquid biomarker development, and dramatic advances in tumor immune therapy, all of which promise new and innovative approaches to tackling the problem of detecting and treating the metastatic spread of CRC to the liver. Our multidisciplinary group held a state-of-the-science symposium this past year to review advances in this rapidly evolving field. Herein, we present a discussion around the issues facing treatment of patients with CRC liver metastases, including the relationship of discrete gene signatures with prognosis. We also discuss the latest advances to maximize regional and systemic therapies aimed at decreasing intrahepatic recurrence, review recent insights into the tumor microenvironment, and summarize advances in noninvasive multimodal biomarkers for early detection of primary and recurrent disease. As we continue to advance clinically and technologically in the field of colorectal tumor biology, our goal should be continued refinement of predictive and prognostic studies to decrease recurrence after curative resection and minimize treatment toxicity to patients through a tailored multidisciplinary approach to cancer care.
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