Low Metastatic Burden Research Articles

Abstract A001: Reciprocal activation of breast cancer metastases and the lung epithelium during metastatic outgrowth

Abstract Introduction. During metastasis, tumor cells interact extensively with endogenous cells in distant organs. These interactions change the behavior of these surrounding cell populations, often inducing a more pro-tumor microenvironment. The lung is one of the most common sites of breast cancer (BC) metastasis, and in the lung, alveolar epithelial cells are the most common cell type. My data suggest that the lung alveolar epithelium contributes to metastatic outgrowth, and I hypothesize that BC lung micrometastases activate surrounding lung epithelial cells which, in turn, support the outgrowth of BC metastases within the lung. The overall purpose of these studies is to identify factors secreted by resident lung epithelial cells that could be used as metastasis-specific therapeutic targets and/or agents. Methods. To test this hypothesis, I utilized immunocompetent preclinical BC metastasis models to study lung metastatic outgrowth, the stage at which most patients are diagnosed with metastatic disease. A custom imaging panel was developed to quantify lung wound repair, and single-cell RNA-sequencing (scRNAseq) was performed on mouse lungs with high or low metastatic burden to identify genes in the lung epithelium that produce potentially targetable pro-metastatic secreted factors. No-contact co-culture experiments were used to directly study reciprocal paracrine interactions between lung type II alveolar epithelial (AT2) and BC cells. Results. A wound repair-related phenotype, characterized by chronic inflammation, developed within the lung microenvironment during metastatic outgrowth, including an increase in the number and activation of AT2 cells surrounding metastases as they grow. Single-cell RNA-sequencing of mouse lungs with a high vs. low metastatic burden showed that metastatic outgrowth significantly changed AT2 gene expression resulting in a modified secretome. No-contact co-culture experiments indicated that TNBC cells directly alter AT2 gene expression, while AT2 secreted factors promoted TNBC growth. I investigated the possible mechanism(s) responsible for these effects and discovered that AT2 pulmonary surfactant protein and lipid levels are altered by BC-derived secreted factors. Interestingly, treatment with the naturally derived calf surfactant Infasurf, which contains native surfactant proteins/lipids and is FDA-approved for use in premature infants, inhibited BC proliferation. Conclusion. Low levels of surfactant are commonly associated with pulmonary disease and lung cancer. My BC lung metastasis data suggest that something similar may be occurring in the lungs during metastatic outgrowth. Overall, my studies demonstrate the potential for targeting lung epithelial cells in the metastatic microenvironment, in addition to directly targeting malignant cells, as an effective way to treat and manage BC lung metastases. Citation Format: Jessica L. Christenson, Nicole S. Spoelstra, Jennifer K. Richer. Reciprocal activation of breast cancer metastases and the lung epithelium during metastatic outgrowth [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A001.

Subgroup analyses from patients with pre-treated metastatic colorectal cancer receiving trifluridine/tipiracil: results of the TALLISUR trial

BackgroundIn the pivotal phase III RECOURSE trial, trifluridine/tipiracil (FTD/TPI) improved progression-free and overall survival (PFS, OS) of patients with pre-treated metastatic colorectal cancer (mCRC). Subsequently, the TALLISUR trial provided post-authorisation efficacy and safety data and patient-reported outcomes on quality of life (QoL) in a German patient cohort. The present analysis reports the final data on efficacy, safety and QoL and investigates the impact of baseline characteristics and associated prognostic subgroups on outcome.MethodsIn this prospective, multi-centre, Germany-wide, phase IV study, patients with pre-treated mCRC were given the choice to receive either FTD/TPI or best supportive care (BSC). To assess the primary endpoint, QoL, EORTC QLQ-C30 questionnaires were employed. Secondary endpoints included QoL assessed through EQ-5D-5L questionnaires, OS, PFS and safety. Additionally, 3 subgroups were defined according to a post-hoc analysis of the RECOURSE trial: best, good and poor prognostic characteristics (BPC, GPC, PPC). Patients with < 3 metastatic sites at inclusion and/or ≥ 18 months from diagnosis to inclusion were considered to have GPC. GPC patients without liver metastasis at inclusion were considered to have BPC. All remaining patients were considered to have PPC.ResultsOf 195 patients, 186 decided to receive FTD/TPI and 9 to receive BSC. The low number of patients in the BSC-arm did not allow statistically meaningful analyses. Treatment with FTD/TPI was associated with maintained QoL. For all patients, median OS was 6.9 months (95% CI 6.1 – 8.3) and for the defined subgroups (BPC n = 20 vs GPC n = 65 vs PPC n = 121) 12.2, 7.9 and 6.8 months (95% CI 6.0 – 18.2, 6.2 – 13.3, 5.4 – 8.1). The most frequent TEAEs were neutropenia (29.6%), anaemia (24.7%) and nausea (23.7%). Febrile neutropenia occurred in 1.1%.ConclusionsTreatment of patients suffering from pre-treated mCRC with FTD/TPI was associated not only with prolonged survival and delayed progression, but also with maintained QoL. Independent of other baseline characteristics such as ECOG performance status and age, low metastatic burden and indolent disease were factors associated with favourable outcome.Clinical trial registrationEudraCT-Number 2017–000292-83, first registration 19/06/2017.

