Search Results (143)

Purpose: To present the findings of our preliminary experience using daily image-guided radiotherapy (IGRT) supported by implanted fiducial markers (FMs) in the radiotherapy of the vaginal cuff, in a cohort of post-surgery endometrial cancer patients. Methods: Patients with vaginal cuff cancer requiring adjuvant radiation with external beams were enrolled. Five patients underwent radiation therapy targeting the pelvic disease and positive lymph nodes, with doses of 50.4 Gy in twenty-eight fractions and a subsequent stereotactic boost on the vaginal vault at a dose of 5 Gy in a single fraction. One patient was administered 30 Gy in five fractions to the vaginal vault. These patients underwent external beam RT following the implantation of three 0.40 × 10 mm gold fiducial markers (FMs). Our IGRT strategy involved real-time 2D kV image-based monitoring of the fiducial markers during the treatment delivery as a surrogate of the vaginal cuff. To explore the potential role of FMs throughout the treatment process, we analyzed cine movies of the 2D kV-triggered images during delivery, as well as the image registration between pre- and post-treatment CBCT scans and the planning CT (pCT). Each CBCT used to trigger fraction delivery was segmented to define the rectum, bladder, and vaginal cuff. We calculated a standard metric to assess the similarity among the images (Dice index). Results: All the patients completed radiotherapy and experienced good tolerance without any reported acute or long-term toxicity. We did not observe any loss of FMs during or before treatment. A total of twenty CBCTs were analyzed across ten fractions. The observed trend showed a relatively emptier bladder compared to the simulation phase, with the bladder filling during the delivery. This resulted in a final median Dice similarity coefficient (DSC) of 0.90, indicating strong performance. The rectum reproducibility revealed greater variability, negatively affecting the quality of the delivery. Only in two patients, FMs showed intrafractional shift > 5 mm, probably associated with considerable rectal volume changes. Target coverage was preserved due to a safe CTV-to-PTV margin (10 mm). Conclusions: In our preliminary study, CBCT in combination with the use of fiducial markers to guide the delivery proved to be a feasible method for IGRT both before and during the treatment of post-operative gynecological cancer. In particular, this approach seems to be promising in selected patients to facilitate the use of SBRT instead of BRT (brachytherapy), thanks to margin reduction and adaptive strategies to optimize dose delivery while minimizing toxicity. A larger sample of patients is needed to confirm our results. Full article

Background/Objectives: Radiotherapy (RT) is a mainstay of clinical cancer therapy that causes broad immune responses. The complement system is a pivotal effector mechanism in the innate immune response, but the impact of RT is less well understood. This study investigates the interaction between RT and the complement system as a possible approach to improve immune responses in cancer treatment. Methods: Human solid cancer (lung, prostate, liver, breast cancer), lymphoma, and leukemia cells were irradiated using X-rays and treated with polyclonal antibodies or anti-CD20 monoclonal antibodies, respectively. Chromium release assay was applied to measure cell lysis after radiation with or without complement-activating antibody treatment. The expression of membrane-bound complement regulatory proteins (mCRPs; CD46, CD55, CD59), which confer resistance against complement activation, CD20 expression, apoptosis, and radiation-induced DNA double-strand breaks (γH2AX), was measured by flow cytometry. The radiosensitivity of tumor cells was assessed by colony-forming assay. Results: We demonstrate that RT profoundly impacts complement function by upregulating the expression of membrane-bound complement regulatory proteins (mCRPs) on tumor cells in a dose- and time-dependent manner. Impaired complement-mediated tumor cell lysis could thus potentially contribute to radiotherapeutic resistance. We also observed RT-induced upregulation of CD20 expression on lymphoma and leukemic cells. Notably, complement activation prior to RT proved more effective in inducing RT-dependent early apoptosis compared to post-irradiation treatment. While complement modulation does not significantly alter RT-induced DNA-damage repair mechanisms or intrinsic radiosensitivity in cancer cells, our results suggest that combining RT with complement-based anti-cancer therapy may enhance complement-dependent cytotoxicity (CDC) and apoptosis in tumor cells. Conclusions: This study sheds light on the complex interplay between RT and the complement system, offering insights into potential novel combinatorial therapeutic strategies and a potential sequential structure for certain tumor types. Full article

