Distant Metastatic Disease Research Articles

Association of Blood Pressure with Prostate Cancer Risk by Disease Severity and Prostate Cancer Death: A Pooled Cohort Study.

The association of blood pressure (BP) with prostate cancer risk after accounting for asymptomatic prostate-specific antigen (PSA) testing, and with prostate cancer death, is unclear. We investigated BP, measured at a mean age of 38 years among 430,472 men from five Swedish cohorts, in association with incident prostate cancer (n = 32,720) and prostate cancer death (n = 6718). HRs were calculated from multivariable Cox regression models. Increasing systolic and diastolic BP levels combined were associated with a slightly lower prostate cancer risk, with a HR of 0.98 (95% CI, 0.97-0.99) per standard deviation (SD) of mid-BP (average of systolic and diastolic BP). The association was restricted to the PSA era (1997 onwards, HR, 0.96; 95% CI, 0.95-0.98), to diagnoses initiated by a PSA test in asymptomatic men (HR, 0.95; 95% CI, 0.93-0.97), and to low-risk prostate cancer (HR, 0.95; 95% CI, 0.92-0.97). There was no clear association with more advanced disease at diagnosis. In cases, a slightly higher risk of prostate cancer death was observed for higher BP levels (HR, 1.05; 95% CI, 1.01-1.08) per SD of mid-BP; however, the association was restricted to distant metastatic disease (Pheterogeneity between case groups = 0.01), and there was no association for BP measured less than 10 years prior to diagnosis. Prediagnostic BP is unlikely an important risk factor for prostate cancer development and death. Less asymptomatic PSA testing among men with higher BP levels may explain their lower risk of prostate cancer. Elevated BP is unlikely to be an important risk factor for prostate cancer.

Abstract #1183700: TERT Promotor Mutation as a Prognostic Indicator in Papillary Thyroid Carcinoma

Papillary thyroid carcinoma (PTC) is generally considered a curable disease. However, not all PTC behaves the same. Knowledge of tumor genetics offers an important tool for guiding clinical decision making and risk stratification in PTC. We present an interesting case of a patient initially thought to have intermediate risk PTC, who later presented with distant metastatic disease, associated with a high-risk tumor mutation.

PD51-09 SURVIVAL IN N3 PENILE CANCER: DOES PELVIC LYMPHADENOPATHY PREDICT A WORSE PROGNOSIS THAN INGUINAL EXTRA-NODAL EXTENSION?

You have accessJournal of UrologyCME1 May 2022PD51-09 SURVIVAL IN N3 PENILE CANCER: DOES PELVIC LYMPHADENOPATHY PREDICT A WORSE PROGNOSIS THAN INGUINAL EXTRA-NODAL EXTENSION? James A. Churchill, Ashwin Sachdeva, Allaudin Issa, Craig Jones, Fowz Azhar, Ikenna Aneke, Noel W. Clarke, Maurice W. Lau, Vijay K. Sangar, and Arie S. Parnham James A. ChurchillJames A. Churchill More articles by this author , Ashwin SachdevaAshwin Sachdeva More articles by this author , Allaudin IssaAllaudin Issa More articles by this author , Craig JonesCraig Jones More articles by this author , Fowz AzharFowz Azhar More articles by this author , Ikenna AnekeIkenna Aneke More articles by this author , Noel W. ClarkeNoel W. Clarke More articles by this author , Maurice W. LauMaurice W. Lau More articles by this author , Vijay K. SangarVijay K. Sangar More articles by this author , and Arie S. ParnhamArie S. Parnham More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002622.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Penile squamous cell cancer (PSCC) with lymph node (LN) disease has a poor overall survival (OS). The current TNM classification system defines clinical N3 (cN3) stage as the presence of fixed inguinal LN metastasis or pelvic lymphadenopathy (PLN), and pathologic N3 (pN3) stage as metastasis in pelvic LN and/or extra-nodal extension (ENE) in any LN. This study has examined whether N3 stage can be further stratified based on ENE and PLN status. We hypothesised a worse OS for patients with PLN on cross-sectional imaging compared to those with ENE present in inguinal LN (iENE) and without PLN. METHODS: We analysed retrospective data for patients treated at a UK tertiary referral centre between 2003 and 2021 with PSCC and suspicion of LN disease (cN+) at diagnosis. We excluded patients with extra-pelvic LN or distant metastatic disease at diagnosis and those without available cross-sectional imaging of the abdomen and pelvis within 6 months of definitive primary (penile) treatment. The primary outcome of OS (time from definitive primary surgery to death, censored for last follow-up) was stratified by PLN present (PLN+) vs PLN absent and iENE present (PLN-iENE+). The PLN absent and iENE absent (PLN-iENE-) group has been included as a reference for OS comparison. Audit approval was obtained from the host clinical governance committee. RESULTS: 199 patients met inclusion criteria, of which 110 were categorised as PLN-iENE-, 58 as PLN-iENE+ and 31 as PLN+. Baseline characteristics of age, primary tumour stage and grade were similar across all groups. Univariate Cox regression analysis demonstrated an increased risk of death in the PLN-iENE+ group (HR=2.23, 95% CI 1.38-3.61, p=0.001) and the PLN+ group (HR=4.08, 95% CI 2.39-6.97, p<0.001) compared to the reference PLN-iENE- group (Figure 1). CONCLUSIONS: In patients with PSCC and clinical evidence of LN metastases, the PLN-iENE+ and PLN+ groups show worse OS compared to those with PLN-iENE- as predicted by the current TNM classification system. The results also demonstrate that the presence of PLN predicts worse OS than the presence of iENE. This suggests that the current TNM classification system should be refined by further stratifying the staging groups based on ENE and PLN status. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e845 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information James A. Churchill More articles by this author Ashwin Sachdeva More articles by this author Allaudin Issa More articles by this author Craig Jones More articles by this author Fowz Azhar More articles by this author Ikenna Aneke More articles by this author Noel W. Clarke More articles by this author Maurice W. Lau More articles by this author Vijay K. Sangar More articles by this author Arie S. Parnham More articles by this author Expand All Advertisement PDF DownloadLoading ...

