Publications by authors named "Giuseppe Sanguineti"

137 Publications

Circulating HPV DNA in the Management of Oropharyngeal and Cervical Cancers: Current Knowledge and Future Perspectives.

J Clin Med 2021 Apr 6;10(7). Epub 2021 Apr 6.

Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy.

Human papillomaviruses (HPVs) are associated with invasive malignancies, including almost 100% of cervical cancers (CECs), and 35-70% of oropharyngeal cancers (OPCs). HPV infection leads to clinical implications in related tumors by determining better prognosis and predicting treatment response, especially in OPC. Currently, specific and minimally invasive tests allow for detecting HPV-related cancer at an early phase, informing more appropriately therapeutical decisions, and allowing for timely disease monitoring. A blood-based biomarker detectable in liquid biopsy represents an ideal candidate, and the use of circulating HPV DNA (ct-DNA) itself could offer the highest specificity for such a scope. Circulating HPV DNA is detectable in the greatest part of patients affected by HPV-related cancers, and studies have demonstrated its potential usefulness for CEC and OPC clinical management. Unfortunately, when using conventional polymerase chain reaction (PCR), the detection rate of serum HPV DNA is low. Innovative techniques such as droplet-based digital PCR and next generation sequencing are becoming increasingly available for the purpose of boosting HPV ct-DNA detection rate. We herein review and critically discuss the most recent and representative literature, concerning the role of HPV ctDNA in OPC and CEC in the light of new technologies that could improve the potential of this biomarker in fulfilling many of the unmet needs in the clinical management of OPC and CEC patients.
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http://dx.doi.org/10.3390/jcm10071525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038737PMC
April 2021

Chemotherapy and radiotherapy in locally advanced head and neck cancer: an individual patient data network meta-analysis.

Lancet Oncol 2021 05 13;22(5):727-736. Epub 2021 Apr 13.

Department of Oncology, Aarhus University Hospital, Aarhus, Denmark.

Background: Randomised, controlled trials and meta-analyses have shown the survival benefit of concomitant chemoradiotherapy or hyperfractionated radiotherapy in the treatment of locally advanced head and neck cancer. However, the relative efficacy of these treatments is unknown. We aimed to determine whether one treatment was superior to the other.

Methods: We did a frequentist network meta-analysis based on individual patient data of meta-analyses evaluating the role of chemotherapy (Meta-Analysis of Chemotherapy in Head and Neck Cancer [MACH-NC]) and of altered fractionation radiotherapy (Meta-Analysis of Radiotherapy in Carcinomas of Head and Neck [MARCH]). Randomised, controlled trials that enrolled patients with non-metastatic head and neck squamous cell cancer between Jan 1, 1980, and Dec 31, 2016, were included. We used a two-step random-effects approach, and the log-rank test, stratified by trial to compare treatments, with locoregional therapy as the reference. Overall survival was the primary endpoint. The global Cochran Q statistic was used to assess homogeneity and consistency and P score to rank treatments (higher scores indicate more effective therapies).

Findings: 115 randomised, controlled trials, which enrolled patients between Jan 1, 1980, and April 30, 2012, yielded 154 comparisons (28 978 patients with 19 253 deaths and 20 579 progression events). Treatments were grouped into 16 modalities, for which 35 types of direct comparisons were available. Median follow-up based on all trials was 6·6 years (IQR 5·0-9·4). Hyperfractionated radiotherapy with concomitant chemotherapy (HFCRT) was ranked as the best treatment for overall survival (P score 97%; hazard ratio 0·63 [95% CI 0·51-0·77] compared with locoregional therapy). The hazard ratio of HFCRT compared with locoregional therapy with concomitant chemoradiotherapy with platinum-based chemotherapy (CLRT) was 0·82 (95% CI 0·66-1·01) for overall survival. The superiority of HFCRT was robust to sensitivity analyses. Three other modalities of treatment had a better P score, but not a significantly better HR, for overall survival than CLRT (P score 78%): induction chemotherapy with taxane, cisplatin, and fluorouracil followed by locoregional therapy (IC-LRT; 89%), accelerated radiotherapy with concomitant chemotherapy (82%), and IC followed by CLRT (80%).

Interpretation: The results of this network meta-analysis suggest that further intensifying chemoradiotherapy, using HFCRT or IC-CLRT, could improve outcomes over chemoradiotherapy for the treatment of locally advanced head and neck cancer.

Fundings: French Institut National du Cancer, French Ligue Nationale Contre le Cancer, and Fondation ARC.
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http://dx.doi.org/10.1016/S1470-2045(21)00076-0DOI Listing
May 2021

Second-line Eribulin in Triple Negative Metastatic Breast Cancer patients. Multicentre Retrospective Study: The TETRIS Trial.

Int J Med Sci 2021 27;18(10):2245-2250. Epub 2021 Mar 27.

Bio-Statistics Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

Large and consistent evidence supports the use of eribulin mesylate in clinical practice in third or later line treatment of metastatic triple negative breast cancer (mTNBC). Conversely, there is paucity of data on eribulin efficacy in second line treatment. We investigated outcomes of 44 mTNBC patients treated from 2013 through 2019 with second line eribulin mesylate in a multicentre retrospective study involving 14 Italian oncologic centres. Median age was 51 years, with 11.4% of these patients being metastatic at diagnosis. Median overall survival (OS) and progression free survival (PFS) from eribulin starting were 11.9 (95%CI: 8.4-15.5) and 3.5 months (95%CI: 1.7-5.3), respectively. We observed 8 (18.2%) partial responses and 10 (22.7%) patients had stable disease as best response. A longer PFS on previous first line treatment predicted a better OS (HR=0.87, 95%CI: 0.77-0.99, p= 0.038) and a longer PFS on eribulin treatment (HR=0.92, 95%CI: 0.85-0.98, p=0.018). Progression free survival to eribulin was also favorably influenced by prior adjuvant chemotherapy (HR=0.44, 95%CI: 0.22-0.88, p=0.02). Eribulin was generally well tolerated, with grade 3-4 adverse events being recorded in 15.9% of patients. The outcomes described for our cohort are consistent with those reported in the pivotal Study301 and subsequent observational studies. Further data from adequately-sized, ad hoc trials on eribulin use in second line for mTNBC are warranted to confirm our findings.
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http://dx.doi.org/10.7150/ijms.54996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040412PMC
March 2021

Validation of a biomarker tool capable of measuring the absorbed dose soon after exposure to ionizing radiation.

