Clinicopathological and molecular predictors of [18F]FDG-PET disease detection in HER2-positive early breast cancer: RESPONSE, a substudy of the randomized PHERGain trial.

BACKGROUND: The PHERGain study (NCT03161353) is assessing early metabolic responses to neoadjuvant treatment with trastuzumab-pertuzumab and chemotherapy de-escalation using a [18Fluorine]fluorodeoxyglucose-positron emission tomography ([18F]FDG-PET) and a pathological complete response-adapted strategy in HER2-positive (HER2+) early breast cancer (EBC). Herein, we present RESPONSE, a PHERGain substudy, where clinicopathological and molecular predictors of [18F]FDG-PET disease detection were evaluated. METHODS: A total of 500 patients with HER2 + EBC screened in the PHERGain trial with a tumor size > 1.5 cm by magnetic resonance imaging (MRI) were included in the RESPONSE substudy. PET[-] criteria entailed the absence of  ≥ 1 breast lesion with maximum standardized uptake value (SUVmax) ≥ 1.5 × SUVmean liver + 2 standard deviation. Among 75 PET[-] patients screened, 21 with SUVmax levels < 2.5 were randomly selected and matched with 21 PET[+] patients with SUVmax levels ≥ 2.5 based on patient characteristics associated with [18F]FDG-PET status. The association between baseline SUVmax and [18F]FDG-PET status ([-] or [+]) with clinicopathological characteristics was assessed. In addition, evaluation of stromal tumor-infiltrating lymphocytes (sTILs) and gene expression analysis using PAM50 and Vantage 3D™ Cancer Metabolism Panel were specifically compared in a matched cohort of excluded and enrolled patients based on the [18F]FDG-PET eligibility criteria. RESULTS: Median SUVmax at baseline was 7.2 (range, 1-39.3). Among all analyzed patients, a higher SUVmax was associated with a higher tumor stage, larger tumor size, lymph node involvement, hormone receptor-negative status, higher HER2 protein expression, increased Ki67 proliferation index, and higher histological grade (p < 0.05). [18F]FDG-PET [-] criteria patients had smaller tumor size (p = 0.014) along with the absence of lymph node involvement and lower histological grade than [18F]FDG-PET [+] patients (p < 0.01). Although no difference in the levels of sTILs was found among 42 matched [18F]FDG-PET [-]/[+] criteria patients (p = 0.73), [18F]FDG-PET [-] criteria patients showed a decreased risk of recurrence (ROR) and a lower proportion of PAM50 HER2-enriched subtype than [18F]FDG-PET[+] patients (p < 0.05). Differences in the expression of genes involved in cancer metabolism were observed between [18F]FDG-PET [-] and [18F]FDG-PET[+] criteria patients. CONCLUSIONS: These results highlight the clinical, biological, and metabolic heterogeneity of HER2+ breast cancer, which may facilitate the selection of HER2+ EBC patients likely to benefit from [18F]FDG-PET imaging as a tool to guide therapy. TRIAL REGISTRATION: Clinicaltrials.gov; NCT03161353; registration date: May 15, 2017.

3-year invasive disease-free survival with chemotherapy de-escalation using an 18F-FDG-PET-based, pathological complete response-adapted strategy in HER2-positive early breast cancer (PHERGain): a randomised, open-label, phase 2 trial.