Lymph node colonization induces tumor-immune tolerance to promote distant metastasis

For many solid malignancies, lymph node (LN) involvement represents a harbinger of distant metastatic disease and, therefore, an important prognostic factor. Beyond its utility as a biomarker, whether and how LN metastasis plays an active role in shaping distant metastasis remains an open question. Here, we develop a syngeneic melanoma mouse model of LN metastasis to investigate how tumors spread to LNs and whether LN colonization influences metastasis to distant tissues. We show that an epigenetically instilled tumor-intrinsic interferon response program confers enhanced LN metastatic potential by enabling the evasion of NK cells and promoting LN colonization. LN metastases resist Tcell-mediated cytotoxicity, induce antigen-specific regulatory Tcells, and generate tumor-specific immune tolerance that subsequently facilitates distant tumor colonization. These effects extend to human cancers and other murine cancer models, implicating a conserved systemic mechanism by which malignancies spread to distant organs.

Sentinel Lymph Node Biopsy and Formal Lymphadenectomy for Soft Tissue Sarcoma: A Single Center Experience of 86 Consecutive Cases.

Lymph node metastases (LNMs) are rare in patients with soft tissue sarcoma (STS), and there is limited evidence to guide clinical management. We describe our experience with sentinel lymph node biopsy (SLNB) and lymphadenectomy in STS patients. A single-center, retrospective review was performed for patients with STS treated with SLNB and/or lymphadenectomy from 1994 to 2018. Clinicopathologic characteristics, multimodality treatment, regional/distant recurrence-free survival (RFS), and overall survival (OS) were examined. Eighty-six patients underwent SLNB (n = 34) and/or lymphadenectomy (n = 60) for STS. The most frequent histologic subtypes were epithelioid, clear cell, and undifferentiated pleomorphic sarcoma. Eight of 34 (23.5%) patients had a positive SLNB with 5-year OS of 71.4% compared with 71.9% for those with a negative SLNB. Eight of the 26 SLN-negative patients (30.8%) eventually developed nodal recurrence (n = 2) and/or (n = 6) distant metastasis with an estimated 5-year OS of 50%. Of patients undergoing lymphadenectomy, estimated 5-year OS was 44.6% and median RFS was 12 months. Eight (13.3%) had distant disease at time of lymphadenectomy, 20 (33.3%) developed distant recurrence after lymphadenectomy, and 6 (10%) developed regional-only recurrence. Patients with regional-only recurrence after lymphadenectomy had an estimated 5-year OS of 66.7% compared with 29.1% for those who recurred distantly. Patients with positive SLNB had similar survival to those with negative SLNB. Lymphadenectomy for isolated nodal disease is associated with poor RFS but reasonable 5-year OS when recurrence is regional-only. In STS, regional disease appears clinically distinct from distant metastatic disease and has better outcomes.

