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UNLABELLED The tumour markers alpha-fetoprotein (AFP), beta human chorionic gonadotropin (βHCG), and lactate dehydrogenase (LDH) have established roles in the management and follow-up of testicular cancer. While a tumour marker rise can serve as an indicator of relapse, the frequency of false-positive marker events has not been studied systematically in larger cohorts. We assessed the validity of serum tumour markers for the detection of relapse in the Swiss Austrian German Testicular Cancer Cohort Study (SAG TCCS). This registry was set up to answer questions on the diagnostic performance and impact of imaging and laboratory tests in the management of testicular cancer, and has included 948 patients between January 2014 and July 2021.A total of 793 patients with a median follow-up of 29.0 mo were included. In total, 71 patients (8.9%) had a proven relapse, which was marker positive in 31 patients (43.6%). Of all patients, 124 (15.6%) had an event of a false-positive marker elevation. The positive predictive value (PPV) of the markers was limited, highest for βHCG (33.8%) and lowest for LDH (9.4%). PPV tended to increase with higher levels of elevation. These findings underline the limited accuracy of the conventional tumour markers to indicate or rule out a relapse. Especially, LDH as part of routine follow-up should be questioned. PATIENT SUMMARY With the diagnosis of testicular cancer, the three tumour markers alpha-fetoprotein, beta human chorionic gonadotropin, and lactate dehydrogenase are routinely measured during follow-up to monitor for relapse. We demonstrate that these markers are often falsely elevated, and, by contrast, many patients do not have marker elevations despite a relapse. The results of this study can lead to improved use of these tumour markers during follow-up of testis cancer patients.

Cisplatinum-based chemotherapy is associated with an increased risk of venous thromboembolism (VTE). We hypothesized that primary thromboprophylaxis in patients with testicular germ cell tumors (GCT) undergoing cisplatinum-based chemotherapy can reduce the risk of VTE.In this single-center retrospective cohort study, we investigated the increased use of primary thromboprophylaxis between January 2000 and December 2021 at our institution and its effect on the risk of VTE. Patients with GCT undergoing adjuvant or curative cisplatinum-based chemotherapy were included.Three hundred forty-six patients with GCT initiating a cisplatinum-based therapy were included in the study, of whom 122 (35%) were treated in the adjuvant and 224 (65%) in the curative setting, respectively. VTE events occurred in 49 (14.2%) patients. In univariable competing risk analysis, a higher clinical tumor stage and large retroperitoneal lymphadenopathy (RPLND5 cm) were the strongest predictors of an elevated VTE risk (SHR for stage IIC - IIIC: 2.6 (95%CI: 5.0-24.7, P.001), SHR for RPLN: 2.36 (95%CI: 1.27-4.4, P.007)). The proportion of patients receiving primary thromboprophylaxis strongly increased over time and reached 100% in CS IIC-III patients from 2019 onwards. After adjusting for tumor stage, primary thromboprophylaxis was associated with a 52% relatively lower risk of VTE (SHR = 0.48, 95% CI: 0.24-0.97; P = .032).In this retrospective cohort study, we showed that TGCT patients undergoing cisplatinum-based chemotherapy have a lower VTE risk when receiving primary thromboprophylaxis. For the duration of chemotherapy, primary thromboprophylaxis should be considered on a risk-benefit ratio.

Supplementary Data

Targeting the ataxia telangiectasia and RAD3-related (ATR) enzyme represents a promising anticancer strategy for tumors with DNA damage response (DDR) defects and replication stress, including inactivation of ataxia telangiectasia mutated (ATM) signaling. We report the dose-escalation portion of the phase I first-in-human trial of oral ATR inhibitor BAY 1895344 intermittently dosed 5 to 80 mg twice daily in 21 patients with advanced solid tumors. The MTD was 40 mg twice daily 3 days on/4 days off. Most common adverse events were manageable and reversible hematologic toxicities. Partial responses were achieved in 4 patients and stable disease in 8 patients. Median duration of response was 315.5 days. Responders had ATM protein loss and/or deleterious ATM mutations and received doses ≥40 mg twice daily. Overall, BAY 1895344 is well tolerated, with antitumor activity against cancers with certain DDR defects, including ATM loss. An expansion phase continues in patients with DDR deficiency.Significance:Oral BAY 1895344 was tolerable, with antitumor activity in heavily pretreated patients with various advanced solid tumors, particularly those with ATM deleterious mutations and/or loss of ATM protein; pharmacodynamic results supported a mechanism of action of increased DNA damage. Further study is warranted in this patient population.See related commentary by Italiano, p. 14.This article is highlighted in the In This Issue feature, p. 1

Figure S2. Continuation of IMP following radiological detection of asymptomatic DILD resulting in clinical deterioration.