BACKGROUND: PHERGain was designed to assess the feasibility, safety, and efficacy of a chemotherapy-free treatment based on a dual human epidermal growth factor receptor 2 (HER2) blockade with trastuzumab and pertuzumab in patients with HER2-positive early breast cancer (EBC). It used an 18fluorine-fluorodeoxyglucose-PET-based, pathological complete response (pCR)-adapted strategy. METHODS: PHERGain was a randomised, open-label, phase 2 trial that took place in 45 hospitals in seven European countries. It randomly allocated patients in a 1:4 ratio with centrally confirmed, HER2-positive, stage I-IIIA invasive, operable breast cancer with at least one PET-evaluable lesion to either group A, where patients received docetaxel (75 mg/m2, intravenous), carboplatin (area under the curve 6 mg/mL per min, intravenous), trastuzumab (600 mg fixed dose, subcutaneous), and pertuzumab (840 mg loading dose followed by 420 mg maintenance doses, intravenous; TCHP), or group B, where patients received trastuzumab and pertuzumab with or without endocrine therapy, every 3 weeks. Random allocation was stratified by hormone receptor status. Centrally reviewed PET was conducted at baseline and after two treatment cycles. Patients in group B were treated according to on-treatment PET results. Patients in group B who were PET-responders continued with trastuzumab and pertuzumab with or without endocrine therapy for six cycles, while PET-non-responders were switched to receive six cycles of TCHP. After surgery, patients in group B who were PET-responders who did not achieve a pCR received six cycles of TCHP, and all patients completed up to 18 cycles of trastuzumab and pertuzumab. The primary endpoints were pCR in patients who were group B PET-responders after two treatment cycles (the results for which have been reported previously) and 3-year invasive disease-free survival (iDFS) in patients in group B. The study is registered with ClinicalTrials.gov (NCT03161353) and is ongoing. FINDINGS: Between June 26, 2017, and April 24, 2019, a total of 356 patients were randomly allocated (71 patients in group A and 285 patients in group B), and 63 (89%) and 267 (94%) patients proceeded to surgery in groups A and B, respectively. At this second analysis (data cutoff: Nov 4, 2022), the median duration of follow-up was 43·3 months (range 0·0-63·0). In group B, the 3-year iDFS rate was 94·8% (95% CI 91·4-97·1; p=0·001), meeting the primary endpoint. No new safety signals were identified. Treatment-related adverse events and serious adverse events (SAEs) were numerically higher in patients allocated to group A than to group B (grade ≥3 62% vs 33%; SAEs 28% vs 14%). Group B PET-responders with pCR presented the lowest incidence of treatment-related grade 3 or higher adverse events (1%) without any SAEs. INTERPRETATION: Among HER2-positive EBC patients, a PET-based, pCR-adapted strategy was associated with an excellent 3-year iDFS. This strategy identified about a third of patients who had HER2-positive EBC who could safely omit chemotherapy. FUNDING: F Hoffmann-La Roche.

Optimal [18F]FDG PET/CT Cutoff for Pathologic Complete Response in HER2-Positive Early Breast Cancer Patients Treated with Neoadjuvant Trastuzumab and Pertuzumab in the PHERGain Trial.

The PHERGain trial investigated the potential of metabolic imaging to identify candidates for chemotherapy deescalation in human epidermal growth factor receptor 2 (HER2)-positive, invasive, operable breast cancer with at least 1 breast lesion evaluable by [18F]FDG PET/CT. [18F]FDG PET/CT responders were defined as patients with an SUVmax reduction (ΔSUVmax) of at least 40% in all of their target lesions after 2 cycles of trastuzumab and pertuzumab (HP) (with or without endocrine therapy). In total, 227 of 285 patients (80%) included in the HP arm showed a predefined metabolic response and received a total of 8 cycles of HP (with or without endocrine therapy). Pathologic complete response (pCR), defined as ypT0/isN0, was achieved in 37.9% of the patients. Here, we describe the secondary preplanned analysis of the best cutoff of ΔSUVmax for pCR prediction. Methods: Receiver-operating-characteristic analysis was applied to look for the most appropriate ΔSUVmax cutoff in HER2-positive early breast cancer patients treated exclusively with neoadjuvant HP (with or without endocrine therapy). Results: The ΔSUVmax capability of predicting pCR in terms of the area under the receiver-operating-characteristic curve was 72.1% (95% CI, 65.1-79.2%). The optimal ΔSUVmax cutoff was found to be 77.0%, with a 51.2% sensitivity and a 78.7% specificity. With this cutoff, 74 of 285 patients (26%) would be classified as metabolic responders, increasing the pCR rate from 37.9% (cutoff ≥ 40%) to 59.5% (44/74 patients) (P < 0.01). With this optimized cutoff, 44 of 285 patients (15.4%) would avoid chemotherapy in either the neoadjuvant or the adjuvant setting compared with 86 of 285 patients (30.2%) using the original cutoff (P < 0.001). Conclusion: In the PHERGain trial, an increased SUVmax cutoff (≥77%) after 2 cycles of exclusive HP (with or without endocrine therapy) achieves a pCR in the range of the control arm with chemotherapy plus HP (59.5% vs. 57.7%, respectively), further identifying a subgroup of patients with HER2-addicted tumors. However, the original cutoff (≥40%) maximizes the number of patients who could avoid chemotherapy.