Sci Rep 2021 Apr 14;11(1):8118. Epub 2021 Apr 14.

IRCCS Azienda Ospedaliera Universitaria di Bologna, 40138, Bologna, Italy.

A radiological or nuclear attack could involve such a large number of subjects as to overwhelm the emergency facilities in charge. Resources should therefore be focused on those subjects needing immediate medical attention and care. In such a scenario, for the triage management by first responders, it is necessary to count on efficient biological dosimetry tools capable of early detection of the absorbed dose. At present the validated assays for measuring the absorbed dose are dicentric chromosomes and micronuclei counts, which require more than 2-3 days to obtain results. To overcome this limitation the NATO SPS Programme funded an Italian-Egyptian collaborative project aimed at validating a fast, accurate and feasible tool for assessing the absorbed dose early after radiation exposure. Biomarkers as complete blood cell counts, DNA breaks and radio-inducible proteins were investigated on blood samples collected before and 3 h after the first fraction of radiotherapy in patients treated in specific target areas with doses/fraction of about: 2, 3.5 or > 5 Gy and compared with the reference micronuclei count. Based on univariate and multivariate multiple linear regression correlation, our results identify five early biomarkers potentially useful for detecting the extent of the absorbed dose 3 h after the exposure.
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http://dx.doi.org/10.1038/s41598-021-87173-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047015PMC
April 2021

Stereotactic body radiotherapy for T1 glottic cancer: dosimetric data in 27 consecutive patients.

Tumori 2021 Apr 6:3008916211000440. Epub 2021 Apr 6.

Department of Physics, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

Aim: Because the clinical feasibility of stereotactic body radiotherapy (SBRT) for early glottic cancer (T1) is controversial, we report dosimetric results in 27 consecutive patients from a prospective phase I and II study that started in 2017.

Methods: In our approach, only the parts of the true vocal cord containing cancer and those immediately adjacent are planned to be treated to 36 Gy and 30 Gy, respectively, in 3 fractions. Several dosimetric metrics for both target volumes and organs at risk were extracted from individual plans and results were compared to those achieved by other authors in a similar setting.

Results: Proper coverage was reached at planning in 2/3 of planning treatment volume 30 Gy, but only 4 planning treatment volume 36 Gy; conversely, the maximum dose objective was met for most of the patients on either arytenoid cartilage, but this was not the case for 51.9% and 96.3% of cricoid and thyroid cartilages, respectively. Our dosimetric results are similar to if not better than those achieved by others.

Conclusion: SBRT in 3 fractions for T1 glottic lesions is dosimetrically challenging. Clinical validation is awaited.
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http://dx.doi.org/10.1177/03008916211000440DOI Listing
April 2021

Toxicity at 1 Year After Stereotactic Body Radiation Therapy in 3 Fractions for Localized Prostate Cancer.

Int J Radiat Oncol Biol Phys 2021 Mar 19. Epub 2021 Mar 19.

Radiation Oncology, IRCCS Regina Elena National Cancer Institute, Rome, Italy. Electronic address:

Purpose: To assess the toxicity profile of prostate cancer stereotactic body radiation therapy (SBRT) in 3 fractions.

Methods And Materials: This was a prospective, multicenter phase 2 toxicity study enrolling patients with low to favorable intermediate-risk prostate cancer. Before simulation, 3 to 4 fiducial markers along with a rectal spacer were placed. The target (prostate only) was prescribed 40 Gy, whereas the maximum dose to the urethra was limited to 33 Gy with the highest priority at planning; less stringent objectives were placed on the bladder, the filling of which was controlled via a Foley catheter. Treatment was delivered every other day. Toxicity was prospectively scored with Common Terminology Criteria for Adverse Events, and several patient-reported outcomes were collected. The maximum allowed prevalence rate of grade 2+ genitourinary (GU) toxicity at 1 year was set at 15%, and the study was sized accordingly.

Results: Between November 2015 and May 2019, 59 patients were enrolled by 3 participating institutions. Acute gastrointestinal toxicity was occasional and mild, whereas 11.9% of patients developed acute grade 2 GU toxicity and 1.7% developed acute grade 3 GU toxicity. No patient had persistent treatment-related grade 2+ GU toxicity at 12 months after SBRT; thus, the null hypothesis was rejected. We observed a clinically relevant worsening of both International Prostate Symptom Score (IPSS) and International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) scores at 12 months compared with baseline. Moreover, we found a strong association between all selected bladder dose/volume metrics at planning and ICIQ-SF worsening at 12 months, whereas for the IPSS, the correlation with bladder dose metrics was marginal.

Conclusions: The results suggest that at 12 months after treatment, the toxicity profile of SBRT in 3 fractions is acceptable.
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http://dx.doi.org/10.1016/j.ijrobp.2021.03.027DOI Listing
March 2021

Acute patient-reported intestinal toxicity in whole pelvis IMRT for prostate cancer: Bowel dose-volume effect quantification in a multicentric cohort study.

Radiother Oncol 2021 May 25;158:74-82. Epub 2021 Feb 25.

San Raffaele Scientific Institute, Milan, Italy.

Background And Purpose: To assess bowel dose-volume relationships for acute patient-reported intestinal symptoms of patients treated with whole-pelvis intensity-modulated radiotherapy (WPRT) for prostate cancer.

Materials And Methods: Complete data of 415 patients enrolled in a multi institute, prospective trial (#NCT02803086) treated with radical (31%), adjuvant (33%) and salvage (36%) intent at a median dose to pelvic nodes/lymph-nodal area of 53 Gy were available. The most severe changes between baseline and radiotherapy mid-point/end toxicity assessed by Inflammatory Bowel Disease Questionnaire (only Bowel Domain) were considered (ΔIBDQ). The 25th percentile values of these score variations were set as endpoints. DVHs of bowel loops for patients with/without toxicity were compared for each endpoint, having excluded patients with baseline scores <5 (rate ranging between 2% and 7% according to the endpoint): the resulting best dosimetric predictors were combined with selected clinical parameters through multivariate logistic regression (MVA) to derive predictive models.