Targeted axillary dissection reduces residual nodal disease in clinically node- positive breast cancer after neoadjuvant chemotherapy

BackgroundAny advantage of performing targeted axillary dissection (TAD) compared to sentinel lymph node (SLN) biopsy (SLNB) is under debate in clinically node-positive (cN+) patients diagnosed with breast cancer. Our objective was to assess the feasibility of the removal of the clipped node (RCN) with TAD or without imaging-guided localisation by SLNB to reduce the residual axillary disease in completion axillary lymph node dissection (cALND) in cN+ breast cancer.MethodsA combined analysis of two prospective cohorts, including 253 patients who underwent SLNB with/without TAD and with/without ALND following NAC, was performed. Finally, 222 patients (cT1-3N1/ycN0M0) with a clipped lymph node that was radiologically visible were analyzed.ResultsOverall, the clipped node was successfully identified in 246 patients (97.2%) by imaging. Of 222 patients, the clipped lymph nodes were non-SLNs in 44 patients (19.8%). Of patients in cohort B (n=129) with TAD, the clipped node was successfully removed by preoperative image-guided localisation, or the clipped lymph node was removed as the SLN as detected on preoperative SPECT-CT. Among patients with ypSLN(+) (n=109), no significant difference was found in non-SLN positivity at cALND between patients with TAD and RCN (41.7% vs. 46.9%, p=0.581). In the subgroup with TAD with axillary lymph node dissection (ALND; n=60), however, patients with a lymph node (LN) ratio (LNR) less than 50% and one metastatic LN in the TAD specimen were found to have significantly decreased non-SLN positivity compared to others (27.6% vs. 54.8%, p=0.032, and 22.2% vs. 50%, p=0.046).ConclusionsTAD by imaging-guided localisation is feasible with excellent identification rates of the clipped node. This approach has also been found to reduce the additional non-SLN positivity rate to encourage omitting ALND in patients with a low metastatic burden undergoing TAD.

Abstract PO3-22-07: Predicting Additional Axillary Metastases in Breast Cancer Patients with Positive Targeted Axillary Dissection Lymph Nodes after Neoadjuvant Treatment

Abstract Background: Neoadjuvant chemotherapy (NACT) is increasingly used for axillary downstaging in clinically node-positive breast cancer patients, and a considerable proportion achieves axillary pathological complete response (ax-pCR). After NACT, axillary staging can be done by targeted axillary dissection (TAD). In case of metastases at TAD, axillary lymph node dissection (ALND) is offered regardless of metastases size. This contrasts primary surgery, where small sentinel node metastases (ypN0(i) and ypN1mi) and ≤2 positive sentinel nodes do not confer ALND, although a proportion of patients with small metastases have additional metastatic lymph nodes (LNs) in the axilla. So far, the residual metastatic burden in the axilla when TAD LNs are positive after NACT is unknown. If subgroups of patients with low residual metastatic burden in the axilla (non-TAD LNs) could be identified, these subgroups may be offered de-escalated axillary treatment. Therefore, we investigated the risk of residual metastatic burden in the axilla when the TAD LNs harbored metastases. Methods: We retrospectively retrieved DBCG data on patients staged by TAD after NACT in Denmark between 1.1.2016-31.8.2021. We registered: age, breast biopsy date, type of surgery, type of axillary surgery, count of LNs, sentinel nodes, and marked lymph nodes with and without metastases, including metastasis size, breast tumor histology and receptor subtype, breast tumor size at diagnosis and in the surgical specimen, malignancy grade and type of neoadjuvant treatment. We excluded patients with inflammatory breast cancer, &amp;lt; 4/&amp;gt;8 cycles of NACT, or a non-standard NACT regimen. The primary outcome was risk factors for having high ( &amp;gt;3), low (1-3), or no residual metastatic burden in the axilla when the TAD LNs harbored metastases. We modeled risk factors for both high and low residual metastatic burden in the axilla using multivariable logistic regression and constructed risk models based on the regression coefficients. Results: We identified 1626 patients receiving NACT and TAD in the inclusion period. After excluding ineligible patients and patients who achieved ax-pCR with no subsequent ALND (46%), the study included 383 patients with positive LNs at TAD for further analysis: thereof 188, 127, and 68 with 0, 1-3 and &amp;gt;3 positive non-TAD LNs, respectively. In the adjusted logistic regression analysis, we found that breast pCR (OR= 0.06, 95% CI &amp;lt; .01-0.41, p &amp;lt; .001) and a low proportion of positive TAD LNs (0-66% vs &amp;gt;66%) (OR=0.32, 95% CI 0.17-0.58, p = &amp;lt; .001) were associated with low risk of high residual metastatic burden in the axilla. Patients with one or both low-risk factors present had an 8% (14 of 176 patients) risk of high residual metastatic burden in the axilla. The predictive value of the model for having &amp;lt; 3 non-TAD LN metastases was 92%. When analyzing the 315 patients with ≤3 positive non-TAD LNs, the adjusted logistic regression analysis of 1-3 vs 0 positive non-TAD LNs showed that ypN0(i) in the TAD LN (OR=0.14, 95% CI 0.04-0.53, p = 0.002), small tumor size at diagnosis (20-49 mm vs ≥ 50 mm) (OR = 0.29, 95% CI 0.14-0.60, p = 0.002), breast pCR (OR= 0.38, 95% CI 0.15-0.98, p = 0.04) and low proportion of positive TAD LNs (33-66% vs &amp;gt;66%) (OR= 0.46, 95% CI 0.27-0.77, p = 0.01) were associated with no residual metastases in the axilla. Using these risk factors, 19% (11/58) of the patients in the lowest risk quartile had further metastatic spread to the axilla. Conclusion: Based on an extensive breast cancer registry, we find that breast pCR, low proportion of positive TAD LNs, small metastases, and small tumor size are associated with low risk of residual metastatic LNs in the axilla when the TAD LNs are positive after NACT. With these risk factors, we propose two models to identify patients with low non-TAD residual metastatic burden and patients with a high likelihood of no further metastases. The models can guide breast surgeons in de-escalating axillary treatment in these groups. Citation Format: Frederikke Munck, Maj-Britt Jensen, Ilse Vejborg, Maria Gerlach, Maja Maraldo, Niels Kroman, Tove Tvedskov. Predicting Additional Axillary Metastases in Breast Cancer Patients with Positive Targeted Axillary Dissection Lymph Nodes after Neoadjuvant Treatment [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-22-07.