Molecular imaging predicts lack of T-DM1 response in advanced HER2-positive breast cancer (final results of ZEPHIR trial).

Efficacy of the human epidermal growth factor receptor (HER)2-targeting trastuzumab emtansine (T-DM1) in breast cancer (BC) relies on HER2 status determined by immunohistochemistry or fluorescence in-situ hybridization. Heterogeneity in HER2 expression, however, generates interest in "whole-body" assessment of HER2 status using molecular imaging. We evaluated the role of HER2-targeted molecular imaging in detecting HER2-positive BC lesions and patients unlikely to respond to T-DM1. Patients underwent zirconium-89 (89Zr) trastuzumab (HER2) PET/CT and [18F]-2-fluoro-2-deoxy-D-glucose (FDG) PET/CT before T-DM1 initiation. Based on 89Zr-trastuzumab uptake, lesions were visually classified as HER2-positive (visible/high uptake) or HER2-negative (background/close to background activity). According to proportion of FDG-avid tumor load showing 89Zr-trastuzumab uptake (entire/dominant part or minor/no part), patients were classified as HER2-positive and HER2-negative, respectively. Out of 265 measurable lesions, 93 (35%) were HER2-negative, distributed among 42 of the 90 included patients. Of these, 18 (19%) lesions belonging to 11 patients responded anatomically (>30% decrease in axial diameter from baseline) after three T-DM1 cycles, resulting in an 81% negative predictive value (NPV) of the HER2 PET/CT. In combination with early metabolic response assessment on FDG PET/CT performed before the second T-DM1 cycle, NPVs of 91% and 100% were reached in predicting lesion-based and patient-based (RECIST1.1) response, respectively. Therefore, HER2 PET/CT, alone or in combination with early FDG PET/CT, can successfully identify BC lesions and patients with a low probability of clinical benefit from T-DM1.

PIK3CA copy-number gain and inhibitors of the PI3K/AKT/mTOR pathway in triple-negative breast cancer.

As wider insights are gained on the molecular landscape of triple-negative breast cancer (TNBC), novel targeted therapeutic strategies might become an option in this setting as well. Activating mutations of PIK3CA represent the second most common alteration in TNBC after the TP53 mutation, with a prevalence of ∼10%-15%. Considering the well-established predictive role of PIK3CA mutations for response to agents targeting the PI3K/AKT/mTOR pathway, several clinical trials are currently evaluating these drugs in patients with advanced TNBC. However, much less is known regarding the actionability of PIK3CA copy-number gains, which represent a thoroughly common molecular alteration in TNBC, with a prevalence estimated at 6%-20%, and are listed as "likely gain-of-function" alterations in the OncoKB database. In the present paper, we describe two clinical cases in which patients harboring PIK3CA-amplified TNBC received a targeted treatment with the mTOR-inhibitor everolimus and the PI3K-inhibitor alpelisib, respectively, with evidence of disease response on 18F-FDG positron-emission tomography (PET) imaging. Hence, we discuss the evidence presently available regarding a possible predictive value of PIK3CA amplification for response to targeted treatment strategies, suggesting that this molecular alteration might represent an intriguing biomarker in this sense. Considering that few of the currently active clinical trials assessing agents targeting the PI3K/AKT/mTOR pathway in TNBC select patients based on tumor molecular characterization, and none of these based on PIK3CA copy-number status, we urge for the introduction of PIK3CA amplification as a criterion for patient selection in future clinical trials in this setting.

[18F]FDG and [18F]FES PET/CT Imaging as a Biomarker for Therapy Effect in Patients with Metastatic ER+ Breast Cancer Undergoing Treatment with Rintodestrant.