A clinical case of a big urethral recurrence after cystectomy in a patient with invasive bladder cancer

The urethral recurrence (UR) of invasive bladder cancer (iBC) after cystectomy is observed in 6% of patients at highest. In this clinical observation of a 38-year old man, a mass (103 38 mm) was found in the proximal urethra by magnetic resonance imaging at 15 months after radical (R0) cystectomy for iBC pT4aN0M0. The clinical picture of UR was characterized by urethrorrhagia and priapism with associated advanced pain syndrome. At 3 months after surgical resection of the UR and subsequent chemotherapy, distant lung, liver and bone metastases were found, which led to the patient's death at 5 months after penectomy. This clinical case indicates that after radical cystectomy, the occurrence of a big-sized urethral recurrence of iBC can cause rapid development of distant metastatic disease.

Metastatic medullary thyroid carcinoma: a new way forward.

Medullary thyroid carcinoma (MTC) is a rare malignancy comprising 1–2% of all thyroid cancers in the United States. Approximately 20% of cases are familial, secondary to a germline RET mutation, while the remaining 80% are sporadic and also harbour a somatic RET mutation in more than half of all cases. Up to 15–20% of patients will present with distant metastatic disease, and retrospective series report a 10-year survival of 10–40% from time of first metastasis. Historically, systemic therapies for metastatic MTC have been limited, and cytotoxic chemotherapy has demonstrated poor objective response rates. However, in the last decade, targeted therapies, particularly multitargeted tyrosine kinase inhibitors (TKIs), have demonstrated prolonged progression-free survival in advanced and progressive MTC. Both cabozantinib and vandetanib have been approved as first-line treatment options in many countries; nevertheless, their use is limited by high toxicity rates and dose reductions are often necessary. New generation TKIs, such as selpercatinib or pralsetinib, that exhibit selective activity against RET, have recently been approved as a second-line treatment option, and they exhibit a more favourable side-effect profile. Peptide receptor radionuclide therapy or immune checkpoint inhibitors may also constitute potential therapeutic options in specific clinical settings. In this review, we aim to present all current therapeutic options available for patients with progressive MTC, as well as new or as yet experimental treatments.

Effect of LOXL2 on metastasis through remodeling of the cell surface matrix in non-small cell lung cancer cells

Lung cancer is the prominent cause of cancer-associated death primarily because of distant metastatic disease. The metastatic potential of non-small cell lung cancer (NSCLC) is associated with tumor cell aggregation. However, the systemic mechanotransduction mechanism by which tumor cells dynamically aggregate and disseminate is poorly understood, especially in NSCLC. In this study, we examine whether the cell surface matrix plays an important role in metastasis. We used poly-2-hydroxyethyl methacrylate-based 3D spheroid formation methods to mimic in vivo metastatic lesions. Supra-structural analysis of human NSCLC A549 cells stained with ruthenium red for transmission electron microscopy (TEM) showed that glycocalyx surrounding the cell surface in 2D culture decreases in 3D culture. Comprehensive gene expression analysis revealed that the genes associated with cell adhesion were distinctly enriched in A549 cell spheroids. Of these, downregulation of the tumor metastatic microenvironment facilitator LOXL2, a copper-dependent enzyme catalyzing posttranslational oxidative deamination of peptidyl lysine, was of special interest. Knockdown of LOXL2 thickened the cell surface matrix in 2D culture and impaired compact aggregate formation in 3D culture. Moreover, A549 cell spheroids with endogenous overexpression of LOXL2 increased their dissemination on basement extracellular matrix Matrigel. Overall, these data imply that cell detachment-downregulated LOXL2 contributes to cell surface matrix remodeling, leading to collective dissemination of free-floating aggregates.

Clinical experience following implementation of routine SPECT-CT imaging following 131-iodine administration for thyroid cancer.

BackgroundPlanar scintigraphy has long been indicated in patients receiving I-131 therapy for thyroid cancer to determine the anatomic location of metastases. We studied our experience upon implementing additional single-photon emission (SPECT)-CT scanning in these patients.MethodWe performed a retrospective study of consecutive adult patients with newly diagnosed thyroid cancer treated with I-131 between 2011 and 2017. Radiologic findings detected with planar scintigraphy alone vs those identified with SPECT-CT scanning were primary endpoints.ResultIn this study, 212 consecutive patients with thyroid cancer were analyzed in two separate cohorts (107 planar scintigraphy alone and 105 planar scintigraphy with SPECT-CT). The addition of SPECT-CT resulted in more findings, both thyroid-related and incidental. However, we identified only 3 of 21 cases in which SPECT-CT provided an unequivocal additional benefit by changing clinical management beyond planar scintigraphy alone. No difference in the detection of distant metastatic disease or outcome was identified between cohorts.ConclusionSynergistic SPECT-CT imaging in addition to planar nuclear scintigraphy adds limited clinical value to thyroid cancer patients harboring a low risk of distant metastases, while frequently identifying clinically insignificant findings. These data from a typical cohort of patients receiving standard thyroid cancer care provide insight into the routine use of SPECT-CT in such patients.