Results: ΔIBDQ ranged between 0.2-1.5 points considering separately each IBDQ symptom. Only four symptoms (IBDQ1 = frequency, IBDQ5 = diarrhea, IBDQ17 = gas passage, IBDQ24 = urgency) showed a median worsening ≥ 1; DVH predicted the risk of worse symptoms for IBDQ5, IBDQ24 and overall Bowel Domain. At multivariable analysis DVHs (best cut-off: V46Gy ≥80 cc) and baseline scores (Odd-Ratio:0.35-0.65) were independently associated to the three end-points. The resulting models were reliable (H&L test: 0.453-0.956), well calibrated (calibration plot: slope = 0.922-1.069, R = 0.725-0.875) and moderately discriminative (Area Under the Curve:0.628-0.669). A bootstrap-based validation confirmed their robustness.

Conclusion: Constraining the bowel loops (V46 < 80 cc) may reduce the risk of several moderate intestinal symptoms, with a much greater impact for patients with lower IBDQ baseline scores.
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http://dx.doi.org/10.1016/j.radonc.2021.02.026DOI Listing
May 2021

Management of prostate cancer radiotherapy during the COVID-19 pandemic: A necessary paradigm change.

Cancer Treat Res Commun 2021 Feb 6;27:100331. Epub 2021 Feb 6.

RadiationOncology Unit, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy.

Purpose: To adapt the management of prostate malignancy in response to the COVID-19 pandemic.

Methods: In according to the recommendations of the European Association of Urology, we have developed practical additional document on the treatment of prostate cancer.

Results: Low-Risk Group Watchful Waiting should be offered to patients >75 years old, with a limited life expectancy and unfit for local treatment. In Active Surveillance (AS) patients re-biopsy, PSA evaluation and visits should be deferred for up to 6 months, preferring non-invasive multiparametric-MRI. The active treatment should be delayed for 6-12 months. Intermediate-Risk Group AS should be offered in favorable-risk patients. Short-course neoadjuvant androgen deprivation therapy (ADT) combined with ultra-hypo-fractionation radiotherapy should be used in unfavorable-risk patients. High-Risk Group Neoadjuvant ADT combined with moderate hypofractionation should be preferred. Whole-pelvis irradiation should be offered to patients with positive lymph nodes in locally advanced setting. ADT should be initiated if PSA doubling time is < 12 months in radio-recurrent patients, as well as in low priority/low volume of metastatic hormone sensitive prostate cancer. If radiotherapy cannot be delayed, hypo-fractionated regimens should be preferred. In high priority class metastatic disease, treatment with androgen receptor-targeted agents should be offered. When palliative radiotherapy for painful bone metastasis is required, single fraction of 8 Gy should be offered.

Conclusions: In Covid-19 Era, the challenge should concern a correct management of the oncologic patient, reducing the risk of spreading the virus without worsening tumor prognosis.
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http://dx.doi.org/10.1016/j.ctarc.2021.100331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864785PMC
February 2021

International Recommendations on Re-irradiation by Intensity-modulated Radiotherapy for Locally Recurrent Nasopharyngeal Carcinoma.

Int J Radiat Oncol Biol Phys 2021 Feb 2. Epub 2021 Feb 2.

Department of Clinical Oncology, University of Hong Kong Shenzhen Hospital and University of Hong Kong, HONG KONG, CHINA. Electronic address:

Purpose: Re-irradiation for locally recurrent nasopharyngeal carcinoma (NPC) is challenging as prior radiation dose delivered in the first course is often close to the tolerance limit of surrounding normal structures. A delicate balance between achieving local salvage and minimizing treatment toxicities is needed. However, high-level evidence is lacking as available reports are mostly retrospective studies on small series of patients. Pragmatic consensus guidelines, based on an extensive literature search and the pooling of opinions by leading specialists, will provide a useful reference to assist decision-making for these difficult decisions.

Methods And Materials: A thorough review of available literature on recurrent NPC was conducted. A set of questions and preliminary draft guideline was circulated to a panel of international specialists with extensive experience in this field for voting on controversial areas and comments. A refined second proposal, based on a summary of the initial voting and different opinions expressed, was re-circulated to the whole panel for review and reconsideration. The current guideline was based on majority voting following repeated iteration for final agreement.

Results: The initial round of questions showed variations in clinical practice even among the specialists, reflecting the lack of high-quality supporting data and the difficulties in formulating clinical decisions. Through exchange of comments and iterative revisions, recommendations with high-to-moderate agreement were formulated on general treatment strategies and details of re-irradiation (including patient selection, targets contouring, dose prescription and constraints).

Conclusion: This paper provides useful reference on radical salvage treatment strategies for recurrent NPC and optimization of re-irradiation through review of published evidence and consensus building. However, the final decision by the attending clinician must include full consideration of an individual patient's conditions, understanding of the delicate balance between risk and benefits, and acceptance of risk of complications.
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http://dx.doi.org/10.1016/j.ijrobp.2021.01.041DOI Listing
February 2021

Stereotactic body radiotherapy (SBRT) in combination with drugs in metastatic kidney cancer: A systematic review.

Crit Rev Oncol Hematol 2021 Mar 2;159:103242. Epub 2021 Feb 2.

Radiation Oncology, A.O.U. Careggi, University of Florence, Largo Brambilla, 3, 50134 Florence, Italy. Electronic address:

Objective: To conduct a systematic review and meta-analysis of the role of SBRTdrug combination in patients affected by mRCC and associated oncologic outcomes and toxicity profiles.

Evidence Acquisition: We performed a critical review of the Pubmed, Medline, and Embase databases from January 1, 2000 through April 30, 2020 according to the Preferred Reporting Items and Meta-Analyses statement. To assess the overall quality of the literature reviewed, we used a modified Delphi tool.

Evidence Synthesis: A total of 6 studies were included, corresponding to a cohort of 216 patients. Tyrosine Kinases Inhibitors were the most widely used drugs in combination with SBRT, being administered in 93% patients. No study reported an increase of radiation-induced toxicity.

Conclusions: SBRT resulted to be safe, without increase in terms of drugs-related adverse events in this setting. Moreover, this approach showed promising clinical outcomes in terms of LC and OS.
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http://dx.doi.org/10.1016/j.critrevonc.2021.103242DOI Listing
March 2021

Loss of HER2 and decreased T-DM1 efficacy in HER2 positive advanced breast cancer treated with dual HER2 blockade: the SePHER Study.