Background: Rectal cancer management involves surgery, chemotherapy (CT), radiotherapy (RT), and patient care strategies, all of which significantly affect health-related quality of life (HRQoL). Understanding these effects is critical for optimizing treatment protocols. This review aimed to systematically analyze the impact of rectal cancer treatment on HRQoL. Methods: Four databases, Scopus, EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials, were searched for randomized controlled trials (RCTs) published between January 2013 and December 2023. RCTs specifically focusing on rectal cancer treatments (surgical interventions, pre- and/or post-CT and/or RT, and patient care strategies) were included. An abstract review, data extraction, and a risk-of-bias assessment were independently conducted by two reviewers. Results: The 41 included studies comprised 9240 patients: 16 evaluated surgical interventions (3507 patients), 15 evaluated pre- and/or post-CT and/or RT protocols (5114 patients), and 10 focused on patient-care strategies (619 patients). Sphincter-sparing procedures were associated with better HRQoL than abdominoperineal resection, and rectal-sparing techniques were associated with better overall HRQoL than rectal resection. RT was associated with a poorer HRQoL. Continuity-of-care interventions improved HRQoL in ostomy patients, whereas transanal irrigation improved HRQoL after ostomy closure. Conclusions: This systematic review of RCTs underscores the importance of organ-sparing strategies, such as rectum-sparing approaches and continuity-of-care packages, in improving HRQoL in patients with rectal cancer. Although RT negatively affects HRQoL, treatment regimens should be individualized. Tailored organ-preservation approaches and structured follow-up care are essential for optimizing HRQoL in patients with rectal cancer. Full article

Background/Objectives: Prostate cancer is the most frequent cancer in men, for which Radiotherapy (RT) is used as a radical or post-surgical treatment. Actinic proctitis is one of the most disabling side effects of RT. Intestinal microbiome studies have highlighted the importance of short-chain fatty acids, in particular butyric acid, for their beneficial effects over intestinal epithelial cells. The aim of this prospective study is to evaluate if treatment with micro-encapsulated sodium butyrate (MESB) can reduce the incidence of actinic proctitis during RT in prostate cancer patients. Methods: In total, 122 consecutive patients with prostate cancer treated in Radiotherapy Unit, Centro di Riferimento Oncologico, IRCCS Aviano, were enrolled. Patients received MESB (3 tablets/day) from one week before until four weeks after RT. They completed a diary, tracking daily bowel movements, rectal bleeding, abdominal pain, and perceived health status before, at the end, and one month after RT. Results: Although an improvement in symptoms was observed, when comparing interpatient data before RT vs. one month after the end of RT, statistically significant differences emerged only regarding abdominal pain (94.2% vs. 81.6% vs. 81.6%) (McNemar’s test p < 0.002). Conclusions: MESB appears effective in reducing radiation-induced bowel toxicity during RT, minimizing stool changes, incontinence, and abdominal pain. Although patients’ health perception declined at RT completion, it improved after one month, suggesting MESB may support clinical recovery post-treatment. Full article