PURPOSE: PET with 16α-[18F]-fluoro-17ß-estradiol ([18F]FES) allows assessment of whole body estrogen receptor (ER) expression. The aim of this study was to investigate [18F]-fluorodeoxyglucose ([18F]FDG) and [18F]FES PET/CT imaging for response prediction and monitoring of drug activity in patients with metastatic ER-positive breast cancer undergoing treatment with the selective estrogen receptor downregulator (SERD) rintodestrant. EXPERIMENTAL DESIGN: In this trial (NCT03455270), PET/CT imaging was performed at baseline ([18F]FDG and [18F]FES), during treatment and at time of progression (only [18F]FES). Visual, quantitative, and mutational analysis was performed to derive a heterogeneity score (HS) and assess tracer uptake in lesions, in relation to the mutation profile. The primary outcome was progression-free survival (PFS). RESULTS: The HS and PFS in the entire group did not correlate (n = 16, Spearman's rho, P = 0.06), but patients with a low HS (< 25.0%, n = 4) had a PFS of > 5 months whereas patients with no [18F]FES uptake (HS 100.0%, n = 3) had a PFS of < 2 months. [18F]FES uptake was not affected by estrogen receptor 1 (ESR1) mutations. On-treatment [18F]FES PET/CT scans showed no [18F]FES uptake in any of the baseline [18F]FES-positive lesions. At progression, [18F]FES uptake remained blocked in patients scanned ≤ 1-2 half-lives of rintodestrant whereas it restored in patients scanned ≥ 5 days after end of treatment. CONCLUSIONS: Absence of ER expression on [18F]FES PET is a predictor for no response to rintodestrant. [18F]FES uptake during treatment and at time of progression is useful to monitor the (reversible) effect of therapy and continued mode of action of SERDs. See related commentary by Linden and Mankoff, p. 2015.

Trastuzumab and pertuzumab without chemotherapy in early-stage HER2+ breast cancer: a plain language summary of the PHERGain study.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of a publication about the PHERGain study, which was published in The Lancet Oncology in May 2021. The study includes 376 women with a type of breast cancer called HER2-positive breast cancer that can be removed by surgery. In the study, researchers wanted to learn if participants could be treated with two medicines called trastuzumab and pertuzumab without the need for chemotherapy. To identify HER2-positive tumors with more sensitivity to anti-HER2 therapies, the researchers used a type of imaging called a FDG-PET scan to check how well the treatments were working. WHAT HAPPENED IN THE PHERGAIN STUDY?: Participants took a treatment before surgery, consisting of either chemotherapy (docetaxel and carboplatin) plus trastuzumab and pertuzumab (group A) or trastuzumab and pertuzumab alone (plus hormone therapy if the tumor was hormone receptor-positive; group B). After two cycles of treatment, participants underwent a FDG-PET scan. Participants assigned to group A completed 6 cycles of treatment regardless of 18F-FDG-PET results. Participants in group B continued the same treatment until surgery if their FDG-PET scan showed the treatment was working. While participants who did not show a response started treatment with chemotherapy in addition to trastuzumab and pertuzumab. All participants then had surgery. WHAT WERE THE RESULTS?: The results revealed that, of the participants in group B who showed a response using FDG-PET scan, 37.9% achieved a disappearance of all invasive cancer in the breast and axillary lymph nodes. This rate appears to be higher than those reported in previous studies evaluating the same treatment. These participants also had less side effects and improved overall quality of life compared with participants taking chemotherapy plus trastuzumab and pertuzumab. WHAT DO THE RESULTS OF THE STUDY MEAN?: Early monitoring of how well participants respond to treatment by FDG-PET scan seems to identify participants with operable HER2-positive breast cancer who were more likely to benefit from trastuzumab and pertuzumab without the need to have chemotherapy. The PHERGain study is still ongoing and results on long-term survival are expected to be released in 2023. Clinical Trial Registration: NCT03161353 (ClinicalTrials.gov).

Serum thymidine kinase activity in patients with hormone receptor-positive and HER2-negative metastatic breast cancer treated with palbociclib and fulvestrant.