Abstract PO4-25-02: Long-range Deployment of Tumor-antigen Specific Cytotoxic T Lymphocytes Inhibits Lung Metastasis of Breast Cancer

Abstract Effector Immune Cell Deployment (EICD) refers to systemic deployment of anti-tumor effector immune cells in cancer patients, including the priming, circulation, trafficking, activity and fate of the immunocytes, and is a panorama to reflect the generation, distribution and development of anti-tumor immunity. Tumor antigen-specific T cells are the main component of effector immune cells in anti-tumor immune responses, but their systemic deployment in breast cancer patients and the underlying mechanisms remain largely unknown. Here, we identified a cluster of CD8+ T cell exhibiting tissue-resident memory (TRM) phenotype in the tumor-draining lymph nodes (TDLNs) of 487 breast cancer patients, whose abundancy specifically predicts improved lung, but not other target organ metastasis-free survival. Also, high lung CD8+ TRM infiltration is associated with lower metastatic burden in breast cancer patients. Using single-cell RNA sequencing, we observed that in multiple mouse cancer models, CD8+TRM accumulate at early tumor stages when lung metastasis was not identified. Functionally, the CD8+TRM isolated from pre-metastatic lungs of the animals were tumor antigen specific and cytotoxic to the tumor cells. Nevertheless, the abundancy of CD8+TRM in the lungs were dramatically decreased in the lungs upon metastasis establishment. Moreover, in Cd8cre/+ Itgaeloxp/+-diphtheria toxin receptor conditional knockout mice, we unambiguously demonstrated that specific depletion of the CD8+ TRM subset facilitates lung metastasis in vivo, while adoptive transfer of CD8+ TRM successfully inhibited lung metastasis and prolonged survival of the mice. Mechanistically, using cell-tracing techniques in the photo-convertible Kaede-Tg mice, we found that tumor-specific CD8+ TRM were generated in the TDLNs of the mice and were recruited to the lungs via CCL25/CCR9 signaling axis. However, the circulating exosomes secreted by primary tumor cells were taken up by alveolar macrophages and polarized them to release IDO1 and impaired anti-tumor T cell immunity, facilitating lung metastasis. More importantly, inhibition of IDO1 effectively retrieves TRM-mediated protection against lung metastasis. Collectively, we have revealed a cross-talk between tumor cells and the inflammatory environment of distant organs, which could drive lung metastasis by impairing EICD. Our findings also highlight the therapeutic potential of orchestrating EICD in turning “cold” metastatic tumor foci to “hot” ones. Citation Format: Yue Xing, Shicheng Su, Erwei Song. Long-range Deployment of Tumor-antigen Specific Cytotoxic T Lymphocytes Inhibits Lung Metastasis of Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-25-02.

The efficacy and safety of stereotactic body radiotherapy combined with systematic therapy for metastatic renal cell carcinoma: a systematic review and meta-analysis.

There is considerable interest in the potential of stereotactic body radiation therapy (SBRT) combined with systemic therapy such as tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitors (ICIs). However, its efficacy and safety remain unclear. The purpose of this study was to evaluate the efficacy and safety of conducting SBRT during ICI or TKI treatment in different disease settings for patients with metastatic renal cell carcinoma (mRCC). A total of 16 studies were ultimately included. Under the random effects model, the pooled 1-year local control rate (1-yr LCR) and objective response rate (ORR) were 90% (95% confidence interval [CI]: 80%-95%, I 2=67%) and 52% (95% CI: 37%-67%, I 2=90%), respectively. SBRT concomitant with different systemic therapy yield significant different 1-yr LCR (p<0.01) and ORR (p=0.02). Regarding survival benefits, the pooled 1-year progression-free survival (1-yr PFS) and 1-year overall survival (1-yr OS) rates were 45% (95% CI: 29%-62%, I 2=91%) and 85% (95% CI: 76%-91%, I 2=66%), respectively. 1-yr PFS and 1-yr OS in different disease settings demonstrated significant difference (p<0.01). As for toxicity, the pooled incidence of grade 3-4 adverse events was 14% (95% CI: 5%-26%, I 2=90%). This study highlights the feasibility of utilizing these strategies in mRCC patients, especially those with a low metastatic tumor burden.

THEMIS2 Impairs Antitumor Activity of NK Cells by Suppressing Activating NK Receptor Signaling.

NK cells are cytotoxic innate lymphocytes that play a critical role in antitumor immunity. NK cells recognize target cells by using a repertoire of activating NK receptors and exert the effector functions. Although the magnitude of activation signals through activating NK receptors controls NK cell function, it has not been fully understood how these activating signals are modulated in NK cells. In this study, we found that a scaffold protein, THEMIS2, inhibits activating NK receptor signaling. Overexpression of THEMIS2 attenuated the effector function of human NK cells, whereas knockdown of THEMIS2 enhanced it. Mechanistically, THEMIS2 binds to GRB2 and phosphorylated SHP-1 and SHP-2 at the proximity of activating NK receptors DNAM-1 and NKG2D. Knockdown of THEMIS2 in primary human NK cells promoted the effector functions. Furthermore, Themis2-deficient mice showed low metastatic burden in an NK cell-dependent manner. These findings demonstrate that THEMIS2 has an inhibitory role in the antitumor activity of NK cells, suggesting that THEMIS2 might be a potential therapeutic target for NK cell-mediated cancer immunotherapy.