Background/Objectives: Treatment of locally advanced rectal cancer (LARC) very often requires a neoadjuvant multimodal approach. Neoadjuvant treatment (NAT) encompasses treatments like chemoradiotherapy (CRT), short-course radiotherapy (SCRT), radiotherapy (RT) or a combination of either of these two with additional induction or consolidation chemotherapy, namely total neoadjuvant treatment (TNT). In case of complete radiological and clinical response, the non-operative watch-and-wait strategy can be adopted in selected patients. This strategy is impacted by a regrowth rate of approximately 30%. Predicting biomarkers of tumor response to NAT could improve guidance of clinicians during clinical decision making, improving treatment outcomes and decreasing unnecessary treatment exposure. To this day, there is no validated biomarker to predict tumor response to any NAT strategies in clinical use. Most research focused on CRT neglects the study of other regimens. Methods: We conducted a narrative literature review which aimed at summarizing the status of biomarkers predicting tumor response to NAT other than CRT in LARC. Results: Two hundred and fourteen articles were identified. After screening, twenty-one full-text articles were included. Statistically significant markers associated with improved tumor response pre-treatment were as follows: low circulating CEA levels; BCL-2 expression; high cellular expression of Ku70, MIB-1(Ki-67) and EGFR; low cellular expression of VEGF, hPEBP4 and nuclear β-catenin; the absence of TP53, SMAD4, KRAS and LRP1B mutations; the presence of the G-allel of LCS-6; and MRI features such as the conventional biexponential fitting pseudodiffusion (Dp) mean value and standard deviation (SD), the variable projection Dp mean value and lymph node characteristics (short axis, smooth contour, homogeneity and Zhang et al. radiomic score). In the interval post-treatment and before surgery, significant markers were as follows: a reduction in the median value of circulating free DNA, higher presence of monocytic myeloid-derived suppressor cells, lower presence of CTLA4+ or PD1+ regulatory T cells and standardized index of shape changes on MRI. Conclusions: Responders to neoadjuvant SCRT and RT tended to have a tumor microenvironment with an immune–active phenotype, whereas responders to TNT tended to have a less active tumor profile. Although some biomarkers hold great promise, scarce publications, inconsistent results, low statistical power, and low reproducibility prevent them from reliably predicting tumor response following NAT. Full article

Background/Objectives: Primary central nervous system lymphoma (PCNSL) is a rare but aggressive tumor, primarily affecting elderly patients. Radiotherapy (RT) remains an important treatment option, particularly for patients who are ineligible for systemic chemotherapy. This study aims to identify prognostic factors and evaluate recurrence patterns in a real-world cohort of PCNSL patients treated with RT. Methods: We retrospectively analyzed 64 PCNSL patients treated with radiotherapy at our institution between 2000 and 2022. Clinical characteristics, treatment details, and outcomes were collected by chart review. Overall survival (OS) was analyzed using Kaplan–Meier and Cox regression methods. Recurrence patterns were assessed based on available post-treatment imaging. Results: Median patient age was 71 years (range: 31–83); 53.1% had an Eastern Cooperative Oncology Group (ECOG) performance status ≥2. Radiotherapy was used as first-line treatment in 62.5% of cases, primarily due to contraindications to chemotherapy. Median OS was 10 months from diagnosis. Age, poor performance status, seizures at presentation, absence of systemic therapy, incomplete radiotherapy, and <80% applied dose of planned radiotherapy were associated with inferior OS in our univariable analysis. Multivariable analysis confirmed age, systemic therapy, seizures, and radiotherapy dose <80% as independent predictors. Among twenty-nine patients with imaging follow-up, eight recurrences after RT were documented: six of those within, and two outside of the initially affected areas. All recurrences occurred within previously irradiated areas. Conclusions: This study confirms known negative prognostic factors in PCNSL and underscores the importance of systemic chemotherapy for curatively intended treatments aiming for prolonged survival. The recurrence patterns observed question the added benefit of whole-brain irradiation in preventing distant relapses. These findings support the need for prospective trials to optimize radiotherapy strategies while balancing efficacy and neurotoxicity. Full article