BACKGROUND: Biomarkers for cyclin-dependent kinase 4/6 inhibitors, such as palbociclib, for patients with hormone receptor-positive/HER2-negative metastatic breast cancer are lacking. Thymidine kinase is a proliferation marker downstream of the cyclin-dependent kinase 4/6 pathway. We prospectively investigated the prognostic role of serum thymidine kinase activity (sTKa), in patients treated with Palbociclib + fulvestrant. PATIENTS AND METHODS: PYTHIA was a phase II, single-arm, multicentre, trial that enrolled 124 post-menopausal women with endocrine-resistant hormone receptor-positive/HER2-negative metastatic breast cancer. Serum samples were collected pre-treatment (pre-trt; n = 122), at day 15 of cycle 1 (D15; n = 108), during the one week-off palbociclib before initiating cycle 2 (D28; n = 108) and at end of treatment (n = 76). sTKa was determined centrally using Divitum®, a refined ELISA-based assay with a limit of detection of 20 Divitum Units (Du)/L. The primary study endpoint was progression-free survival, assessed for its association with pre- and on-treatment sTKa. RESULTS: Data from 122 women were analysed. Pre-treatment sTKa was not associated with clinical characteristics and moderately correlated with tissue Ki-67. Palbociclib + fulvestrant markedly suppressed sTKa levels at D15, with 83% of patients recording levels below limit of detection. At D28, sTKa showed a rebound in 60% of patients. At each timepoint, higher sTKa was associated with shorter progression-free survival (each p < 0.001), with the strongest effect at D15. CONCLUSIONS: STKa is an independent prognostic biomarker in patients treated with palbociclib. High pre-treatment sTKa and its incomplete suppression during treatment may identify patients with poorer prognosis and primary resistance. This warrants validation in prospective comparative trials. CLINICALTRIALS. GOV IDENTIFIER: NCT02536742; EudraCT 2014-005387-15.

FDG positron emission tomography imaging and ctDNA detection as an early dynamic biomarker of everolimus efficacy in advanced luminal breast cancer.

Biomarkers to identify patients without benefit from adding everolimus to endocrine treatment in metastatic breast cancer (MBC) are needed. We report the results of the Pearl trial conducted in five Belgian centers assessing 18F-FDG-PET/CT non-response (n = 45) and ctDNA detection (n = 46) after 14 days of exemestane-everolimus (EXE-EVE) to identify MBC patients who will not benefit. The metabolic non-response rate was 66.6%. Median PFS in non-responding patients (using as cut-off 25% for SUVmax decrease) was 3.1 months compared to 6.0 months in those showing response (HR: 0.77, 95% CI: 0.40-1.50, p = 0.44). The difference was significant when using a "post-hoc" cut-off of 15% (PFS 2.2 months vs 6.4 months). ctDNA detection at D14 was associated with PFS: 2.1 months vs 5.0 months (HR-2.5, 95% CI: 1.3-5.0, p = 0.012). Detection of ctDNA and/or the absence of 18F-FDG-PET/CT response after 14 days of EXE-EVE identifies patients with a low probability of benefiting from treatment. Independent validation is needed.

Chemotherapy de-escalation using an 18F-FDG-PET-based pathological response-adapted strategy in patients with HER2-positive early breast cancer (PHERGain): a multicentre, randomised, open-label, non-comparative, phase 2 trial.