Evidence and emerging trends in local therapy for metastatic hormone-sensitive prostate cancer: a narrative review.

Metastatic hormone-sensitive prostate cancer (mHSPC) displays both simultaneous and sequential patterns of metastasis, emphasizing a comprehensive treatment approach that integrates both local therapy and systemic treatment strategies. The increasing use of molecular imaging has led to a rise in mHSPC diagnoses, underscoring the importance of identifying the right patient population and effective treatment concepts for this disease state. Two prospective trials, HORRAD and STAMP EDE, investigated prostate radiotherapy (RT) for mHSPC; however, they did not show an overall survival (OS) benefit in the unselected cohort. Nonetheless, RT showed favorable outcomes in patients with fewer than five bone metastases, resulting in a 7% 3-year survival improvement and supporting the integration of RT in multimodal treatment for men with oligometastatic mHSPC. Regarding cytoreductive prostatectomy (cRP), the TRoMbone Trial confirmed its feasibility and safety. In addition, findings from the FUSCC-OMPCa Trial demonstrated improved 3-year radiographic progression-free survival and OS rates with acceptable rates of complications and incontinence. Recent data from the LoMP registry have further supported superior OS and cancer-specific survival (CSS) in patients undergoing cRP compared to systemic therapy alone. Notably, no significant differences in OS and CSS were observed between the cRP and RT groups. However, cRP-treated patients exhibited superior 2-year local event-free survival when compared to those treated with RT. RT in combination with systemic therapy remains the established first-line treatment for low-burden mHSPC, though the exact definition of low metastatic burden remains contentious. Precise assessment of metastatic burden is vital to identify patients who would derive the greatest benefit from RT. As treatment paradigms evolve, embracing multimodal approaches holds potential for optimizing outcomes in patients with mHSPC. Further research is needed to solidify the role of cRP as a standard therapeutic approach and to refine treatment strategies for improved patient outcomes.

Prognostic Significance of Radiographic Lymph Node Invasion in Contemporary Metastatic Renal Cell Carcinoma Patients

PurposeTo test the prognostic significance of radiographic cN-stage in metastatic renal cell carcinoma (mRCC) patients with low metastatic burden (1 site of metastasis), relying on the Surveillance, Epidemiology, and End Results database (SEER 2010-2020). MethodsIncluded were mRCC patients with 1 site of metastasis, treated with systemic therapy without cytoreductive nephrectomy (CN). Kaplan-Meier plots and multivariable Cox-regression models addressed cancer-specific mortality (CSM) according to radiographic cN-stage (ccN1 vs. ccN0). Separate subgroup analyses were performed, addressing radiographic N-stage in patients with distinct histology (clear-cell vs. RCC not otherwise specified [RCC NOS]). ResultsOf 1756 mRCC patients, 545 (31%) were radiographic cN1. Overall, the median CSM-free survival of the cohort was 11 months. Median CSM-free survival was 8 vs. 14 months in radiographic cN1 vs. cN0 mRCC patients (HR 1.49, P < .0001). In multivariable Cox regression analyses, radiographic cN1 status was an independent predictor of higher CSM (HR 1.39; P = .01). In subgroup analyses, addressing patients with clear-cell histology and patients with RCC NOS separately, radiographic cN1 status remained independently associated with a higher CSM in both groups (clear-cell: HR 1.36; P = .03; RCC NOS: HR 2.06; P = .009). ConclusionIn mRCC patients with low metastatic burden, presence or absence of radiographic lymph node invasion results in a clinically meaningful discrimination between those with poor prognosis and others. In consequence, consideration of radiographic lymph node invasion might be of great value in this specific population of mRCC patients.

Prostate irradiation in men with de novo, low-volume, metastatic, castration-sensitive prostate cancer (mCSPC): Results of PEACE-1, a phase 3 randomized trial with a 2x2 design.