Table S1. Frequency of DILD as per category

Purpose:Drug-induced interstitial lung disease (DILD) is a rare, but potentially fatal toxicity. Clinical and radiological features of DILD in the early experimental setting are poorly described.Patients and Methods:A total of 2,499 consecutive patients with advanced cancer on phase I clinical trials were included. DILD was identified by a dedicated radiologist and investigators, categorized per internationally recognized radiological patterns, and graded per Common Terminology Criteria for Adverse Events (CTCAE) and the Royal Marsden Hospital (RMH) DILD score. Clinical and radiological features of DILD were analyzed.Results:Sixty patients overall (2.4%) developed DILD. Median time to onset of DILD was 63 days (range, 14–336 days). A total of 45% of patients who developed DILD were clinically asymptomatic. Incidence was highest in patients receiving drug conjugates (7.4%), followed by inhibitors of the PI3K/AKT/mTOR pathway (3.9%). The most common pattern seen was hypersensitivity pneumonitis (33.3%), followed by nonspecific interstitial pneumonia (30%), and cryptogenic organizing pneumonia (26.7%). A higher DILD score [OR, 1.47, 95% confidence interval (CI), 1.19–1.81; P < 0.001] and the pattern of DILD (OR, 5.83 for acute interstitial pneumonia; 95% CI, 0.38–90.26; P = 0.002) were significantly associated with a higher CTCAE grading. The only predictive factor for an improvement in DILD was an interruption of treatment (OR, 0.05; 95% CI, 0.01–0.35; P = 0.01).Conclusions:DILD in early-phase clinical trials is a toxicity of variable onset, with diverse clinical and radiological findings. Radiological findings precede clinical symptoms. The extent of the affected lung parenchyma, scored by the RMH DILD score, correlates with clinical presentation. Most events are low grade, and improve with treatment interruption, which should be considered early.

Figure S1A. Correlation of patterns of DILD as per ATS/ERS classification and clinical severity. AIP correlated significantly with worse severity (P=0.002). NSIP, non-specific interstitial pneumonia; COP, cryptogenic organizing pneumonia; AIP, acute interstitial pneumonia; HP, hypersensitivity pneumonitis. Figure S1B. A higher RMH DILD score predicts for increasing clinical severity of DILD as per CTCAE grading. Shown are CTCAE grading and RMH DILD Score at the time of DILD detection. Box plot mapping RMH DILD Scores against CTCAE grading showing statistically significant worsening of CTCAE grading and symptoms with higher RMH DILD score (P=0.004); DILD was confirmed to be the cause of death in one patient who had an initial RMH DILD score of 5 and was asymptomatic with an excellent partial response to therapy and so was continued on therapy. This patient then developed symptomatic DILD with a worsening RMH DILD score of 8, deteriorated and died. RMH DILD score, Royal Marsden Hospital Score for drug induced interstitial lung disease; CTCAE, Common Terminology Criteria for Adverse Events Version 5.0. Figure S2. Continuation of IMP following radiological detection of asymptomatic DILD resulting in clinical deterioration. Images from a patient with breast cancer treated with an investigational drug-conjugate. Patient had no prior lung disease and no lung metastases at baseline. Cartoons (left) show RMH DILD scoring of matched sagittal radiographic images (right). The first row shows initial development of radiographic changes after 2 cycles of treatment when patient was asymptomatic (RMH DILD score of 5) and otherwise had a remarkable RECIST PR. With a further cycle of treatment, the changes had significantly worsened (RMH DILD score of 8), with development of rapidly progressive clinical symptoms which was ultimately fatal despite treatment with antibiotics, steroids, and respiratory support.

SummaryNeoadjuvant checkpoint inhibition in resectable non-small-cell lung cancer (NSCLC) is safe and high major pathologic response (MPR) and pathologic complete response (pCR) rates can be achieved in combination with chemotherapy. The Checkmate 816 trial gives evidence that pathologic response also leads to EFS benefit. This opens new opportunities in the curative setting but also raises questions: What is the value of adjuvant treatment with checkpoint inhibitors? Or should we treat our patients peri-operatively? Which biomarkers can we use for treatment decisions and monitoring of curative patients? Targeted therapies in the neoadjuvant setting lead to promising response rates and data for EFS and overall survival are eagerly awaited.