BACKGROUND: Several de-escalation approaches are under investigation in patients with HER2-positive, early-stage breast cancer. We assessed early metabolic responses to neoadjuvant trastuzumab and pertuzumab using 18F-fluorodeoxyglucose (18F-FDG)-PET (18F-FDG-PET) and the possibility of chemotherapy de-escalation using a pathological response-adapted strategy. METHODS: We did a multicentre, randomised, open-label, non-comparative, phase 2 trial in 45 hospitals in Spain, France, Belgium, Germany, the UK, Italy, and Portugal. Eligible participants were women aged 18 years or older with centrally confirmed, HER2-positive, stage I-IIIA, invasive, operable breast cancer (≥1·5 cm tumour size) with at least one breast lesion evaluable by 18F-FDG-PET, an Eastern Cooperative Oncology Group performance status of 0 or 1, and a baseline left ventricular ejection fraction of at least 55%. We randomly assigned participants (1:4), via an interactive response system using central block randomisation with block sizes of five, stratified by hormone receptor status, to either docetaxel (75 mg/m2 intravenous), carboplatin (area under the concentration-time curve 6 mg/mL per min intravenous), trastuzumab (subcutaneous 600 mg fixed dose), and pertuzumab (intravenous 840 mg loading dose, 420 mg maintenance doses; group A); or trastuzumab and pertuzumab (group B). Hormone receptor-positive patients allocated to group B were additionally given letrozole if postmenopausal (2·5 mg/day orally) or tamoxifen if premenopausal (20 mg/day orally). Centrally reviewed 18F-FDG-PET scans were done before randomisation and after two treatment cycles. Patients assigned to group A completed six cycles of treatment (every 3 weeks) regardless of 18F-FDG-PET results. All patients assigned to group B initially received two cycles of trastuzumab and pertuzumab. 18F-FDG-PET responders in group B continued this treatment for six further cycles; 18F-FDG-PET non-responders in this group were switched to six cycles of docetaxel, carboplatin, trastuzumab, and pertuzumab. Surgery was done 2-6 weeks after the last dose of study treatment. Adjuvant treatment was selected according to the neoadjuvant treatment administered, pathological response, hormone receptor status, and clinical stage at diagnosis. The coprimary endpoints were the proportion of 18F-FDG-PET responders in group B with a pathological complete response in the breast and axilla (ypT0/is ypN0) as determined by a local pathologist after surgery after eight cycles of treatment, and 3-year invasive disease-free survival of patients in group B, both assessed by intention to treat. The definitive assessment of pathological complete response was done at this primary analysis; follow-up to assess invasive disease-free survival is continuing, hence these data are not included in this Article. Safety was assessed in all participants who received at least one dose of study drug. Health-related quality-of-life was assessed with EORTC QLQ-C30 and QLQ-BR23 questionnaires at baseline, after two cycles of treatment, and before surgery. This trial is registered with EudraCT (2016-002676-27) and ClinicalTrials.gov (NCT03161353), and is ongoing. FINDINGS: Between June 26, 2017, and April 24, 2019, we randomly assigned 71 patients to group A and 285 to group B. Median follow-up was 5·7 months (IQR 5·3-6·0). 227 (80%) of 285 patients in group B were 18F-FDG-PET responders, of whom 86 (37·9%, 95% CI 31·6-44·5; p<0·0001 compared with the historical rate) of 227 had a pathological complete response. The most common haematological grade 3-4 adverse events were anaemia (six [9%] of 68 patients in group A vs four [1%] of 283 patients in group B), neutropenia (16 [24%] vs ten [4%]), and febrile neutropenia (14 [21%] vs 11 [4%]). Serious adverse events occurred in 20 (29%) of 68 patients in group A versus 13 (5%) of 283 patients in group B. No deaths were reported during neoadjuvant treatment. Global health status declined by at least 10% in 65·0% (95% CI 46·5-72·4) and 35·5% (29·7-41·7) of patients in groups A and B, respectively INTERPRETATION: 18F-FDG-PET identified patients with HER2-positive, early-stage breast cancer who were likely to benefit from chemotherapy-free dual HER2 blockade with trastuzumab and pertuzumab, and a reduced impact on global health status. Depending on the forthcoming results for the 3-year invasive disease-free survival endpoint, this strategy might be a valid approach to select patients not requiring chemotherapy. FUNDING: F Hoffmann-La Roche.

How COVID-19 pandemic affected cancer progression: Three different scenarios evidenced by PET imaging.

COVID-19 pandemic is having a strong impact on healthcare providers around the world, by refocusing and reducing non-essential medical activities. Nuclear medicine departments among others, have been reorganizing and reprioritizing diagnostic and theragnostic procedures. This reorganizing had a negative impact on the supply of positron emission tomography (PET) services to oncologic patients, whose health was affected. We herein present the PET findings in three different cancer scenarios in which disease course was dramatically affected by the COVID-19 outbreak.

Mechanisms of resistance to trastuzumab emtansine (T-DM1) in HER2-positive breast cancer.