Background/Objectives: Cancer patients undergoing chemotherapy (CT) or radiotherapy (RT) are at increased risk of oral complications. Preventive dental care has been proposed to mitigate these risks, yet its effectiveness is not sufficiently evaluated. This systematic review and meta-analysis aimed to assess the impact of preventive oral health interventions on key clinical outcomes in oncology patients. Methods: A systematic search of MEDLINE, Embase, and CENTRAL databases was conducted (March 2025), adhering to PRISMA guidelines with a PROSPERO-registered protocol (CRD 420251006799). Eligible studies included randomized trials, cohort studies, and pre–post intervention studies evaluating preventive dental care in patients receiving CT or RT. The outcomes included gingival index (GI), dental caries (DMFT), plaque levels, and periodontal health. Meta-analyses were performed on GI and DMFT outcomes using random-effects models. Results: Eleven studies were included in the qualitative synthesis and four in the meta-analyses. Preventive interventions, such as fluoride applications, oral hygiene education, and regular professional cleanings, were associated with stabilization or improvement of gingival health. The pooled estimate for GI showed no significant deterioration over time (MD = −0.05, 95% CI: −0.34 to 0.24, p = 0.72). For DMFT, a slight but significant increase was observed (MD = 1.07, 95% CI: 0.08 to 2.05, p = 0.03), suggesting a continued risk of caries despite intervention. Conclusions: Preventive dental care interventions appear to support the maintenance of gingival health in cancer patients undergoing CT or RT. However, despite these interventions, a slight increase in dental caries was still observed, indicating that preventive strategies may not fully eliminate the risk of caries. These findings highlight the importance of sustained and individualized oral health programs as part of comprehensive oncology care. Future studies using standardized protocols and longer follow-up periods are needed to better evaluate their long-term effectiveness across diverse cancer populations. Full article

Objective: The SHARON (Short course RadiatiON therapy for palliative treatment) Bone trial is a phase III randomized non-inferiority multicentric study comparing symptom relief for complicated bone metastases (BMs) achieved through hypofractionated accelerated palliative radiotherapy (RT) to a standard RT regimen. Methods: Eligible participants were adults with ECOG PS ≤ 3 who were referred for palliative RT for painful BMs. Patients were assigned to receive either 30 Gy delivered in 10 daily fractions or 20 Gy in 4 fractions over two consecutive days. The primary outcome was pain relief one month post-treatment. Pain relief and adverse events were also evaluated at 2, 3, 6, and 12 months after RT. This trial was registered at clinicaltrials.gov (NCT03503682). Results: Between February 2018 and November 2021, 83 patients were enrolled (30 Gy: 41; 20 Gy: 42). In the standard RT group, five patients did not complete the prescribed RT, while none in the experimental arm discontinued treatment (p = 0.026). Due to early mortality, the primary endpoint was evaluable in 73 patients (35 and 38 in the standard and experimental arms, respectively). The rate of complete pain response at one month was 22.9% and 28.9% in the 30 Gy and 20 Gy arms, respectively (p: 0.571). The overall pain response rates, which included complete and partial responses, were 74.3% and 78.9% in the 30 Gy and 20 Gy arms, respectively (p = 0.638), when considering at least a 2-point reduction in the numerical rating scale. In both arms, 4.8% of patients experienced Grade >2 toxicity. Conclusions: Administering 20 Gy in four fractions twice a day is non-inferior to the standard 30 Gy delivered in 10 fractions for pain relief in the context of complicated BMs. Furthermore, this regimen demonstrated comparable safety in terms of acute toxicity, with a lower incidence of definitive interruptions of radiotherapy. Full article