PURPOSE The classification of the International Germ Cell Cancer Collaborative Group (IGCCCG) plays a pivotal role in the management of metastatic germ cell tumors but relies on data of patients treated between 1975 and 1990. MATERIALS AND METHODS Data on 9,728 men with metastatic nonseminomatous germ cell tumors treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Europe, North America, and Australia. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS). The survival estimates were updated for the current era. Additionally, a novel prognostic model for PFS was developed in 3,542 patients with complete information on potentially relevant variables. The results were validated in an independent data set. RESULTS Compared with the original IGCCCG publication, 5-year PFS remained similar in patients with good prognosis with 89% (87%-91%) versus 90% (95% CI, 89 to 91), but the 5-year OS increased from 92% (90%-94%) to 96% (95%-96%). In patients with intermediate prognosis, PFS remained similar with 75% (71%-79%) versus 78% (76%-80%) and the OS increased from 80% (76%-84%) to 89% (88%-91%). In patients with poor prognosis, the PFS increased from 41% (95% CI, 35 to 47) to 54% (95% CI, 52 to 56) and the OS from 48% (95% CI, 42 to 54) to 67% (95% CI, 65 to 69). A more granular prognostic model was developed and independently validated. This model identified a new cutoff of lactate dehydrogenase at a 2.5 upper limit of normal and increasing age and presence of lung metastases as additional adverse prognostic factors. An online calculator is provided ( https://www.eortc.org/IGCCCG-Update ). CONCLUSION The IGCCCG Update model improves individual prognostication in metastatic nonseminomatous germ cell tumors. Increasing age and lung metastases add granularity to the original IGCCCG classification as adverse prognostic factors.

Purpose: Radiation therapy is a possible treatment strategy for patients with testicular seminoma after orchiectomy in clinical stage I or II disease. Little is known about the outcome of patients who experience a relapse after radiation therapy. ----- Methods and materials: Data from 61 patients who relapsed after adjuvant or curative radiation therapy from 17 centers in 11 countries were collected and retrospectively analyzed. Primary outcomes were disease-free and overall survival. Secondary outcomes were time to relapse, stage at relapse, treatment for relapse, and rate of febrile neutropenia during chemotherapy for relapse. ----- Results: With a median follow-up of 9.9 years (95% confidence interval [CI], 7.5-10.9), we found a 5-year disease-free survival of 90% (95% CI, 79-95) and a 5-year overall survival of 98% (95% CI, 89-100). Sixty-six percent of patients had stage III disease at time of relapse and 93% of patients fell into the good prognosis group per the International Germ Cell Cancer Collaborative Group classification. The median time to relapse after radiation therapy was 15.6 months (95% CI, 12-23). Twenty-two (36%) patients relapsed more than 2 years after radiation therapy and 7 (11.5%) patients relapsed more than 5 years after radiation therapy. One-third of relapses was detected owing to patients' symptoms, whereas two-thirds of relapses were detected during routine follow-up. The majority (93%) of cases were treated with cisplatin-based chemotherapy. The rate of febrile neutropenia during chemotherapy was 35%. Five patients experienced a second relapse. At last follow-up, 55 patients (90%) were alive without disease. Only 1 patient died owing to disease progression. ----- Conclusions: Cisplatin-based chemotherapy for patients with seminoma who have relapsed after treatment with radiation therapy alone leads to excellent outcomes. Patients and physicians should be aware of possible late relapses after radiation therapy.