The HER2-targeted antibody-drug conjugate trastuzumab emtansine (T-DM1) is approved for the treatment of metastatic, HER2-positive breast cancer after prior trastuzumab and taxane therapy, and has also demonstrated efficacy in the adjuvant setting in incomplete responders to neoadjuvant therapy. Despite its objective activity, intrinsic and acquired resistance to T-DM1 remains a major clinical challenge. T-DM1 mediates its activity in a number of ways, encompassing HER2 signalling blockade, Fc-mediated immune response and payload-mediated microtubule poisoning. Resistance mechanisms relating to each of these features have been demonstrated, and we outline the findings of these studies in this review. In our overview of the substantial literature on T-DM1 activity and resistance, we conclude that the T-DM1 resistance mechanisms most strongly supported by the experimental data relate to dysfunctional intracellular metabolism of the construct and subversion of DM1-mediated cell killing. Loss of dependence on signalling initiated by HER2-HER2 homodimers is not substantiated as a resistance mechanism by clinical or experimental studies, and the impact of EGFR expression and tumour immunological status requires further investigation. These findings are instructive with respect to strategies that might overcome T-DM1 resistance, including the use of second-generation anti-HER2 antibody-drug conjugates that deploy alternative linker-payload chemistries.

Added value of para-aortic surgical staging compared to 18F-FDG PET/CT on the external beam radiation field for patients with locally advanced cervical cancer: An ONCO-GF study.

OBJECTIVE: Extended field chemoradiation is recommended for patients with locally advanced cervical cancer (LACC) and para-aortic lymph node (PALN) metastases. The radiation planning may be based on PET/CT while others recommend to rely on surgical staging. We report the rate of patients for whom the radiation field defined on PET/CT was modified by the histological PALN status. METHODS: Between March 2010 and December 2016, 168 consecutive patients with LACC underwent a pre-therapeutic PET/CT and PALN dissection. The data were reviewed retrospectively. The diagnostic performance of the PET/CT for definition of PALN status was calculated. We determined the percentage of patients for whom PALN dissection altered the external beam radiotherapy (EBRT) field defined on the PET/CT basis. RESULTS: Of 151 patients with negative PALNs on PET/CT, 26 had histological PALN metastases. Of 17 patients with positive PALNs on PET/CT, 9 were negative on histology of which 7 were located in the common iliac region. Sensitivity, specificity, positive and negative predictive value of PET/CT were 23.5, 93.3, 47.1 and 82.8% respectively. In total, 35 out of 168 patients underwent EBRT - field adaptation (pelvic vs extended field). The rate of radiation field modification (27,7%) was particularly high in the subgroup of patients with metastatic pelvic lymph nodes (PLNs) on PET/CT. CONCLUSION: Para-aortic surgical staging contributes significantly to individualize the radiation treatment of patients with LACC, particularly for those with positive PLNs at PET/CT. Indication of surgical staging deserves particular attention when the PET/CT suggests positive LNs in the common iliac region.

Tumor Drug Penetration Measurements Could Be the Neglected Piece of the Personalized Cancer Treatment Puzzle.

Precision medicine aims to use patient genomic, epigenomic, specific drug dose, and other data to define disease patterns that may potentially lead to an improved treatment outcome. Personalized dosing regimens based on tumor drug penetration can play a critical role in this approach. State-of-the-art techniques to measure tumor drug penetration focus on systemic exposure, tissue penetration, cellular or molecular engagement, and expression of pharmacological activity. Using in silico methods, this information can be integrated to bridge the gap between the therapeutic regimen and the pharmacological link with clinical outcome. These methodologies are described, and challenges ahead are discussed. Supported by many examples, this review shows how the combination of these techniques provides enhanced patient-specific information on drug accessibility at the tumor tissue level, target binding, and downstream pharmacology. Our vision of how to apply tumor drug penetration measurements offers a roadmap for the clinical implementation of precision dosing.

Strategies and technical challenges for imaging oligometastatic disease: Recommendations from the European Organisation for Research and Treatment of Cancer imaging group.