J Exp Clin Cancer Res 2020 Dec 10;39(1):279. Epub 2020 Dec 10.

Medical Oncology, Paolo Giaccone University Hospital, Palermo, Italy.

Background: HER2-targeting agents have dramatically changed the therapeutic landscape of HER2+ advanced breast cancer (ABC). Within a short time frame, the rapid introduction of new therapeutics has led to the approval of pertuzumab combined with trastuzumab and a taxane in first-line, and trastuzumab emtansine (T-DM1) in second-line. Thereby, evidence of T-DM1 efficacy following trastuzumab/pertuzumab combination is limited, with data from some retrospective reports suggesting lower activity. The purpose of the present study is to investigate T-DM1 efficacy in pertuzumab-pretreated and pertuzumab naïve HER2 positive ABC patients. We also aimed to provide evidence on the exposure to different drugs sequences including pertuzumab and T-DM1 in HER2 positive cell lines.

Methods: The biology of HER2 was investigated in vitro through sequential exposure of resistant HER2 + breast cancer cell lines to trastuzumab, pertuzumab, and their combination. In vitro experiments were paralleled by the analysis of data from 555 HER2 + ABC patients treated with T-DM1 and evaluation of T-DM1 efficacy in the 371 patients who received it in second line. Survival estimates were graphically displayed in Kaplan Meier curves, compared by log rank test and, when possibile, confirmed in multivariate models.

Results: We herein show evidence of lower activity of T-DM1 in two HER2+ breast cancer cell lines resistant to trastuzumab+pertuzumab, as compared to trastuzumab-resistant cells. Lower T-DM1 efficacy was associated with a marked reduction of HER2 expression on the cell membrane and its nuclear translocation. HER2 downregulation at the membrane level was confirmed in biopsies of four trastuzumab/pertuzumab-pretreated patients. Among the 371 patients treated with second-line T-DM1, median overall survival (mOS) from diagnosis of advanced disease and median progression-free survival to second-line treatment (mPFS2) were 52 and 6 months in 177 patients who received trastuzumab/pertuzumab in first-line, and 74 and 10 months in 194 pertuzumab-naïve patients (p = 0.0006 and 0.03 for OS and PFS2, respectively).

Conclusions: Our data support the hypothesis that the addition of pertuzumab to trastuzumab reduces the amount of available plasma membrane HER2 receptor, limiting the binding of T-DM1 in cancer cells. This may help interpret the less favorable outcomes of second-line T-DM1 in trastuzumab/pertuzumab pre-treated patients compared to their pertuzumab-naïve counterpart.
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http://dx.doi.org/10.1186/s13046-020-01797-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731769PMC
December 2020

Two distinct TP53 mutations in HNSCC primary tumor: Only one circulates in the blood.

Oral Oncol 2021 04 21;115:105096. Epub 2020 Nov 21.

Oncogenomic and Epigenetic Unit, IRCSS Regina Elena National Cancer Institute, Via Elio Chianesi, 53, Rome 00144, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.oraloncology.2020.105096DOI Listing
April 2021

Predictive classifier for intensive treatment of head and neck cancer.

Cancer 2020 Dec 5;126(24):5263-5273. Epub 2020 Oct 5.

Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California.

Background: This study was designed to test the hypothesis that the effectiveness of intensive treatment for locoregionally advanced head and neck cancer (LAHNC) depends on the proportion of patients' overall event risk attributable to cancer.

Methods: This study analyzed 22,339 patients with LAHNC treated in 81 randomized trials testing altered fractionation (AFX; Meta-Analysis of Radiotherapy in Squamous Cell Carcinomas of Head and Neck [MARCH] data set) or chemotherapy (Meta-Analysis of Chemotherapy in Head and Neck Cancer [MACH-NC] data set). Generalized competing event regression was applied to the control arms in MARCH, and patients were stratified by tertile according to the ω score, which quantified the relative hazard for cancer versus competing events. The classifier was externally validated on the MACH-NC data set. The study tested for interactions between the ω score and treatment effects on overall survival (OS).

Results: Factors associated with a higher ω score were a younger age, a better performance status, an oral cavity site, higher T and N categories, and a p16-negative/unknown status. The effect of AFX on OS was greater in patients with high ω scores (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.85-0.99) and medium ω scores (HR, 0.91; 95% CI, 0.84-0.98) versus low ω scores (HR, 0.97; 95% CI, 0.90-1.05; P for interaction = .086). The effect of chemotherapy on OS was significantly greater in patients with high ω scores (HR, 0.81; 95% CI, 0.75-0.88) and medium ω scores (HR, 0.86; 95% CI, 0.78-0.93) versus low ω scores (HR, 0.96; 95% CI, 0.86-1.08; P for interaction = .011).

Conclusions: LAHNC patients with a higher risk of cancer progression relative to competing mortality, as reflected by a higher ω score, selectively benefit from more intensive treatment.
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http://dx.doi.org/10.1002/cncr.33212DOI Listing
December 2020

TMPRSS2, a SARS-CoV-2 internalization protease is downregulated in head and neck cancer patients.

J Exp Clin Cancer Res 2020 Sep 23;39(1):200. Epub 2020 Sep 23.

UOSD Clinical Trial Center, Biostatistics and Bioinformatics, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

Background: SARS-coronavirus-2 enters host cells through binding of the Spike protein to ACE2 receptor and subsequent S priming by the TMPRSS2 protease. We aim to assess differences in both ACE2 and TMPRSS2 expression in normal tissues from oral cavity, pharynx, larynx and lung tissues as well as neoplastic tissues from the same areas.

Methods: The study has been conducted using the TCGA and the Regina Elena Institute databases and validated by experimental model in HNSCC cells. We also included data from one COVID19 patient who went under surgery for HNSCC.

Results: TMPRSS2 expression in HNSCC was significantly reduced compared to the normal tissues. It was more evident in women than in men, in TP53 mutated versus wild TP53 tumors, in HPV negative patients compared to HPV positive counterparts. Functionally, we modeled the multivariate effect of TP53, HPV, and other inherent variables on TMPRSS2. All variables had a statistically significant independent effect on TMPRSS2. In particular, in tumor tissues, HPV negative, TP53 mutated status and elevated TP53-dependent Myc-target genes were associated with low TMPRSS2 expression. The further analysis of both TCGA and our institutional HNSCC datasets identified a signature anti-correlated to TMPRSS2. As proof-of-principle we also validated the anti-correlation between microRNAs and TMPRSS2 expression in a SARS-CoV-2 positive HNSCC patient tissues Finally, we did not find TMPRSS2 promoter methylation.