LBA5000 Background: PEACE-1 demonstrated that combining ADT and docetaxel with abiraterone acetate plus prednisone (AAP) improves both overall survival (OS) and radiographic progression-free-survival (rPFS) in men with de novo mCSPC. The present analysis examines the second pre-planned primary endpoint of PEACE-1 in the low-volume population: the impact of prostate irradiation (RT) in men receiving intensified systemic treatment. Methods: PEACE-1 is an academic, multicentre, international, 2x2 design, phase 3 trial. The co-primary endpoints for each question were rPFS and OS. The standard of care (SOC) was ADT alone or ADT plus docetaxel (Doce) at investigator’s discretion until 2017, then accrual was restricted to men receiving ADT+Doce. RT (74 Gy/37 fractions) was delivered after Doce completion when applicable. SOC included continuous ADT, with or without Doce at 75 mg/m² every 3 weeks for 6 cycles. AAP, 1000 mg/day with prednisone 10 mg/day was given to men randomized to the AAP arms until disease progression or intolerance. The overall type I error testing the RT effect was 5% (4.9% for OS, 0.1% for rPFS). In the low-volume population, 299 and 213 events were required to detect an HR of 0.62 for rPFS and 0.68 for OS with 80% power, respectively. Results: Between 11/2013 and 12/2018, 1172 men were randomized to receive either SOC (+/- AAP) plus RT (n=584) or SOC (+/- AAP) without RT (n=588). 505 patients had low-volume disease (0-3 bone metastases +/- lymph nodes), 252 in the RT arms, 253 in the non-RT arms. Baseline characteristics were similar across arms. With a median follow-up of 6.1 years, 303 rPFS and 214 OS events were recorded for the low-volume population. A qualitative interaction between RT and AAP was observed for rPFS (p=0.026) and therefore, each experimental arm was assessed individually. RT did not improve rPFS with a median of 3 years (99.9%CI 2.3-4.8) for SOC vs 2.6 (1.7-4.6) for SOC+RT; HR=1.12 (0.68-1.85). When compared individually to SOC, rPFS was improved by SOC+AAP+RT (median 7.5 years (99.9%CI: 4.0-NR); HR=0.49, [0.28-0.87], p&lt;0.0001) and borderline improved by SOC+AAP (median 4.4 years (95% CI: 2.5-7.6); HR=0.74, [0.44-1.26], p=0.066). The HR between AAP arms was 0.66 [0.36-1.19]. For OS the predefined threshold for a statistical interaction was not reached (p=0.11). OS was not improved by RT: median OS was 6.9 years (95.1%CI: 5.9-7.5) without RT vs 7.5 (6.0-NR) with RT (HR=0.97 [0.74-1.27], p=0.81). Median OS was 7.1 years in the SOC arm and not yet reached in the SOC+AAP+RT arm. Data on the RT prevention effect on severe urinary symptoms are pending. Conclusions: Combining prostate RT to systemic treatment did not improve OS in men with de novo mCSPC and low metastatic burden. However, best outcomes (rPFS and OS) were observed in men receiving SOC+AAP+RT. The impact of RT on severe urinary symptom prevention will be presented. Clinical trial information: NCT01957436 .

Trifluridine/tipiracil (FTD/TPI) in extensively pre-treated metastatic colorectal cancer (mCRC) patients: Evaluation of prognostic subgroups of the TALLISUR study.

3556 Background: Compared to placebo, FTD/TPI significantly improved overall survival (OS) in patients (pts) with pre-treated mCRC in the pivotal phase III RECOURSE trial. Subgroup analyses indicated that all subgroups benefitted from FTD/TPI. Of note, FTD/TPI prolonged survival even more in pts ≥ 65 years old. To evaluate these observations with data from daily clinical practice, we performed a subgroup analysis of the TALLISUR study. Methods: In this prospective, multi-center, German, open-label, phase IV study, pts with extensively pre-treated mCRC chose between best supportive care (BSC) or oral FTD/TPI (35 mg/m2 bid on days 1 – 5 and 8 – 12 of each 28-day cycle). Duration of treatment and OS were analyzed for various subgroups. Based on a post-hoc analysis of the RECOURSE trial, 3 subgroups were defined according to: best, good and poor prognostic characteristics (BPC, GPC, PPC). Pts with &lt; 3 metastatic sites at inclusion and ≥ 18 months from diagnosis to inclusion were considered to have GPC. GPC pts without liver metastasis at inclusion were considered to have BPC. All remaining pts were considered to have PPC. Results: Of 195 eligible pts, 186 pts chose treatment with FTD/TPI, while 9 pts decided to receive BSC only. Median OS was 6.9 (95% CI 6.1 – 8.3) months. Mean duration of treatment with FTD/TPI was 14.6 (range 0.1 – 102.7) weeks. Results of the subgroup analysis are summarized in the table. Pts ≥ 65 years old presented a longer median OS (7.2 vs 6.2 months). Conclusions: When given the choice between treatment and BSC in late-stage CRC, the vast majority of pts opted for treatment. Low metastatic burden and indolent disease were factors of good prognosis for FTD/TPI therapy regarding OS. Independent of baseline characteristics such as age, sidedness, and time of onset of metastases, virtually all pts benefitted from therapy with FTD/TPI. Albeit not statistically significant, elderly pts tend to have improved survival with FTD/TPI, consistent with results from RECOURSE. Clinical trial registration number: EudraCT No 2017-000292-83 . [Table: see text]

Accuracy of genome-wide mutational analysis for tumor-informed ctDNA-guided MRD monitoring in bladder cancer.

4589 Background: Neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) is the standard management of localized muscle-invasive bladder cancer (MIBC). However, about 45% of patients develop metastases within 2 years after RC. Biomarkers for treatment efficacy evaluation and early detection of minimal residual disease (MRD) are needed for earlier treatment initiation and monitoring of treatment response. Tumor-informed detection of mutations in cell-free DNA (cfDNA) has shown promising results to monitor MRD. However, the low tumor fraction after surgery and limited input material obtained from a typical plasma sample limits the probability of detecting low metastatic burden scenarios. Here we implemented and applied a whole-genome sequencing (WGS) approach to monitor circulating tumor DNA (ctDNA) for sensitive ctDNA detection. Methods: 110 MIBC patients undergoing NAC and RC were enrolled. cfDNA was extracted from ~1mL plasma (n=978) and procured from longitudinal plasma sampling during NAC and pre-RC and post-RC. WGS of tumor/germline pairs (30x/20x) and plasma cfDNA (&gt;20x) was performed, facilitating detection of genome-wide genomic alterations and quantification of ctDNA using the C2inform method. Results: For each patient we developed a tumor-informed WGS model by integrating genome-wide mutation and copy number variation data coupled with advanced signal processing and AI-based error suppression. Patient-specific somatic variant patterns were used for detection and measuring ctDNA levels in low-input blood samples by WGS. Post-RC ctDNA analysis identified patients with recurrence with 78% sensitivity and 95% specificity and with a median lead time over radiographic imaging of 118 days (full follow-up included). When restricting follow-up time to 12 months following the latest ctDNA test, a sensitivity of 86% and specificity of 94% was achieved. ctDNA status was associated with recurrence-free (p&lt;0.0001) and overall survival (p&lt;0.0001). Furthermore, ctDNA clearance during NAC was also associated with recurrence-free survival (p=0.0051). The APOBEC associated signatures SBS2 and SBS13 were identified as the primary contributors to the mutational landscape of the primary tumors and TP53, KMT2D, PIK3CA, RB1 and KDM6A were the main affected driver genes. Half of the tumors displayed whole genome doubling. Moreover, our analysis of plasma samples after treatment showed the presence of chemotherapy-induced mutational signatures not present in the primary tumor, along with increases in copy numbers on chromosomes 19q and 20, and a focal amplification of the FGFR3 gene on chromosome 4. Conclusions: Our results highlight the clinical potential of personalized genome-wide mutation integration as an ultra-sensitive, non-invasive method for MRD detection and treatment response monitoring.