End-of-life intravenous chemotherapy administration patterns in the treatment of Queensland lung and pancreas cancer patients: a 10-year retrospective analysis.

End-of-life (EOL) chemotherapy administration rates for solid tumours are 12-20% and are associated with a reduced quality of life, increased hospitalisation and incidence of death within an acute care facility. We sought to determine the rate of EOL chemotherapy in government and private hospitals and determine the impact on hospitalisations and location of death in lung and pancreatic cancer patients. Data were obtained from the Queensland Oncology Repository between 2005 and 2014. Lung (n = 16 501) and pancreatic cancer (n = 4144) deaths were analysed. EOL chemotherapy was determined to be within 30 days of death. Demographics, location of treatment and death are reported. Chemotherapy was administered to 6518 (40%) lung cancer and 1694 (41%) pancreatic cancer patients. A total of 1474 (9%) and 477 (12%) patients, respectively, received EOL chemotherapy. EOL chemotherapy was more common in males and those with distant metastatic disease, while less likely in the elderly and those with a lower socioeconomic status. EOL chemotherapy was more prevalent in large hospitals and was more common in private compared with government hospitals for pancreatic cancer (30 vs 26%; P < 0.001), while it was similar for lung cancer (24 vs 22%; P = 0.115). Death after EOL chemotherapy compared with all cancer deaths was more common in an acute care facility (lung cancer: 60 vs 37%; P < 0.001; pancreatic cancer: 53 vs 36%; P < 0.001). EOL chemotherapy rates were similar to Australian yet marginally lower than international rates, with variation dependent on the size and type of facility and increased the rate of deaths within an acute care facility.

Chemoradiotherapy Versus Chemotherapy Alone for Advanced Esophageal Squamous Cell Carcinoma: The Role of Definitive Radiotherapy for Primary Tumor in the Metastatic Setting.

IntroductionThe role of definitive radiotherapy in advanced esophageal squamous cell carcinoma (ESCC), especially in the metastatic setting, remains unclear. Therefore, we aimed to investigate the efficacy of chemoradiotherapy (CRT) versus chemotherapy (CT) alone in these selected patients.MethodsWe retrospectively evaluated 194 newly diagnosed advanced ESCC who underwent definitive CRT or CT alone, including 97 patients with locally advanced and 97 patients with distant metastatic disease. Cumulative overall survival (OS) and progression-free survival (PFS) were evaluated with a log-rank test. Propensity score matching was used to simulate random allocation. In addition, we performed subgroup analysis in the locally advanced and metastatic disease.ResultsAfter matching, 63 well-paired patients were selected. The adjusted median OS (12.5 vs. 7.6 months, p = 0.002) and PFS (9.0 vs. 4.8 months, p = 0.0025) in the CRT group were superior to that in the CT-alone group. Further subgroup analysis revealed that CRT conferred survival benefits to both locally advanced and metastatic cohorts. For patients with distant metastasis, median OS (12.9 vs. 9.3 months, p = 0.029) and PFS (9.9 vs. 4.0 months, p =0.0032) in the CRT group were superior to that in the CT-alone group. In a multivariate Cox regression analysis of the entire cohort, additional definitive radiotherapy was independently associated with better OS (p = 0.041) and PFS (p = 0.007).ConclusionsIn both locally advanced and metastatic ESCC, additional definitive-dose radiotherapy was associated with improved clinical outcomes. Therefore, more consideration should be given to its application in the metastatic setting.