Conclusions: Collectively, these findings suggest that tumoral tissues, herein exemplified by HNSCC and lung cancers might be more resistant to SARS-CoV-2 infection due to reduced expression of TMPRSS2. These observations may help to better assess the frailty of SARS-CoV-2 positive cancer patients.
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http://dx.doi.org/10.1186/s13046-020-01708-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510014PMC
September 2020

Neoadjuvant Immune-Checkpoint Blockade in Triple-Negative Breast Cancer: Current Evidence and Literature-Based Meta-Analysis of Randomized Trials.

Cancers (Basel) 2020 Sep 3;12(9). Epub 2020 Sep 3.

Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy.

Chemotherapy based on the sequential use of anthracyclines and taxanes has long represented the most efficacious approach in the management of early-stage, triple-negative breast cancer, whose aggressive behavior is widely renowned. This standard chemotherapy backbone was subsequently enriched by the use of carboplatin, based on its association with increased pathologic complete response and efficacy in the metastatic setting. Following the results from the IMpassion130 trial, the recent approval of the immunotherapic agent atezolizumab in combination with chemotherapy as first-line treatment for programmed-death ligand 1-positive, unresectable locally advanced, or metastatic triple-negative breast cancer increasingly fueled the flourishing of trials of immune-checkpoint inhibitors in the early setting. In this work, we review the most recent inherent literature in light of key methodological issues and provide a quantitative summary of the results from phase II-III randomized trials of immunotherapic agents combined with chemotherapy in the setting of interest. Hints regarding future directions are also discussed.
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http://dx.doi.org/10.3390/cancers12092497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565914PMC
September 2020

Breast cancer surgery during the Covid-19 pandemic: a monocentre experience from the Regina Elena National Cancer Institute of Rome.

J Exp Clin Cancer Res 2020 Aug 27;39(1):171. Epub 2020 Aug 27.

Department of Surgery, Division of Breast Surgery, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.

The Covid-19 pandemic has challenged hard the national health systems worldwide. According to the national policy issued in March 2020 in response to the evolving Covid-19 pandemic, several hospitals were re-configured as Covid-19 centers and elective surgery procedures were rescheduled according to the most recent recommendations. In addition, Covid-19 protected cancer hubs were established, including the Regina Elena National Cancer Institute of Rome, Central Italy. At our Institute, the Breast Surgery Department continued working under the sign of a multidisciplinary approach. The number of professional figures involved in case evaluation was reduced to a minimum and interactions took place in the full respect of the required safety measures. Treatments for benign disease, pure prophylactic surgery and elective reconstructive procedures were all postponed and priority was assigned to the histologically-proven malignant breast tumors and highly suspicious lesions. From March 15th though April 30th 2020, we treated a total of 79 patients. This number is fully consistent with the average quantitative standards reached by our Department under ordinary circumstances. Patients were mostly discharged the day after surgery and none was readmitted due to surgery-related late complications. More generally, post-operative complications rates were unexpectedly low, particularly in light of the relatively high number of reconstructive procedures performed in this emergency situation. A strict follow up was performed based on the close contact with the surgical staff by telephone, messaging apps and telemedicine.Patients ascertainment for their Covid-19 status prior to hospital admission and hospital discharge allowed to maintain the "no-Covid-19" status at our Institution. In addition, during the aforementioned time window, none of the care providers developed SARS-CoV-2 infection or disease, as shown by the results of anti-SARS-CoV-2 immunoglobulin M and G profiling. In conclusions, elective breast cancer surgery procedures were successfully performed in a lockdown situation due to a novel viral pandemic. The well-coordinated regional and hospital efforts in terms of medical resource re-allocation and definition of clinical priorities allowed to maintain high quality standards of breast cancer care while ensuring safety to the cancer patients and care providers involved.
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http://dx.doi.org/10.1186/s13046-020-01683-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450921PMC
August 2020

Predictors of 2-Year Incidence of Patient-Reported Urinary Incontinence After Post-prostatectomy Radiotherapy: Evidence of Dose and Fractionation Effects.

Front Oncol 2020 23;10:1207. Epub 2020 Jul 23.

Istituto Scientifico Ospedale San Raffaele, Radiotherapy, Milan, Italy.

To investigate predictors of patient-reported urinary incontinence (PRUI) in the first 2 years after post-prostatectomy radiotherapy (PORT) with particular emphasis on possible dose-effect relationships. Two-hundred-thirteen patients, whose clinical and dosimetric data were prospectively collected within a registered multi-institutional cohort study, underwent PORT with adjuvant ( = 106) or salvage ( = 107) intent with conventional ( = 123, prescribed dose to the prostatic bed: 66.6-79.8Gy in 1.8-2.0Gy/fr) or moderately hypo- ( = 90, 65.8-76.8Gy in 2.1-2.7Gy/fr) fractionation during the period 2011-2017. PRUI was evaluated through the ICIQ-SF questionnaire filled in at baseline and every 6 months thereafter. The analysis focused on three ICIQ-based clinically relevant endpoints: (a) very frequent leakage (FREQUENCY, ICIQ3 score >3), (b) moderate to severe amount of urine loss (AMOUNT, ICIQ4>2) (c) objective severe symptoms (OBJECTIVE, ICIQ3+4>5). Predictors of the incidence within 2 years for the three endpoints were investigated focusing only on patients without endpoint symptoms at baseline. A uni-variable logistic regression analysis was performed in order to determine the best dose metrics describing PRUI risk in terms of 2-Gy equivalent dose (EQD2) calculated with different α/β values reported in the literature (0.8, 3, 5Gy), and to identify the most significant clinical variables. Variables showing < 0.20 at uni-variable analysis were entered into a backward stepwise multi-variable logistic regression analysis. Lastly, the goodness of fit and model calibration were evaluated and internally validated. Patients without symptoms at baseline experienced (a), (b), and/or (c) within 2 years in 41/130 (32%), 40/192 (21%), and 41/129 (32%) of the cases, respectively. EQD2 for α/β = 0.8Gy was the best dose metric associated with PRUI. Multi-variable analysis identified baseline incontinence levels as the strongest predictor for all endpoints ( < 0.006). Both FREQUENCY and OBJECTIVE were significantly influenced also by EQD2(α/β = 0.8Gy). The goodness of fit was excellent, as was the calibration; internal calibration confirmed apparent performance. Baseline mild urinary incontinence symptoms strongly modulate the 2-year risk of PRUI. In addition, FREQUENCY is characterized by a marked dose-effect relationship also influencing the trend of OBJECTIVE, with results more reliable than AMOUNT as an objective index. A strong impact of fractionation on severe PRUI after post-prostatectomy radiotherapy also emerged.
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http://dx.doi.org/10.3389/fonc.2020.01207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396712PMC
July 2020