Purpose: Myxoid liposarcoma (MLPS) is a malignant tumor that occurs predominantly in the deep soft tissues of the extremities. Preoperative radiotherapy (RT) is used to reduce tumor volume to achieve adequate surgical margins. This systematic review aims to evaluate the impact of preoperative RT on surgical margins, local recurrence (LR) rates, metastasis development, and overall survival in patients with MLPS and associated prognostic factors. Methods: A systematic literature search was conducted by two reviewers following PRISMA guidelines on PubMed, Scopus, and the Cochrane Library on 30 November 2024. We included prospective and retrospective cohort studies published in English that evaluate surgical margin status, LR and metastasis rates, and survival outcomes in patients undergoing surgical excision of MLPS following neoadjuvant radiotherapy. Two authors extracted tumor characteristics, percentage of round cells (RCs), change in tumor volume post-RT, surgical margins, postoperative complications, LR and metastasis rates, survival rates, and related prognostic factors. Results: The twelve studies included in this review involved 1483 patients with a mean age of 44.8 years. Tumors were mostly located in the lower limbs, deeply localized, and larger than 5 cm in most cases. The average LR and metastasis rates were 5.2% and 17%, respectively. The mean 5-year and 10-year overall survival rates were 87% and 74%, respectively. Poor prognosis was associated with >5% RC components, tumors larger than 15 cm, deep localization, and inadequate surgical margins. Conclusion: The management of MLPS requires a multidisciplinary approach. Preoperative radiotherapy offers several advantages in reducing tumor volume and facilitating the achievement of adequate surgical margins, finally improving local control and long-term outcomes. Full article

Radiation is often used as the primary treatment for a range of cancers. Nonetheless, its ability to trigger secondary tumors has emerged as a significant issue. Therefore, gaining insight into and predicting radiation-induced secondary cancers is essential for enhancing the long-term prognosis of cancer survivors. Background and Objectives: Previous studies have identified several factors; however, research on the use of serum-based inflammatory markers as prognostic tools for predicting radiation-induced secondary malignancies is limited. Investigating the potential of serum-based inflammation prognostic scores could provide a minimally invasive and affordable method for the early prediction of secondary malignancies. Methods: We retrospectively analyzed a patient cohort with radiation-induced secondary malignancy from the electronic database MIMIC-IV to investigate whether a serum-based inflammatory marker score can serve as a predictive tool. Results: This study seeks not only to assess the efficacy of the risk score, but also to develop a clinical utility tool nomogram for predicting the occurrence of radiation-induced secondary cancers. A RISM of 4.28% was observed in a cohort from the MIMIC-IV database using SIRI-RT as a risk index, with the Charlson comorbidity index, chemotherapy, and creatinine levels as significant confounding risk factors. Conclusions: Our study suggests that elevated serum-based inflammation prognostic scores and the nomogram developed herein can be used to predict a greater likelihood of developing secondary malignancies following radiation therapy. Full article

Purpose: This study aimed to compare long-term patient-reported outcomes in bowel and urinary domains between intensity-modulated radiotherapy (IMRT) and intensity-modulated proton therapy (IMPT) for localized prostate cancer. Methods and Materials: Patients with clinical T1–T2 prostate cancer receiving IMRT or IMPT at a tertiary cancer center from 2015–2018 were analyzed to determine the changes in the prospectively collected bowel function (BF), urinary irritative/obstructive symptoms (UO), and urinary incontinence (UI) domains of EPIC-26. The mean changes in EPIC-26 scores were evaluated from pretreatment to 24 months post-radiotherapy for each modality. A score change >50% of the baseline standard deviation was considered a clinically meaningful change. Results: A total of 82 patients treated with IMRT (52.2%) and 56 patients treated with IMPT (53.3%) completed the questionnaire at baseline and 24 months post-RT. There were no baseline differences in domain scores between treatment modalities. At 24 months post-radiotherapy, there was a significant and clinically meaningful decline in the BF mean score in the IMRT cohort (−4.52 (range −50, 29.17), p = 0.003), whereas the decline in BF score did not reach clinical relevance or significance (−1.88 (range −37.5, 50), p = 0.046) when accounting for the Bonferroni adjustment in the IMPT cohort. A higher proportion of patients treated with IMRT had a clinically relevant reduction in BF when compared with IMPT (47.37% vs. 25.93%, p = 0.017). The mean changes in the UI and UO scores of the IMRT and IMPT cohorts were neither statically significant nor clinically relevant. Conclusions: IMPT leads to a smaller decrease in BF than IMRT at 24 months post-RT, while there was no differential effect on UO and UI. Full article