Neuroendocrine Neoplasms of the Oropharynx—A Literature Review

<h3>Purpose/Objective(s)</h3> Neuroendocrine neoplasms (NEN) are a diverse group of rare tumors. The most common primary sites are gastrointestinal tract and lung, though these neoplasms can occur throughout the body. Neuroendocrine neoplasms of the head and neck are rare, with those of the oropharynx being especially uncommon. Case studies and small series make up most of the literature on oropharyngeal neuroendocrine tumors, and there is no clear consensus on how to treat these unique cancers. Therefore, we aim to explore the current literature describing neuroendocrine neoplasms of the oropharynx. <h3>Materials/Methods</h3> A comprehensive search of several databases including Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, Web of Science, and Scopus from inception to May 19, 2021 was conducted. Inclusion criteria included diagnosis of neuroendocrine neoplasm of the tonsil, base of tongue, soft palate, or posterior pharyngeal wall with histopathology available for review. Cases with distant metastatic disease at presentation, review papers, large database studies, papers not in English, papers without outcomes of interest reported, and conference abstracts were excluded. Information including patient demographics, symptoms at presentation, radiologic findings, diagnostic approach, treatment approach, and outcomes were recorded. <h3>Results</h3> The search resulted in 1,154 papers. After title and abstract screening, 93 papers qualified for full review, with 28 were included ultimately in our review. In these papers, 52 unique cases were identified. The average age at presentation was 62 years. Of the patients identified, 73% were male (n=38), 25% were female (n=13), and 2%were unspecified (n=1). The most common site was the tonsil at 36% (n= 21). This was followed by 35% in the tongue base (n=18), 17% in the oropharynx (unspecified) (n=10), 2% in the soft palate (n=1), and 3% unknown primary sites (n=2). The most common histology was small cell neuroendocrine carcinoma at 45% (n= 26). HPV status was reported in 24 patients, with 75% being HPV positive (n=18) and 25% HPV negative (n=6). Treatment modalities varied, with definitive therapy being the most common, in 19 cases. <h3>Conclusion</h3> Neuroendocrine neoplasms of the head and neck are a rare subtype of oropharyngeal cancer, and there is limited data available to drive treatment. More work is needed to elucidate guidelines for how to treat these rare tumors.

The Continuum of Metastatic Prostate Cancer: Interpreting PSMA PET Findings in Recurrent Prostate Cancer.

Simple SummaryMolecular imaging with PSMA PET–CT is more accurate and sensitive than conventional imaging with CT, MRI, and a Technetium-99 bone scan. This new imaging modality will result in more advanced disease being diagnosed earlier which may improve survival, however, it could also lead to overtreatment. Since molecular imaging has the potential to identify disease prior to its detection on conventional imaging, this highlights that advanced prostate cancer exists on a continuum. This review discusses how PSMA PET–CT can be used in managing prostate cancer using clinical scenarios.Conventional imaging has been the standard imaging modality for assessing prostate cancer recurrence and is utilized to determine treatment response to therapy. Molecular imaging with PSMA PET–CT has proven to be more accurate, sensitive, and specific at identifying pelvic or distant metastatic disease, resulting in earlier diagnosis of advanced disease. Since advanced disease may not be seen on conventional imaging, due to its lower sensitivity, but can be identified by molecular imaging, this reveals that metastatic prostate cancer occurs on a continuum from negative PSMA PET–CT and negative conventional imaging to positive PSMA PET–CT and positive conventional imaging. Understanding this continuum, the accuracy of these modalities, and treatment related outcomes based on imaging, will allow the clinician to counsel patients on management. This review will highlight the differences in conventional and molecular imaging in prostate cancer and how PSMA PET–CT can be used for the management of prostate cancer patients in different clinical scenarios, while providing cautionary notes for overtreatment.

Oncological outcomes of surgery for isolated retroperitoneal recurrence in renal cancer patients after radical nephrectomy.

Isolated retroperitoneal recurrence (IRR) in renal cancer patients after radical nephrectomy (RN) is a rare event and poses a therapeutic dilemma. We evaluated oncologic outcomes in surgically treated patients with IRR and established prognostic factors associated with survival. The benefit of metastasis-directed therapy (MDT) in those with clinical progression after extirpation of IRR was assessed. This was a retrospective single-institutional study in which 60 renal cancer patients after previous RN underwent surgery for suspicion of IRR within the period of 2004-2019; in 55 of them, RCC recurrence was histologically confirmed. No patient had distant metastatic disease at the time of IRR diagnosis. In cases of clinical progression after IRR surgery, MDT (metastasectomy, stereotactic radiotherapy) was selectively used. Kaplan-Meier curves were used to estimate survival outcomes. Univariable and multivariable Cox proportional hazards regression analyses were used to evaluate associations between clinicopathological parameters and cancer-specific survival. Median age at IRR diagnosis was 64 years (range 23-81). IRR was diagnosed at a median of 42 months (IQR 19-99) after RN. Surgical complications of grade 3-5 after IRR extirpation were rare (7%). Median follow-up time was 50 months (IQR 19-80). Five-year recurrence-free survival and cancer-specific survival rates were 32% and 66%, respectively. Radiographic progression was observed in 34 (62%) patients at a median of 11 months after IRR surgery, out of which 22 patients (40%) underwent MDT. When compared with 12 patients without MDT, the MDT patients had a prolonged median time to systemic treatment of 58 (vs. 16 months), and median cancer-specific survival of 88 (vs. 46 months). Upon multivariable analysis, the interval from nephrectomy ≤12 months (HR 7.77), tumour grade 3-4 (HR 13.24) and female sex (HR 7.42) were determined to be independent prognostic factors of cancer-related mortality. Aggressive surgical therapy of IRR is feasible with relatively low morbidity. More than half of the patients experience long-term survival. The interval from nephrectomy to IRR less than 12 months, tumour grade 3-4 and female sex were negative prognostic predictors. In the case of progression, metastasis-directed therapy may prolong the interval to initiation of systemic treatment.