Head and neck radiotherapy amid the COVID-19 pandemic: practice recommendations of the Italian Association of Radiotherapy and Clinical Oncology (AIRO).

Med Oncol 2020 Aug 17;37(10):85. Epub 2020 Aug 17.

Department of Radiotherapy, Policlinico Umberto I, "Sapienza" University of Rome, Rome, Italy.

Management of patients with head and neck cancers (HNCs) is challenging for the Radiation Oncologist, especially in the COVID-19 era. The Italian Society of Radiotherapy and Clinical Oncology (AIRO) identified the need of practice recommendations on logistic issues, treatment delivery and healthcare personnel's protection in a time of limited resources. A panel of 15 national experts on HNCs completed a modified Delphi process. A five-point Likert scale was used; the chosen cut-offs for strong agreement and agreement were 75% and 66%, respectively. Items were organized into two sections: (1) general recommendations (10 items) and (2) special recommendations (45 items), detailing a set of procedures to be applied to all specific phases of the Radiation Oncology workflow. The distribution of facilities across the country was as follows: 47% Northern, 33% Central and 20% Southern regions. There was agreement or strong agreement across the majority (93%) of proposed items including treatment strategies, use of personal protection devices, set-up modifications and follow-up re-scheduling. Guaranteeing treatment delivery for HNC patients is well-recognized in Radiation Oncology. Our recommendations provide a flexible tool for management both in the pandemic and post-pandemic phase of the COVID-19 outbreak.
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http://dx.doi.org/10.1007/s12032-020-01409-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430932PMC
August 2020

Moderately accelerated intensity-modulated radiation therapy using simultaneous integrated boost: Practical reasons or evidence-based choice? A critical appraisal of literature.

Head Neck 2020 11 6;42(11):3405-3414. Epub 2020 Aug 6.

Radiotherapy 2 Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Concurrent chemo-radiotherapy is the non-surgical mainstay of treatment for locally advanced head and neck squamous cell carcinoma (HNSCC). The following aspects have emerged as fundamental components of the combined approach: first, intensity modulated radiotherapy (IMRT) is the minimum standard technical requirement, with level 1 evidence in support of its reduction of late treatment-induced morbidity in comparison with 3D conformal radiotherapy. Second, cisplatin-based chemotherapy is the preferred systemic agent to be associated with radiation, with 100 mg/m every 3 weeks deemed as the reference schedule. Because of significant progress in irradiation techniques achieved in last 15 years, the optimal fractionation schedule in modern radiation era remains controversial, especially for locally advanced disease. The purpose of this work was to perform a critical review on the value of moderately accelerated IMRT using simultaneous-integrated boost (SIB) in HNSCC, aiming to provide insights on current clinical practice and directions for future research.
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http://dx.doi.org/10.1002/hed.26400DOI Listing
November 2020

Is postoperative radiotherapy routinely indicated after total laryngectomy for pT3N0-1 supraglottic carcinoma?

Oral Oncol 2020 08 31;107:104825. Epub 2020 May 31.

Department of Otolaryngology Head and Neck Surgery, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, Rome, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.oraloncology.2020.104825DOI Listing
August 2020

Neoadjuvant Endocrine Therapy in Breast Cancer: Current Knowledge and Future Perspectives.

Int J Mol Sci 2020 May 16;21(10). Epub 2020 May 16.

Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy.

In locally advanced (LA) breast cancer (BC), neoadjuvant treatments have led to major achievements, which hold particular relevance in HER2-positive and triple-negative BC. Conversely, their role in hormone receptor positive (HR+), hormone epidermal growth factor 2 negative (HER2-) BC is still under debate, mainly due to the generally low rates of pathological complete response (pCR) and lower accuracy of pCR as predictors of long-term outcomes in this patient subset. While administration of neoadjuvant chemotherapy (NCT) in LA, HR+, HER2- BC patients is widely used in clinical practice, neoadjuvant endocrine therapy (NET) still retains an unfulfilled potential in the management of these subgroups, particularly in elderly and unfit patients. In addition, NET has gained a central role as a platform to test new drugs and predictive biomarkers in previously untreated patients. We herein present historical data regarding Tamoxifen and/or Aromatase Inhibitors and a debate on recent evidence regarding agents such as CDK4/6 and PI3K/mTOR inhibitors in the neoadjuvant setting. We also discuss key issues concerning the optimal treatment length, appropriate comparisons with NCT efficacy and use of NET in premenopausal patients.
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http://dx.doi.org/10.3390/ijms21103528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278946PMC
May 2020

Non-coding RNAs as Putative Biomarkers of Cancer-Associated Cachexia.

Front Cell Dev Biol 2020 21;8:257. Epub 2020 Apr 21.