Proton Beam Therapy in the Oligometastatic/Oligorecurrent Setting: Is There a Role? A Literature Review.

Stereotactic ablative radiotherapy (SABR) and stereotactic radiosurgery (SRS) with conventional photon radiotherapy (XRT) are well-established treatment options for selected patients with oligometastatic/oligorecurrent disease. The use of PBT for SABR-SRS is attractive given the property of a lack of exit dose. The aim of this review is to evaluate the role and current utilisation of PBT in the oligometastatic/oligorecurrent setting. Using Medline and Embase, a comprehensive literature review was conducted following the PICO (Patients, Intervention, Comparison, and Outcomes) criteria, which returned 83 records. After screening, 16 records were deemed to be relevant and included in the review. Six of the sixteen records analysed originated in Japan, six in the USA, and four in Europe. The focus was oligometastatic disease in 12, oligorecurrence in 3, and both in 1. Most of the studies analysed (12/16) were retrospective cohorts or case reports, two were phase II clinical trials, one was a literature review, and one study discussed the pros and cons of PBT in these settings. The studies presented in this review included a total of 925 patients. The metastatic sites analysed in these articles were the liver (4/16), lungs (3/16), thoracic lymph nodes (2/16), bone (2/16), brain (1/16), pelvis (1/16), and various sites in 2/16. PBT could represent an option for the treatment of oligometastatic/oligorecurrent disease in patients with a low metastatic burden. Nevertheless, due to its limited availability, PBT has traditionally been funded for selected tumour indications that are defined as curable. The availability of new systemic therapies has widened this definition. This, together with the exponential growth of PBT capacity worldwide, will potentially redefine its commissioning to include selected patients with oligometastatic/oligorecurrent disease. To date, PBT has been used with encouraging results for the treatment of liver metastases. However, PBT could be an option in those cases in which the reduced radiation exposure to normal tissues leads to a clinically significant reduction in treatment-related toxicities.

Cytoreductive radical prostatectomy (cRP) in the management of patients with newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC).

161 Background: Although still discussed controversially, cRP represents a therapeutic option for mHSPC patients in the context of a multimodality approach. It was the purpose of our study to retrospectively review the oncological and functional outcome of a single-center cohort of cRP patients. Methods: A total of 134 mHSPC patients underwent cRP with pelvic lymphadenectomy. All patients received neoadjuvant androgen deprivation therapy (ADT, n = 34), ADT + docetaxel (n=15), or ADT plus ABI/ENZA/APA (n=85) for 6 months which was continued postop. Follow-up studies were performed at 3-month intervals, new imaging studies with 68Ga-PSMA PET/CT was done at PSA-levels &gt; 1.0 ng/ml. Perioperative complications were evaluated according to Clavien-Dindo classification. Clinical progression free survival (cPFS) and cancer specific survival (CSS) were calculated via Kaplan-Maier analysis. Multivariate regression analysis was used to assess the impact of biopsy ISUP grade, PSA at diagnosis and preop., PSA decrease, T stage, and metastatic burden on PFS and CSS. Results: 115 and 19 had low and high volume mHSPC, resp. Mean age was 64.2 (42-88) years, mean preop. PSA was 3.2 (0.1-21.6) ng/ml. The median Follow-up ist 53.7 (4 – 168) months. M1a, M1b and M1c were present in 28 (20.9%), 98 (73.1%) and 8 (6.0%) men. Pathohistology demonstrated pT0 in 3 (2.2%), pT2a-c in 21 (15.7%), pT3 and pT4 in 105 (78.3%) and 5 (3.7%). pN0 and pN+ was diagnosed in 38 (28.3%) and 96 (71.7%) pts. There was no significant difference between type of ADT and final pathohistology. Clavien-Dindo Grad 3a-b and 4 complications were observed in 13 (9.7%) and 2 (1.5%) pts. CSS was 88.1% and cPFS was 53%. None of the pts developed locally recurrent disease. Overall survival was reduced in M1 high volume (61.9% vs 92.8%, p=0.002) and pN+ (85.7% vs 96.7%, p=0.001). cT≥3b (HR=2.24, p=0.02) and M1 high volume (HR=2.35, p=0.01) were associated with reduced cPFS; M1 high volume (HR=1.49, p=0.03) and relative PSA decrease £60% (HR=1.37, p=0.03) were associated with reduced CSS. Conclusions: cRP can be performed with minimal morbidity. mHSPC patients with clinically localized high risk PCA, low metastatic burden and good response to nADT benefit most from this approach. The risk for symptomatic local relapse is low. Limitation of the study is its retrospective design.