Poorly differentiated thyroid carcinoma: a clinician's perspective.

Poorly differentiated thyroid carcinoma (PDTC) is a rare thyroid carcinoma originating from follicular epithelial cells. No explicit consensus can be achieved to date due to sparse clinical data, potentially compromising the outcomes of patients. In this comprehensive review from a clinician’s perspective, the epidemiology and prognosis are described, diagnosis based on manifestations, pathology, and medical imaging are discussed, and both traditional and emerging therapeutics are addressed as well. Turin consensus remains the mainstay diagnostic criteria for PDTC, and individualized assessments are decisive for treatment option. The prognosis is optimal if complete resection is performed at early stage but dismal in nearly half of patients with locally advanced and/or distant metastatic diseases, in which adjuvant therapies such as 131I therapy, external beam radiation therapy, and chemotherapy should be incorporated. Emerging therapeutics including molecular targeted therapy, differentiation therapy, and immunotherapy deserve further investigations to improve the prognosis of PDTC patients with advanced disease.

A single arm, phase I/II trial of neoadjuvant androgen deprivation, darolutamide, and ipatasertib in men with localized, high-risk prostate cancer.

TPS286 Background: Most patients (pts) who die of prostate cancer (pca) had potentially curable localized disease when first diagnosed, but their cancer subsequently relapsed to an incurable state. Neoadjuvant intense androgen deprivation therapy (ADT) has led to exceptional pathologic responses in up to 30% of pts with intermediate or high risk localized disease, with evidence of longer term clinical benefit. Prostate cancers with loss of the tumor suppressor gene PTEN, however, are resistant to neoadjuvant therapy that only targets the Androgen Receptor. Ipatasertib has shown efficacy in metastatic castration resistant prostate cancer (mCRPC), especially in pts with tumors that lack PTEN. Methods: This is a single arm study of darolutamide 600 mg BID, ipatasertib, and ADT. The initial phase I portion includes pts with nonmetastatic or mCRPC. Pts start with a lead-in of ipatasertib for 7 days, followed by ipatasertib combined with darolutamide 600 mg BID. The dose limiting toxicity period is the first 4 weeks of combination therapy. The phase I portion will enroll 6-18 pts. The phase II portion is given neoadjuvantly and includes pts with high risk localized pca. Pts receive up to 24 weeks of darolutamide 600 mg BID and ipatasertib at the recommended phase II dose (RP2D), followed by prostatectomy 14-42 days after cycle 6. The phase II portion will enroll up to 20 pts (17 evaluable pts) with high risk pca, with an early evaluation for efficacy after 9 pts are enrolled and with an additional stopping rule for safety. Key eligibility criteria for the phase II portion include 2 or more cores of grade group 4 or higher cancer on prostate needle biopsy or grade group 3 or higher with T3 or T4 disease, no distant metastatic disease, and PTEN loss (defined as 50% or more of tumor tissue being negative for PTEN expression). Exclusion criteria for both portions include small cell carcinoma, bowel inflammation, lung disease, diabetes mellitus requiring insulin, and conditions requiring strong CYP3A inducers or inhibitors. The primary endpoint for the phase I lead-in is to identify the RP2D of ipatasertib. The primary endpoint for the phase II portion is the combined rate of pathologic complete response (defined as absence of pathologic disease on hematoxylin and eosin (H&amp;E) stain (ypT0)), or with presence of minimal residual disease ( &lt; 5 mm linearly). We employ a Simon MiniMax two-stage design with 90.5% power to detect the difference between the null hypothesis (5% or less response rate) and the alternative hypothesis (30% response rate) with one-sided type I error of 0.05. Key secondary endpoints are safety, 2 year biochemical recurrence free survival, and rate of PSA0 (undetectable PSA with testosterone recovery and no additional therapy). Enrollment to the phase 1 portion began in September 2021, and the study is available at select Big Ten institutions. Clinical trial information: NCT04737109.