Oncogenomic and Epigenetic Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

Cachexia is a complex metabolic syndrome that determines a severe body weight loss characterized by a marked reduction in muscle mass. About 80% of patients with advanced cancer develop cachexia due to both the tumor itself and cancer treatment (radiotherapy and/or chemotherapy), which is associated to a worse prognosis. Despite its clinical relevance, this syndrome is still under-diagnosed and it lacks effective treatments. Radio-chemotherapy treatment is essential in patients with advanced head and neck cancers (HNSCC). Although this treatment has improved patients' life expectancy, it has also dramatically increased their need for assistance and support. The management of adverse symptoms, including cachexia, is of great importance in order to avoid delays in therapy, reduction of dosages and hospitalizations. MicroRNAs (miRNAs) are small non-coding RNA molecules, which have emerged as powerful biomarkers in stratifying human cancers. Due to their high stability in body fluids, miRNAs might be excellent non-invasive biomarkers for the early detection and follow-up of cancer patients. Here, we will summarize the current knowledge and debate the strong need to identify circulating biomarkers for the early diagnosis of cachexia. We will propose circulating non-coding RNAs as biomarkers for detecting early cachexia and implementing specific treatment. We will also discuss the potential use of circulating miRNAs as biomarkers of cachexia in HNSCC patients' blood samples collected before and after radio-chemotherapy treatment. Our intent is to pave the way to the identification of specific circulating miRNAs associated to cachexia occurrence and to the design of specific interventions aimed at improving the quality of life of cancer patients.
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http://dx.doi.org/10.3389/fcell.2020.00257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187787PMC
April 2020

Laryngeal vs oropharyngeal cancer: T2 or not T2.

Oral Oncol 2020 10 7;109:104678. Epub 2020 Apr 7.

Department of Radiation Oncology, IRCSS Regina Elena National Cancer Institute, Rome, Italy.

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http://dx.doi.org/10.1016/j.oraloncology.2020.104678DOI Listing
October 2020

Observational Multicenter Study on the Prognostic Relevance of Coagulation Activation in Risk Assessment and Stratification in Locally Advanced Breast Cancer. Outline of the ARIAS Trial.

Cancers (Basel) 2020 Apr 1;12(4). Epub 2020 Apr 1.

Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi, 00144 Rome, Italy.

A hypercoagulable state may either underlie or frankly accompany cancer disease at its onset or emerge in course of cancer development. Whichever the case, hypercoagulation may severely limit administration of cancer therapies, impose integrative supporting treatments and finally have an impact on prognosis. Within a flourishing research pipeline, a recent study of stage I-IIA breast cancer patients has allowed the development of a prognostic model including biomarkers of coagulation activation, which efficiently stratified prognosis of patients in the study cohort. We are now validating our risk assessment tool in an independent cohort of 108 patients with locally advanced breast cancer with indication to neo-adjuvant therapy followed by breast surgery. Within this study population, we will use our tool for risk assessment and stratification in reference to 1. pathologic complete response rate at definitive surgery, intended as our primary endpoint, and 2. rate of thromboembolic events, intended as our secondary endpoint. Patients' screening and enrollment procedures are currently in place. The trial will be shortly enriched by experimental tasks centered on next-generation sequencing techniques for identifying additional molecular targets of treatments which may integrate current standards of therapy in high-risk patients.
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http://dx.doi.org/10.3390/cancers12040849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226579PMC
April 2020

Response on DCE-MRI predicts outcome of salvage radiotherapy for local recurrence after radical prostatectomy.

Tumori 2021 Feb 17;107(1):55-63. Epub 2020 Mar 17.

Medical Physics, IRCSS Regina Elena National Cancer Institute, Rome, Italy.

Objective: To assess the predictive role of response on dynamic contrast enhancement on magnetic resonance imaging (DCE-MRI) of visible local lesions in the setting of salvage radiotherapy (sRT) after radical prostatectomy.

Methods: All patients referred for sRT for biochemical failure after radical prostatectomy from February 2014 to September 2016 were considered eligible if they had been restaged with DCE-MRI and had been found to have a visible lesion in the prostatic bed, but no distant/nodal disease on choline positron emission tomography (PET)-computed tomography (CT). Eligible patients were contacted during follow-up and offered reimaging with serial DCE-MRI until lesion resolution. Complete response (CR) was defined as the disappearance of the target lesion on DCE-MRI; prostate-specific antigen (PSA) recurrence was defined as a 0.2 ng/mL PSA rise above the nadir. Median follow-up after sRT was 41.5 months (range, 12.1-61.2 months).

Results: Fifty-nine patients agreed to undergo repeated DCE-MRI for a total of 64 studied lesions. Overall, 57 lesions (89.1%) showed a CR after 1 (51 patients) or 2 (6 patients) scans, while 7 lesions did not show any change (no response [NR]). At 42 months, no evidence of biochemical disease (bNED) survival was 74.7±6.4% and 64.3±21.0% for patients with CR and NR lesions, respectively (hazard ratio [HR], 3.181; 95% confidence interval [CI], 0.157-64.364; = 0.451). When only patients treated with sRT without androgen deprivation were selected ( = 41), bNED survival rates at 42 months were 72.1±8.0% and 0, respectively (HR, 52.830; 95% CI, 1.893-1474.110; = 0.020).

Conclusions: Patients whose lesions disappear during follow-up have a better outcome than those with unchanged lesions after sRT alone.
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http://dx.doi.org/10.1177/0300891620908950DOI Listing
February 2021

Correlation between histogram-based DCE-MRI parameters and 18F-FDG PET values in oropharyngeal squamous cell carcinoma: Evaluation in primary tumors and metastatic nodes.

PLoS One 2020 2;15(3):e0229611. Epub 2020 Mar 2.

Medical Physics Laboratory, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

Objectives: To investigate the correlation between histogram-based Dynamic Contrast-Enhanced magnetic resonance imaging (DCE-MRI) parameters and positron emission tomography with 18F-fluorodeoxyglucose (18F-FDG-PET) values in oropharyngeal squamous cell carcinoma (OPSCC), both in primary tumors (PTs) and in metastatic lymph nodes (LNs).

Methods: 52 patients with a new pathologically-confirmed OPSCC were included in the present retrospective cohort study. Imaging including DCE-MRI and 18F-FDG PET/CT scans were acquired in all patients. Both PTs and the largest LN, if present, were volumetrically contoured. Quantitative parameters, including the transfer constants, Ktrans and Kep, and the volume of extravascular extracellular space, ve, were calculated from DCE-MRI. The percentiles (P), P10, P25, P50, P75, P90, and skewness, kurtosis and entropy were obtained from the histogram-based analysis of each perfusion parameter. Standardized uptake values (SUV), SUVmax, SUVpeak, SUVmean, metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were calculated applying a SUV threshold of 40%. The correlations between all variables were investigated with the Spearman-rank correlation test. To exclude false positive results under multiple testing, the Benjamini-Hockberg procedure was applied.

Results: No significant correlations were found between any parameters in PTs, while significant associations emerged between Ktrans and 18F-FDG PET parameters in LNs.