BACKGROUND: Targeted treatment modalities for non-small cell lung carcinoma (NSCLC) patients are expanding rapidly and demand a constant adaptation of molecular testing strategies. In this regard, broad reflex testing via next-generation sequencing (NGS) might have several advantages. However, real-world data regarding practical feasibility and clinical relevance are scarce, especially for RNA-based NGS. METHODS: We performed a retrospective study comparing NGS use in two consecutive years (2019 and 2020). In 2019, reflex testing mainly consisted of DNA-based NGS for mutations and immunohistochemistry (IHC) for ALK, ROS1, and NTRK fusion products. At the beginning of 2020, our approach has changed, with DNA- and RNA-based NGS panels now being simultaneously performed. This change in protocol allowed us to retrospectively evaluate if broad molecular reflex testing brings additional value to lung cancer patients. RESULTS: Within the whole cohort (n=432), both DNA- and RNA-based NGS yielded almost always evaluable results. Only in 6 cases, the RNA content was too little for an appropriate analysis. After integrating RNA-based NGS in the reflex testing approach, the number of detected fusions increased significantly (2.6% vs. 8.2%; P=0.0021), but also more patients received targeted therapies. Furthermore, exceedingly rare alterations were more likely to be detected, including the so far undescribed EGFR-NUP160 fusion. CONCLUSIONS: Our study demonstrates that a comprehensive approach to reflex NGS testing is practically feasible and clinically relevant. Including RNA-based panels in the reflex testing approach results in more detected fusions and more patients receiving targeted therapies. Additionally, this broad molecular profiling strategy identifies patients with emerging biomarkers, underscoring its usefulness in the rapidly evolving landscape of targeted therapies.

SummaryMalignant pleural mesothelioma (MPM) is a rare tumour that originates from the inner linings of the pleural cavity. The majority of cases are associated with exposure to asbestos for what was banned in the European Union in 1991. Due to the long latency between exposure and onset (20–40 years) the peak of MPM in Western Europe will be reached within the next years. Often diagnosed at an unresectable stage, treatment options remain palliative in the majority of cases. The highly aggressive nature of MPM leads to a dismal prognosis with a median overall survival of approximately one year.Platinum-based chemotherapy in combination with pemetrexed has been the mainstay of first line treatment in unresectable MPM for many years. Only recently, check point inhibitors have found their way into MPM treatment. The results of the phase III CheckMate 743 trial last year have finally led to a paradigm shift in the treatment of unresectable MPM. This trial showed a significant overall survival benefit for the combination of nivolumab and ipilimumab over standard chemotherapy, especially in nonepithelioid histology. Apart from histology, predictive biomarkers have not been identified for the treatment of MPM so far. Several trials investigating combination therapies with checkpoint inhibitors are currently ongoing and give hope to further improve prognosis for our patients.

The treatment of hormone receptor positive metastatic breast cancer patients has changed dramatically over the last few years and combination strategies attempting to overcome resistance of the disease are gaining importance. After introducing CDK 4/6 inhibitors in the treatment one of the subsequent strategies is definitely targeting PI3 kinase pathway. Several drugs have been tested, but only recently, SOLAR-1 phase III trial demonstrated the benefit of adding alpelisib to fulvestrant, with acceptable tolerability. With this trial the importance of PIK3CA, testing was postulated. In the present study a comparison of liquid biopsy and tissue-based detection of PIK3CA mutations in HR positive metastatic breast cancer patients was performed. Materials and Methods: Plasma and the most recent tumor tissue were screened for PIK3CA hotspot mutations from 58 patients with metastatic hormone-receptor positive breast cancer. For plasma samples, SiMSen-Seq NGS sequencing was used covering 11 frequent PIK3CA mutations, which were applied for stratification in SOLAR-1. Only plasma samples with variant allele frequency (VAF) >1% were considered as positive. For tumor tissue samples, targeted Ion Torrent NGS was used. Matched tissue plasma samples were available from 40 patients.Results: PIK3CA mutations were detected in 25/50 (50.0%) tissue samples and in 18/48 (37.5%) plasma samples. VAF ranged from 4.4 to 72.9% with an average of 28.7% in tissue samples, and from 1.1% to 49.9% with an average of 8.2% in plasma samples. In tumor samples, the most frequent variant was H1047R (11/25, 44.0%), followed by E545K (8/25, 32.0%), E542K (4/25, 16.0) and H1047L (2/25, 8.0%). In plasma samples, the most frequent PIK3CA variant was H1047R (12/18, 66.7%), followed by E542K (6/18, 33.3%), and E545K (2/18, 11.1%). Double mutations in plasma samples occurred in two patients (both with H1047R + E542K). In 15/48 (31.3%) plasma samples, 19 low-level mutations (AF between 0.1% and 1.0 %) were detected, with an average of 0.49% (range 0.18-0.98).Matched tissue and plasma samples were available from 40/58 (68.9%) patients with a median time between matched tissue and plasma collection of 285 days (25th-75th percentile: 24-1833 days). The overall concordance rate between plasma and tissue samples was 62.5% (25/40 patients). In detail, 8/40 patients (20.0%) had the same PIK3CA mutation in plasma and tumor tissue, while in 17/40 patients (42.5%) were tested negative in both sample types Discordant results occurred in 15/40 samples (37.5%). Specifically, nine patients had a PIK3CA mutation in the tissue sample only, while four patients had a PIK3CA mutation in the plasma sample only. In addition, in two patients a different PIK3CA mutation was detected in the plasma sample compared to the tissue sample.Conclusion: SiMSen-Seq based detection of PIK3CA mutations from plasma demonstrated promising results for selection of candidate patients for Alpelisib treatment. However, these results will be validated in a larger cohort of patients. Our data align with FDA recommendation to initially carry out the mutation testing in ctDNA. Only if the test is negative for PIK3CA mutations in plasma, patients should undergo testing for PIK3CA mutations in tumor tissue. Citation Format: Christoph Suppan, Qing Zhou, Stephan Jahn, Ricarda Graf, Eva Valentina Klocker, Angelika Terbuch, Karl Kashofer, Florian Posch, Hanno Gerritsmann, Nadia Dandachi, Ellen Heitzer, Marija Balic. Comparison of liquid biopsy and tissue based detection of PIK3CA mutations in HR positive metastatic breast cancer patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS4-06.