Abstract P4-11-02: Prevalence and impact of fertility concerns in young women with breast cancer

Abstract Introduction: Breast cancer treatments can impair fertility via direct gonadotoxicity (chemotherapy) as well as by introducing delays in childbearing that allow natural ovarian aging. Guidelines strongly recommend fertility counseling and consideration of fertility preservation techniques for premenopausal women who have not completed their desired childbearing at the time of cancer diagnosis. Prior studies have identified high rates of fertility concern but relatively low rates of fertility counseling and use of fertility preservation techniques. We sought to investigate rates of fertility counseling, use of fertility preservation techniques, and how fertility concerns impact cancer treatment decisions in a modern cohort of patients with breast cancer at a large academic medical center in the United States. Methods: All patients seen at Mayo Clinic Rochester with a new diagnosis (within the year prior) of stage 0-4 breast cancer were invited (by mail or in person) to participate in the Mayo Clinic Breast Registry. After informed consent, participants were asked to complete a baseline survey and annual follow-up surveys. On baseline and one-year surveys, patients were queried about desire for future children and fertility concerns. Nurse chart abstraction was used to collect information about tumor subtype, stage, and treatments received. We examined survey data from women diagnosed under the age of 50 who expressed an interest in having future biological children on either the baseline or year 1 survey between February 2015 and October 2020. Descriptive statistics were used to summarize the degree of fertility concern in this population, the impact of that concern on cancer treatment decisions, and steps taken to preserve fertility. Results: Between February 2015 and October 2020, 865 women under age 50 at diagnosis consented to the registry. Of these women, 627 completed a baseline and/or 1-year survey and 100 answered either “yes” or “unsure” to the question: “At the present time, do you wish to have any more biological children in the future?” on one or both surveys. Among the 100 women expressing interest in future child-bearing, 92% were white, 27% had node-positive and one had distant metastatic disease at diagnosis. The age at diagnosis ranged from 19 to 49 years, with a mean age of 33.8 years. Of the 75 who reported a desire for future children at baseline, 28% felt “somewhat concerned” about their future fertility and 40% felt “very concerned.” Of the 70 who reported a desire for future children on the year 1 survey, 17% felt “somewhat concerned” and 59% felt “very concerned.” For those “very concerned” about future fertility at year 1, 65% reported that this concern had a major impact on their treatment decisions. Often, that treatment modification entailed using endocrine therapy for less than 5 years; 52% of those who specified the type of treatment modification they had made indicated this option. Of note, six women who reported no desire for future biological children at baseline were “unsure” at year 1. At year 1, 93% of women recalled a discussion about fertility with their doctor prior to starting treatment, and 49% had taken steps to preserve fertility (32.5% with embryo cryopreservation, 20% with oocyte cryopreservation and 65% with a GnRH agonist; some selected multiple options). Conclusion: We found a reassuringly high rate of patient-reported fertility counseling and use of reproductive endocrinology technologies to preserve fertility in women who reported a desire for additional children at or soon after diagnosis with breast cancer. Consistent with prior studies, fertility concerns frequently impacted breast cancer treatment decisions. It is important to err on the side of inclusivity when providing fertility counseling because desire for fertility can change over time. Citation Format: Samantha Mannion, Alexandra Higgins, Elizabeth A Stewart, Zaraq Khan, Chandra Shenoy, Nicole Larson, Hazel B Nichols, H Irene Su, Ann H Partridge, Fergus J Couch, Janet E Olson, Kathryn Ruddy. Prevalence and impact of fertility concerns in young women with breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-11-02.

Abstract P2-01-07: Detection of early-stage breast cancer recurrence using a personalised liquid biopsy-based sequencing approach