Conclusions: Evident relationships emerged between DCE-MRI and 18F-FDG PET parameters in OPSCC LNs, while no association was found in PTs. The complex relationships between perfusion and metabolic biomarkers should be interpreted separately for primary tumors and lymph-nodes. A multiparametric approach to analyze PTs and LNs before treatment is advisable in head and neck squamous cell carcinoma (HNSCC).
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229611PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051076PMC
June 2020

Refinement & validation of rectal wall dose volume objectives for prostate hypofractionation in 20 fractions.

Clin Transl Radiat Oncol 2020 Mar 31;21:91-97. Epub 2020 Jan 31.

Departments of Physics, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

Background And Purpose: Dose-volume objectives for the rectum have been proposed to limit long term toxicity after moderately hypofractionated radiotherapy (MHRT) for localized prostate cancer. The purpose of the present study is to validate and possibly refine dose volume objective for the rectal wall after 20-fraction MHRT.

Materials And Methods: All patients treated by 20-fraction MHRT at a single Institution were identified and relative rectal wall (%RW) DVH retrieved. The endpoint of the study is the development of grade 2+ late rectal bleeding (LRB) according to a modified RTOG scale. Clinical and dosimetric predictors of LRB were investigated at both uni- and multi-variable analysis.

Results: 293 patients were identified and analyzed. Of them, 35 (12%) developed the endpoint. At univariable analysis, antithrombotic drug usage (yes vs no), technique (3DCRT vs IMRT/VMAT) and several %RW DVH cut-points were significantly correlated with LRB. However, within patients treated by 3DCRT (N = 106), a bi-variable model including anti-thrombotic drug usage and selected %RW dose/volume metrics failed to identify independent dosimetric predictors of LRB. Conversely, within patients treated with intensity modulation (N = 187), the same model showed a progressively higher impact of the percent of RW receiving doses above 40 Gy. Based on this model, we were able to confirm (V32), refine (V60) and identify a novel (V50) cut-point for the %RW.

Conclusion: We recommend the following dose volume objectives for the %RW in order to minimize the risk of LRB after 20-fraction MHRT: V32 ≤ 50%; V50 ≤ 25.8% and V60 ≤ 10%.
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http://dx.doi.org/10.1016/j.ctro.2020.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015822PMC
March 2020

PI3K Inhibitors Curtail MYC-Dependent Mutant p53 Gain-of-Function in Head and Neck Squamous Cell Carcinoma.

Clin Cancer Res 2020 06 22;26(12):2956-2971. Epub 2020 Jan 22.

Oncogenomic and Epigenetic Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

Purpose: Mutation of gene is a hallmark of head and neck squamous cell carcinoma (HNSCC) not yet exploited therapeutically. mutation frequently leads to the synthesis of mutant p53 proteins with gain-of-function activity, associated with radioresistance and high incidence of local recurrences in HNSCC.

Experimental Design: Mutant p53-associated functions were investigated through gene set enrichment analysis in the Cancer Genome Atlas cohort of HNSCC and in a panel of 22 HNSCC cell lines. Mutant p53-dependent transcripts were analyzed in HNSCC cell line Cal27, carrying mutant p53H193L; FaDu, carrying p53R248L; and Detroit 562, carrying p53R175H. Drugs impinging on mutant p53-MYC-dependent signature were identified interrogating Connectivity Map (https://clue.io) derived from the Library of Integrated Network-based Cellular Signatures (LINCS) database (http://lincs.hms.harvard.edu/) and analyzed in HNSCC cell lines and patient-derived xenografts (PDX) models.

Results: We identified a signature of transcripts directly controlled by gain-of-function mutant p53 protein and prognostic in HNSCC, which is highly enriched of MYC targets. Specifically, both in PDX and cell lines of HNSCC treated with the PI3Kα-selective inhibitor BYL719 (alpelisib) the downregulation of mutant p53/MYC-dependent signature correlates with response to this compound. Mechanistically, mutant p53 favors the binding of MYC to its target promoters and enhances MYC protein stability. Treatment with BYL719 disrupts the interaction of MYC, mutant p53, and YAP proteins with MYC target promoters. Of note, depletion of MYC, mutant p53, or YAP potentiates the effectiveness of BYL719 treatment.

Conclusions: Collectively, the blocking of this transcriptional network is an important determinant for the response to BYL719 in HNSCC.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2485DOI Listing
June 2020

Impact of BMI on HER2+ metastatic breast cancer patients treated with pertuzumab and/or trastuzumab emtansine. Real-world evidence.

J Cell Physiol 2020 11 15;235(11):7900-7910. Epub 2020 Jan 15.

Medical Oncology Unit, Belcolle Hospital, Viterbo, Italy.

Body mass index (BMI) is a main indicator of obesity and its association with breast cancer is well established. However, little is known in the metastatic setting, especially in HER2-positive patients. We assessed the influence of BMI on clinical outcomes of patients treated with pertuzumab and/or trastuzumab emtansine (T-DM1) for HER2+ metastatic breast cancer (mBC). BMI was addressed as a categorical variable, being classified on the basis of the following ranges, that is, 18.5-24.9, 25-29.9, and 30.0-34.9, namely, normal weight, overweight, and Class I obesity. The outcomes chosen were progression-free survival to first-line chemotherapy (PFS1) and overall survival (OS). Overall (N = 709), no impact of BMI was observed on PFS1 (p = .15), while BMI ≥ 30 was associated with worse OS (p = .003). In subjects who progressed to first line (N = 575), analyzing data across PFS1 quartiles and strata of disease burden, BMI predicted lower PFS1 in patients within the I PFS1 quartile and with the lowest disease burden (p = .001). Univariate analysis showed a detrimental effect of BMI ≥ 30 on OS for women within the I PFS1 quartile (p = .03). Results were confirmed in multivariate analysis. According to PFS1 quartiles a higher percentage of patients with high BMI and low disease burden progressed within 6 months of therapy. The effect of BMI on prognosis was also confirmed in multivariate analysis of OS for overall population. In our cohort, a BMI ≥ 30 correlated with worse OS in patients with HER2+ mBC who received pertuzumab and/or T-DM1 but had no impact on PFS to first line. BMI predicted worse I PFS1 quartile.
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http://dx.doi.org/10.1002/jcp.29445DOI Listing
November 2020