Background: Recurrent oral squamous cell carcinoma (re-OSCC) poses a serious therapeutic challenge and is linked to poor survival outcomes. SOX2 and NANOG, key transcription factors in cancer stem cell biology, may drive tumor progression and therapy resistance. However, their prognostic value in re-OSCC and their relationship to adjuvant therapy remain unclear. Methods: We retrospectively analyzed a single-center cohort of 94 patients with re-OSCC treated with curative intent via (1) surgery alone, (2) surgery plus adjuvant radiotherapy (RT), or (3) surgery plus adjuvant radiochemotherapy (RCT). Tissue microarrays (TMAs) were constructed from matched primary and recurrent tumors and immunohistochemical (IHC) staining for SOX2, and NANOG was quantified using H-scores. Post-recurrence overall survival (prOS) and post-recurrence disease-free survival (prDFS) were evaluated using Kaplan–Meier analysis and Cox proportional hazards models. Results: SOX2 expression and survival: Elevated SOX2 expression (H-score > 14) in re-OSCC was significantly associated with improved prOS (p = 0.013) and prDFS (p = 0.026). Notably, patients who had received adjuvant therapy (particularly RCT) showed higher SOX2 levels in recurrent tumors compared to those treated with surgery alone. NANOG expression and therapy: NANOG expression declined markedly from primary to recurrent tumors (median H-score 42.2 vs. 8.7; p < 0.001). This decline was most pronounced in patients treated with surgery alone. Despite this dynamic change, NANOG expression did not correlate significantly with prOS or prDFS. Other prognostic factors include advanced tumor stage (rT2–rT4) and lymph node involvement (rN+/x)m which remained significant predictors of worse survival in the recurrent setting, regardless of adjuvant therapy. Conclusion: SOX2 overexpression in re-OSCC correlates with better survival, suggesting a unique prognostic role distinct from primary disease. Adjuvant therapy, especially RCT, appears to maintain or elevate SOX2 levels, potentially contributing to improved treatment response. In contrast, although NANOG expression decreases in recurrence, particularly in patients who undergo surgery alone, it does not significantly affect survival outcomes. These findings underscore the importance of context-specific biomarker assessments and provide a rationale for incorporating SOX2 status into personalized treatment strategies for re-OSCC. Full article

Background: The majority of head and neck cancers (HNCs) occur in the larynx. In clinical practice, adverse effects are frequently observed in laryngeal cancer (LC) patients undergoing radiotherapy (RT). Therefore, investigating markers that can predict these unfavorable events is of interest. Long non-coding RNAs (lncRNAs) have emerged as potential biomarkers for the early identification of patients susceptible to post-RT toxicity. MALAT1 and NEAT1 regulate various cellular processes, the inflammatory response, and resistance to anti-cancer treatments; however, their impact on the portability of post-RT adverse effects remains unknown. The aim of this study was to evaluate the clinical value of two plasma-circulating lncRNAs, MALAT1 and NEAT1, as predictive biomarkers for post-RT adverse effects in LC patients. Methods: The expression levels of the studied lncRNAs were determined using real-time quantitative reverse transcription PCR (qRT-PCR) in plasma samples obtained from 70 LC patients before the initiation of RT. These levels were then correlated with patient outcomes. Results: A low expression of MALAT1 was associated with a significantly higher probability of anemia, liver failure, and severe malnutrition (OR = 5.36; p = 0.040, OR = 6.07; p = 0.037, OR = 9.75; p < 0.001, respectively) after the completion of RT. Similarly, patients with low NEAT1 expression had a significantly higher risk of anemia, liver failure, and mild or severe malnutrition (OR = 5.26; p = 0.020, OR = 5.70; p = 0.016, OR = 13.09; p = 0.002, respectively). Simultaneous lower expression levels of both lncRNAs were significantly associated with shorter median overall survival (OS) in RT-treated LC patients (HR = 5.44; p = 0.001). Conclusions: The analysis of MALAT1 and NEAT1 expression indicates clinical utility in predicting toxic events induced by RT-based therapy. Full article