Impact of Gleason grading on survival outcomes in patients with low loco-regional lymphogenic metastatic burden at radical prostatectomy

Impact of Gleason grading on survival outcomes in patients with low loco-regional lymphogenic metastatic burden at radical prostatectomy

Abstract B008: The role of the androgen receptor in reciprocal activation of breast cancer metastases and the lung epithelium during metastatic outgrowth

Abstract The lung is one of the most common sites of breast cancer (BC) metastasis. A major gap in our ability to effectively treat BC patients with established lung metastases lies in our lack of knowledge regarding how the lung microenvironment is remodeled during metastasis and how this contributes to disease progression. Our data suggest that the lung epithelium, in particular lung type II alveolar epithelial (AT2) cells, contribute to metastatic outgrowth. We hypothesize that BC lung micrometastases activate surrounding lung epithelial cells which, in turn, support the survival and outgrowth of BC metastases within the lung. The overall goal of these studies is to identify factors secreted by resident lung cells that could be used as metastasis-specific therapeutic targets/agents. We utilized immunocompetent mouse metastasis models to study metastatic progression within the lung. Multispectral fluorescent imagining of metastases demonstrated that a wound repair-related phenotype, characterized by chronic inflammation, develops within the lung microenvironment during metastatic outgrowth. We observed an increase in the number and activation of AT2 cells surrounding metastases as they grow. To gain mechanistic insight into how growing metastases may impact AT2 cells, we conducted single-cell RNA-sequencing (scRNAseq) on mouse lungs with high vs. low metastatic burden. This investigation showed that metastatic outgrowth significantly changes AT2 gene expression resulting in a modified secretome. Cell culture experiments, using multiple AT2 cell models, indicated that no contact co-culture with TNBC also caused significant changes in AT2 gene expression. Upstream regulator analysis of these datasets predicted that the androgen receptor (AR) may contribute to AT2 activation during metastatic outgrowth. Compared to non-adjacent tumor-free MMTV-PyMT lung tissue, there was an increased percentage of AR+ cells in the lung adjacent to metastases, which was further associated with large metastases only. Co-immunofluorescence experiments demonstrated that these lung-specific AR+ cells were primarily AT2 cells and fibroblasts, while in human lungs the majority of AR+ cells were AT2 cells and macrophages. Interestingly, co-culturing of TNBC and AT2 cells enhanced BC proliferation, suggesting that following activation, AT2 secreted factors may reciprocally impact metastatic growth. In conclusion, these data indicate that a tumor supportive microenvironment develops as lung metastases grow and suggests that by the time patients present with established/detectable lung metastases, the lung microenvironment has already undergone fundamental alterations that promote metastatic progression. Future studies will elucidate how activated lung cells support metastatic progression and could lead to the development or repurposing of therapeutic strategies to prevent destructive metastatic outgrowth. Citation Format: Jessica L. Christenson, Nicole S. Spoelstra, G. Devon Trahan, Kathleen I. O'Neill, Michelle M. Williams, Jennifer K. Richer. The role of the androgen receptor in reciprocal activation of breast cancer metastases and the lung epithelium during metastatic outgrowth [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B008.

Prostate-specific Membrane Antigen–radioguided Surgery Facilitates Pelvic Lymph Node Dissection During Radical Prostatectomy for the Treatment of Locally Advanced Prostate Cancer with Regional Lymph Node Metastases

Lymph node metastases (LNMs) are common in intermediate- to high-risk prostate cancer (PC) and may be missed during extended pelvic lymph node dissection (ePLND). Here we report on the use of prostate-specific membrane antigen (PSMA)-radioguided surgery (RGS) during open radical prostatectomy (RP) with ePLND to resect locoregional LNMs identified on preoperative PSMA positron emission tomography (PET). Preoperative PSMA PET showed 78 LNMs in 35 patients undergoing RP with ePLND and RGS between January 2018 and June 2020. In 14 patients (40%), LNMs were located outside the ePLND template. RGS achieved resection of PSMA-positive LNMs in 33/35 patients (94%). On univariable analysis, lower metastatic burden with up to two PSMA-positive LNMs on preoperative PET was associated with better postoperative outcomes. Limitations include the retrospective analysis and the small sample size. RGS facilitates resection of PSMA-positive LNs in patients treated with RP. Our data indicate a favorable treatment outcome in patients with low metastatic LN burden on preoperative PSMA PET. Patient summaryWe investigated the use of radioactive guidance to remove lymph nodes affected by prostate cancer during surgical removal of the prostate. This approach can help to identify cancerous lymph nodes that might otherwise be missed and could lead to better survival outcomes.

The Use of Machine Learning to Reduce Overtreatment of the Axilla in Breast Cancer: Retrospective Cohort Study.

Patients with early breast cancer undergoing primary surgery, who have low axillary nodal burden, can safely forego axillary node clearance (ANC). However, routine use of axillary ultrasound (AUS) leads to 43% of patients in this group having ANC unnecessarily, following a positive AUS. The intersection of machine learning with medicine can provide innovative ways to understand specific risks within large patient data sets, but this has not yet been trialed in the arena of axillary node management in breast cancer. The objective of this study was to assess if machine learning techniques could be used to improve preoperative identification of patients with low and high axillary metastatic burden. A single-center retrospective analysis was performed on patients with breast cancer who had a preoperative AUS, and the specificity and sensitivity of AUS were calculated. Standard statistical methods and machine learning methods, including artificial neural network, naive Bayes, support vector machine, and random forest, were applied to the data to see if they could improve the accuracy of preoperative AUS to better discern high and low axillary burden. The study included 459 patients; 142 (31%) had a positive AUS; among this group, 88 (62%) had 2 or fewer macrometastatic nodes at ANC. Logistic regression outperformed AUS (specificity 0.950 vs 0.809). Of all the methods, the artificial neural network had the highest accuracy (0.919). Interestingly, AUS had the highest sensitivity of all methods (0.777), underlining its utility in this setting. We demonstrated that machine learning improves identification of the important subgroup of patients with no palpable axillary disease, positive ultrasound, and more than 2 metastatically involved nodes. A negative ultrasound in patients with no palpable lymphadenopathy is highly indicative of low axillary burden, and it is unclear whether sentinel node biopsy adds value in this situation. Further studies with larger patient numbers focusing on specific breast cancer subgroups are required to refine these techniques in this setting.