Abstract BACKGROUNDDetection of minimal residual disease (MRD) using circulating tumor DNA (ctDNA) represents an attractive alternative to imaging, currently considered the gold standard in routine surveillance of early breast cancer (BrCa) following primary therapy. ctDNA has the potential to identify patients who may eventually develop distant metastatic disease and, as such, its implementation in the routine clinical follow-up setting may offer the means for earlier intervention for patients with oligometastatic disease and improved overall survival. However, due to the highly heterogeneous nature of the genomic alterations in BrCa, ultra-sensitive ctDNA assays are required for follow-up surveillance. Here we evaluate RaDaR™, a personalised liquid biopsy-based sequencing assay for the detection of residual disease and monitoring after standard treatment in early-stage BrCa. METHODS38 early-stage BrCa patients recruited through the BRandO BiO registry study were included (18% TNBC, 74% HR+/HER2-, 8% HER2+). 21 patients experienced clinical recurrence (13 distant and 8 local), with a median time to progression of 18.9 months. The remaining 17 case-control patients had no disease recurrence at the time of 3-year follow-up. Whole exome sequencing (WES) was performed on formalin-fixed, paraffin-embedded (FFPE) tumor tissue from curative-intent surgery and selected variants were used to design personalised RaDaR panels (38-54 variants/panel: median 49). In total, 52 plasma samples were analyzed using RaDaR. This included samples taken at the time of recurrence and at 12-months post-diagnosis where available (33 samples from 21 patients), or in the case of no recurrence, samples taken at 3-year follow up, including one control case that had two additional samples analyzed at 12-months and 4-years of follow up (19 samples from 17 patients). RESULTSIn total, ctDNA was detected in 12/13 (92%) patients with distant recurrence and 3/8 (38%) patients with local recurrence at an estimated median variant allele frequency (VAF) of 0.827% (range: 0.0029% - 38%). The lowest levels were seen in the 3 patients with local recurrence (0.0029%, 0.0146% and 0.0248% VAF). Of the 6 patients negative for ctDNA, 5 had local and one distant recurrence of unusual histology, indicating a possible alternative origin or second primary tumor. Only one of the 17 control cases was positive for ctDNA (0.0085% VAF), from a patient with a Luminal A, stage I tumor, potentially indicating the presence of early molecular recurrence that precedes clinical progression. Two additional time points from this patient also showed positive ctDNA results, which could be indicative of residual disease remaining dormant. Of the 12 patients with disease recurrence for which an earlier plasma sample was available, 4 patients (3 with distant and one with local recurrence) had ctDNA detected at the earlier time point, a median of 92 days (range 42 – 308 days) prior to clinical recurrence. 3 patients had ctDNA detected only at the time of recurrence (one distant and 2 local). None of the 5 patients with ctDNA negative results at the time of recurrence had detectable ctDNA levels at the earlier timepoint. CONCLUSIONIn this real-world pilot study, the RaDaR assay detected the presence of ctDNA in plasma to levels as low as 0.0029% VAF. We found that ctDNA detection was strongly associated with distant recurrence in early-stage BrCa, with a sensitivity of 92% (12 of 13 cases detected). In a limited number of cases where samples were available prior to recurrence, ctDNA could be detected ahead of clinical progression, potentially offering the opportunity for earlier intervention. Citation Format: Wolfgang Janni, Jens Huober, Sophia Huesmann, Christodoulos Pipinikas, Tatjana Braun, Volkmar Müller, Giovanni Marsico, Angelina Fink, Paula Freire-Pritchett, Karin Koretz, Charlene Knape, Amelie deGregorio, Brigitte Rack, Thomas WP Friedl, Lisa Wiesmueller, Peter Möller, Karen Howarth, Klaus Pantel, Nitzan Rosenfeld. Detection of early-stage breast cancer recurrence using a personalised liquid biopsy-based sequencing approach [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-01-07.

Neoadjuvant Intratumoral Immunotherapy with TLR9 Activation and Anti-OX40 Antibody Eradicates Metastatic Cancer.

This work demonstrates the ability of neoadjuvant intratumoral immunotherapy to target local and distant metastatic disease and consequently improve survival.

Histopathological growth distribution of ductal carcinoma in situ: tumor size is not "one size fits all".

Ductal carcinoma in situ (DCIS) is a group of preinvasive breast neoplasms. Studies have shown excellent survival among patients with lumpectomy-amenable disease. Patients requiring mastectomy have been less well characterized. We aim to characterize this cohort and identify whether growth distribution pattern is associated with sentinel lymph node involvement at time of surgery or subsequent development of metastatic disease. Patients were identified using local cancer registry data and were chart reviewed using electronic medical records. Growth pattern was classified as unifocal, multifocal, or diffuse. Chi-squared, Analysis of Variance (ANOVA), and Kaplan-Meier analyses were performed. Two hundred and twenty-six patients were identified with median age at diagnosis 49 and follow up 7.1 years. 42 had unifocal, 51 had multifocal and 20 had diffuse lesions. 3/20 patients with diffuse type lesions developed subsequent distant metastatic disease, while none of the patients with unifocal or multifocal lesions did. 1/20 patients with diffuse and 2/51 with multifocal disease had sentinel lymph node involvement (SLNI) at surgery. Tumor extent was not associated with sentinel lymph node involvement or distant metastatic disease (P=0.2, Kaplan-Meier analysis) but growth pattern was (P=0.01). It was also associated on Kaplan-Meier with development of distant metastatic disease alone (P=0.01). Patients with diffuse growth pattern DCIS were more likely to have SLNI or development of distant metastatic disease. Our findings suggest that patients with diffuse type lesions are at greater risk of metastatic disease and therefore breast cancer death from DCIS. Optimal therapy for these patients will need further elucidation.