Background/Objectives: This study was designed to evaluate skin-sparing mastectomy with implant reconstruction complication rates in patients operated on due to high penetrant gene profile. All patients went to skin-sparing mastectomy with implant reconstruction and risk-reducing salpingo-oophorectomy. The effect of radiotherapy and chemotherapy on wound healing is a frequently discussed topic in the literature. However, studies on the effect of these on patients undergoing implant-based reconstruction are rare. In our clinic, two surgeries are performed under the same anesthesia and it is aimed to investigate the effect of this situation on complications in this rare patient group. In this retrospective study, we report our clinical experience regarding complication rates due to these factors among the high penetrant gene group. Methods: Between June 2022 and June 2024, 61 patients were grouped according to demographic data. Post-operative complications were defined as any of the following: major complications which were active bleeding or wound dehiscence; minor complications which were hematoma, seroma, surgical-site infection, <20% skin or nipple necrosis, and reoperation due to wound dehiscence or any other complication. Patients were compared in terms of complications according to whether they received previous radiotherapy (RT), neoadjuvant chemotherapy (CT), or underwent skin-reducing mammoplasty. Results: Patients receiving neoadjuvant chemotherapy, patients receiving preoperative RT, and patients undergoing skin-reducing mastectomy were compared in terms of major and minor complications. While neoadjuvant CT and preoperative RT only increased the risk of seroma, it was found that skin-reducing mastectomy had no significant effect on complication rates. Conclusions: Skin-sparing mastectomy with implant reconstruction and risk-reducing salphingo-oophorectomy is a comprehensive operation method in this patient group. Complication control can be achieved by performing two surgeries in a single anesthesia period, using the spy immunofluorescence device for vascularization control, and performing all surgeries with the same experienced team. Full article

Background: This study aims to explore metabolic biomarkers and pathways in breast cancer prognosis. Methods: We performed a global post-radiotherapy (RT) urinary metabolomic analysis of 120 breast cancer patients: 60 progression-free (PF) patients as the reference and 60 with progressive disease (PD: recurrence, second primary, metastasis, or death). UPLC-MS/MS (Metabolon Inc.) identified 1742 biochemicals (1258 known and 484 unknown structures). Following normalization to osmolality, log transformation, and imputation of missing values, a Welch’s two-sample t-test was used to identify biochemicals and metabolic pathways that differed between PF and PD groups. Data analysis and visualization were performed with MetaboAnalyst. Results: Metabolic biomarkers and pathways that significantly differed between the PD and PF groups were the following: amino acid metabolism, including phenylalanine, tyrosine, and tryptophan biosynthesis (impact value (IV) = 1.00; p = 0.0007); histidine metabolism (IV = 0.60; p < 0.0001); and arginine and proline metabolism (IV = 0.70; p = 0.0035). Metabolites of carbohydrate metabolism, including glucose (p = 0.0197), sedoheptulose (p = 0.0115), and carboxymethyl lysine (p = 0.0098), were elevated in patients with PD. Gamma-glutamyl amino acids, myo-inositol, and oxidative stress biomarkers, including 7-Hydroxyindole Sulfate and sulfate, were elevated in patients who died (p ≤ 0.05). Conclusions: Amino acid metabolism emerged as a key pathway in breast cancer progression, while carbohydrate and oxidative stress metabolites also showed potential utility as biomarkers for breast cancer progression. These findings demonstrate applications of metabolomics in identifying metabolic biomarkers and pathways as potential targets for predicting breast cancer progression. Full article