Patients with oligometastatic disease (OMD) often have controllable symptoms, and cures are possible. Technical improvements in surgery and radiotherapy have introduced the option of metastasis-directed ablative therapies as an adjunct or alternative to standard-of-care systemic therapies. Several clinical trials and registries are investigating the benefit of these therapeutic approaches across several cancer sites. This requires that patients are correctly included and followed with appropriate imaging. This article discusses the evidence and offers recommendations for the implementation of standard-of-care (Response Evaluation Criteria in Solid Tumours measurements on computed tomography [CT], magnetic resonance imaging [MRI] and bone scintigraphy) and advanced imaging modalities (functional, metabolic and radionuclide targeted) for identifying and following up patients with OMD. Imaging requirements for recognising OMD vary with tumour type, metastatic location, and timing of measurement in relation to previous treatment. At each point in the disease cycle (diagnosis, response assessment and follow-up), imaging must be tailored to the clinical question and the context of prior treatment. The differential use of whole-body approaches such as 18F-FDG-positron emission tomography (PET)/CT, diffusion-weighted MRI, 18F-Choline-PET/CT and 68Ga-prostate specific membrane antigen-PET/CT require rationalisation depending on clinical risk assessment. Optimal standardised imaging approaches will enable OMD trials to document patterns of disease progression and outcomes of treatment. Quality assured and quality controlled imaging data included in databases such as the European Organisation for Research and Treatment of Cancer Imaging platform for the Oligocare trial (a prospective, large-scale observational basket study being set up to collect outcome data from patients with OMD treated with radiation therapy) will establish a large and high-quality imaging warehouse for future research.

N-Acetylcysteine breaks resistance to trastuzumab caused by MUC4 overexpression in human HER2 positive BC-bearing nude mice monitored by 89Zr-Trastuzumab and 18F-FDG PET imaging.

Trastuzumab remains an important drug in the management of human epidermal growth factor receptor 2 (HER2) overexpressing breast cancer (BC). Several studies reported resistance mechanisms to trastuzumab, including impaired HER2-accessibility caused by mucin 4 (MUC4). Previously, we demonstrated an increase of Zirconium-89-radiolabeled-trastuzumab (89Zr-Trastuzumab) accumulation when MUC4-overexpressing BC-cells were challenged with the mucolytic drug N-Acetylcysteine (NAC). Hereby, using the same approach we investigated whether tumor exposure to NAC would also enhance trastuzumab-efficacy. Dual SKBr3 (HER2+/MUC4-, sensitive to trastuzumab) and JIMT1 (HER2+/MUC4+, resistant to trastuzumab) HER2-BC-bearing-xenografts were treated with trastuzumab and NAC. Treatment was monitored by molecular imaging evaluating HER2-accessibility/activity (89Zr-Trastuzumab HER2-immunoPET) and glucose metabolism (18F-FDG-PET/CT), as well as tumor volume and the expression of key proteins. In the MUC4-positive JIMT1-tumors, the NAC-trastuzumab combination resulted in improved tumor-growth control compared to trastuzumab alone; with smaller tumor volume/weight, lower 18F-FDG uptake, lower %Ki67 and pAkt-expression. NAC reduced MUC4-expression, but did not affect HER2-expression or the trastuzumab-sensitivity of the MUC4-negative SKBr3-tumors. These findings suggest that improving HER2-accessibility by reducing MUC4-masking with the mucolytic drug NAC, results in a higher anti-tumor effect of trastuzumab. This provides a rationale for the potential benefit of this approach to possibly treat a subset of HER2-positive BC overexpressing MUC4.

HER2-positive breast cancer is lost in translation: time for patient-centered research.

No biomarker beyond HER2 itself, which suffers from a low positive predictive value, has demonstrated clinical utility in breast cancer, despite numerous attempts to improve treatment tailoring for the growing number of anti-HER2 targeted therapies. This prompted us to examine the body of evidence, using a systematic approach, to identify putative predictive biomarkers in HER2-positive breast cancer, and discuss the hitherto failure to address the needs of patients. In the future, it is hoped immune-based biomarkers will predict benefit from anti-HER2 treatments in the neoadjuvant and adjuvant settings. In advanced-stage disease, the quantification of tumour heterogeneity using molecular-imaging technology has generated informative data on the success or failure of the antibody-drug conjugate T-DM1. Treatment tailoring remains a high priority, in cost-constrained health-care systems, but such tailoring will require a dramatic shift in the way translational research is being conducted, with the establishment of large, easily accessible, and well-annotated databases of candidate predictive biomarkers. Single-centre biomarker research should become a thing of the past.