About 15% of patients with non-small cell lung cancer (NSCLC) harbor the Kirsten rat sarcoma homolog G12C mutation (KRASG12C). Selective KRASG12C inhibitors offer new treatment opportunities, but little is known about the prevalence, characteristics, and outcomes of standard-of-care treatment (SOC) in this population. We retrospectively assessed the clinicopathological features of patients with KRASG12C-mutated advanced NSCLC and responses to SOC at two high-volume centers in Austria. Out of 2495 NSCLC patients tested, we identified 174 patients with advanced-stage disease carrying a KRASG12C mutation. Most patients were ≥65 years old (55%), heavy smokers (55%), and presented with comorbidities. The most frequent co-alteration was TP53 (18%). PD-L1 expression was high (TPS ≥ 50%) in 31%, very high (TPS ≥ 90%) in 11%, and negative in 31% of patients. A total of 138 patients (79%) received oncologic systemic treatment. The most common first-line therapy (1 L) was anti-PD-1/PD-L1 plus platinum-based chemotherapy. Median overall survival measured from 1 L treatment was 15.3 months (95% CI, 8.6–21.9), 9.4 (95% CI, 5.3–13.5) from 2 L treatment, and 8.4 (95% CI, 1.7–15.1) from 3 L treatment. The time-to-next-treatment was 8.4 (95% CI, 5.2–11.6) from 1 L and 6.1 (95% CI, 2.7–9.7) months from 2 L to 3 L. These poor outcomes underscore the need for the implementation of new treatment options and for specific molecular testing.

Despite improved clinical outcomes, intrinsic or acquired resistance to CDK4/6 inhibitor treatment has limited the success of this treatment in HR+ HER2- metastatic breast cancer patients. Biomarkers are urgently needed, and longitudinal biomarker measurements may harbor more dynamic predictive and prognostic information compared to single time point measurements. The aim of this study was to explore the longitudinal evolution of circulating tumor fractions within cell-free DNA assessed by an untargeted sequencing approach during CDK4/6 therapy and to quantify the potential association between longitudinal z-score measurements and clinical outcome by using joint models. Forty-nine HR+ HER2- metastatic breast cancer patients were enrolled, and z-score levels were measured at baseline and during 132 follow-up visits (median number of measurements per patient = 3, 25th -75th percentile: 3-5, range: 1-8). We observed higher baseline z-score levels (estimated difference 0.57, 95% CI: 0.147-0.983, P-value = 0.008) and a constant increase of z-score levels over follow-up time (overall P-value for difference in log z-score over time = 0.024) in patients who developed progressive disease. Importantly, the joint model revealed that elevated z-score trajectories were significantly associated with higher progression risk (HR of log z-score at any time of follow-up = 3.3, 95% CI, 1.44-7.55, P = 0.005). In contrast, single z-score measurement at CDK4/6 inhibitor treatment start did not predict risk of progression. In this prospective study, we demonstrate proof-of-concept that longitudinal z-score trajectories rather than single time point measurements may harbor important dynamic information on the development of disease progression in HR+ HER2- breast cancer patients undergoing CDK4/6 inhibitor treatment.