Overall Survival after Y-90 Selective Internal Radiotherapy of Liver Metastases in Oligometastatic Patients

<h3>Purpose/Objective(s)</h3> Y-90 Selective Internal Radiotherapy (SIRT) is an ablative therapy used for patients with inoperable liver metastasis. The purpose of this investigation was to examine the impact of local control after SIRT on overall survival (OS) in oligometastatic patients, hypothesizing that local failure after SIRT would be correlated with lower OS. <h3>Materials/Methods</h3> A retrospective, single-institution, IRB-approved study selected oligometastatic patients defined as 5 or fewer total non-CNS metastases at the time of unilateral or bilateral lobar Y-90 SIRT from 2009 to 2021. Patients were staged with CT and/or MRI. The primary endpoint was OS defined from Y-90 SIRT completion to date of death or last follow-up. Local failure was classified as progressive disease at the target lesion(s) by RECIST v1.1 criteria starting at 3 months after SIRT. Failure was defined by imaging or if salvage locoregional therapy was performed. OS outcomes were calculated using the Kaplan-Meier method, and correlations with clinical variables were evaluated using log-rank testing. <h3>Results</h3> Twenty-three oligometastatic patients, with a total of 57 liver lesions, completed SIRT. The cohort was comprised of patients with colorectal adenocarcinoma (n=15), pancreatic adenocarcinoma (n=6), thymic carcinoma (n=1), and uveal melanoma (n=1). Fifteen patients (65%) received bilateral lobar SIRT and 8 (35%) received unilateral lobar treatment. Median follow up was 15.6 months (range 2.7-54.3). Twenty patients were treated with resin Y-90 microspheres and 3 received glass microspheres. On volumetric analysis of liver tumor burden, the range of liver involvement was 0.03% to 18.2%. The range of liver metastases was 1 to 5 with a median of 3. Of the 57 individual lesions treated, 19 (33%) failed. Fourteen patients (61%) failed in a treated lesion, including 9 as the first site of failure. Seven patients received salvage liver-directed therapy following intrahepatic failure; six received repeat SIRT. Seven patients did not receive post-SIRT chemotherapy, of which 5 experienced intralesional failure. Median OS (mOS) was 20.1 months, and 12-month OS was 68.6%. Metachronous versus synchronous metastasis at presentation was not found to be prognostic of OS (21.7 months vs 17.9 months (p<0.96)). Those with tumor involving <5% of the liver (n=17) had a mOS of 21.7 months vs 15.1 months for those with >5% (n=6) (p<0.12). Intralesional failure was associated with worse mOS (15.1 months vs. not reached, p<0.03). <h3>Conclusion</h3> These results suggest that intralesional failure following Y-90 may be associated with inferior OS, emphasizing the importance of disease control in low metastatic burden patients. Percentage of liver involvement may be predictive of local failure after SIRT. Larger prospective studies examining oligometastatic patients treated with SIRT are needed for further patient risk stratification.

The value of whole-lesion histogram analysis based on field‑of‑view optimized and constrained undistorted single shot (FOCUS) DWI for predicting axillary lymph node status in early-stage breast cancer

BackgroundThis study aims to estimate the amount of axillary lymph node (ALN) involvement in early-stage breast cancer utilizing a field of view (FOV) optimized and constrained undistorted single-shot (FOCUS) diffusion-weighted imaging (DWI) approach, as well as a whole-lesion histogram analysis.MethodsThis retrospective analysis involved 81 individuals with invasive breast cancer. The patients were divided into three groups: N0 (negative ALN metastasis), N1–2 (low metastatic burden with 1–2 ALNs), and N≥3 (heavy metastatic burden with ≥ 3 ALNs) based on their sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND). Histogram parameters of apparent diffusion coefficient (ADC) depending basically on FOCUS DWI were performed using 3D-Slicer software for whole lesions. The typical histogram characteristics for N0, N1–2, and N≥ 3 were compared to identify the significantly different parameters. To determine the diagnostic efficacy of significantly different factors, the area under their receiver operating characteristic (ROC) curves was examined.ResultsThere were significant differences in the energy, maximum, 90 percentile, range, and lesion size among N0, N1–2, and N≥ 3 groups (P < 0.05). The energy differed significantly between N0 and N1–2 groups (P < 0.05), and some certain ADC histogram parameters and lesion sizes differed significantly between N0 and N≥3, or N1–2 and N≥3 groups. For ROC analysis, the energy yielded the best diagnostic performance in distinguishing N0 and N1–2 groups from N≥3 group with an AUC value of0.853. All parameters revealed excellent inter-observer agreement with inter-reader consistencies data ranging from0.919 to 0.982.ConclusionBy employing FOCUS DWI method, the analysis of whole-lesion ADC histogram quantitatively provides a non-invasive way to evaluate the degree of ALN metastatic spread in early-stage breast cancer.