The Clinical Utility of a 7-Gene Biosignature on Radiation Therapy Decision Making in Patients with Ductal Carcinoma In Situ Following Breast-Conserving Surgery: An Updated Analysis of the DCISionRT® PREDICT Study.

BACKGROUND: Breast-conserving surgery (BCS) followed by adjuvant radiotherapy (RT) is a standard treatment for ductal carcinoma in situ (DCIS). A low-risk patient subset that does not benefit from RT has not yet been clearly identified. The DCISionRT test provides a clinically validated decision score (DS), which is prognostic of 10-year in-breast recurrence rates (invasive and non-invasive) and is also predictive of RT benefit. This analysis presents final outcomes from the PREDICT prospective registry trial aiming to determine how often the DCISionRT test changes radiation treatment recommendations. METHODS: Overall, 2496 patients were enrolled from February 2018 to January 2022 at 63 academic and community practice sites and received DCISionRT as part of their care plan. Treating physicians reported their treatment recommendations pre- and post-test as well as the patient's preference. The primary endpoint was to identify the percentage of patients where testing led to a change in RT recommendation. The impact of the test on RT treatment recommendation was physician specialty, treatment settings, individual clinical/pathological features and RTOG 9804 like criteria. Multivariate logisitc regression analysis was used to estimate the odds ratio (ORs) for factors associated with the post-test RT recommendations. RESULTS: RT recommendation changed 38% of women, resulting in a 20% decrease in the overall recommendation of RT (p < 0.001). Of those women initially recommended no RT (n = 583), 31% were recommended RT post-test. The recommendation for RT post-test increased with increasing DS, from 29% to 66% to 91% for DS <2, DS 2-4, and DS >4, respectively. On multivariable analysis, DS had the strongest influence on final RT recommendation (odds ratio 22.2, 95% confidence interval 16.3-30.7), which was eightfold greater than clinicopathologic features. Furthermore, there was an overall change in the recommendation to receive RT in 42% of those patients meeting RTOG 9804-like low-risk criteria. CONCLUSIONS: The test results provided information that changes treatment recommendations both for and against RT use in large population of women with DCIS treated in a variety of clinical settings. Overall, clinicians changed their recommendations to include or omit RT for 38% of women based on the test results. Based on published clinical validations and the results from current study, DCISionRT may aid in preventing the over- and undertreatment of clinicopathological 'low-risk' and 'high-risk' DCIS patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03448926 ( https://clinicaltrials.gov/study/NCT03448926 ).

Prostate cancer in transgender women.

INTRODUCTION: As the transgender patient population continues to increase, urologists and other providers who treat genitourinary malignancies will increasingly encounter cases of prostate cancer in transgender women. Little exists in the current literature to help summarize the challenges and opportunities which face this unique patient population. Similarly, little exists to provide guidance on how we may best diagnose, manage, and follow transgender women diagnosed with prostate cancer. We sought to review the available literature in hopes of providing a resource for providers moving forward. MATERIALS AND METHODS: We collaboratively reviewed the currently available literature, guidelines, and statements of best practice to compile a comprehensive review of this emerging and important topic. RESULTS: Transgender persons face numerous systemic barriers to care with well documented increased risks of suicide and poor health outcomes. Though uncommon, the diagnosis of prostate cancer in transgender women is often associated with significant disease. While many options for management remain in line with standard guidelines, the unique aspects of care in this population-prior/current hormone usage, gender-affirming surgical procedures etc.-must be considered. Surgical, radiation, and hormonal treatments all play a potential role in appropriate treatment. Longitudinal studies are currently lacking and clinical trials are often structured with exclusive language which may lead to further marginalization of this patient population. CONCLUSION: Transgender persons will almost certainly continue to grow as a population encountered and treated by healthcare professionals. Better training and understanding are needed to ensure all healthcare needs are met as best possible. Prostate cancer represents an area in which great strides may be made to improve both diagnosis and treatment. Urologists, and others who manage urologic cancers, must take the lead to improve the care of transgender persons with genitourinary malignancies.

Therapeutic radiation dose delivered to the low axilla during whole breast radiation therapy in the prone position: implications for targeting the undissected axilla.

PURPOSE: One interpretation of the American College of Surgeons Oncology Group Z0011 trial is that whole breast radiation therapy, known to treat a portion of the low axilla when delivered in the supine position, can treat residual microscopic disease in patients with involved axillary nodes that were not removed by axillary dissection. The purpose of this study was to quantify radiation dose delivered to the axilla for patients treated in the prone position. METHODS AND MATERIALS: We analyzed treatment plans from 40 consecutive patients who received radiation targeting the intact breast with tangent fields in the prone position. Axillary levels were contoured using Radiation Therapy Oncology Group (RTOG) definitions and radiation dose- volume calculations were made for axillary levels, heart, and lungs. We generated revised plans for 10 patients by modifying the tangent beams to increase axillary dose and compared original with modified plans. RESULTS: The median proportion of the axilla covered by 90% of the prescription dose was 13% of level I (range, 0%-61%), 0% of level II (range, 0%-6%), and 0% of level III (range, 0%-0%). More of the level I axilla was covered in obese compared with nonobese patients (P = .013). Level I coverage did not differ significantly by laterality (P = .740) or tumor location (P = .527). Modification of the treatment plans significantly increased level I coverage (P = .005) with all modified plans delivering 90% of the prescription dose to at least 96% of the level I axilla. The modified plans had increased lung (P = .005) and heart (P = .028) dose, which were within acceptable RTOG normal tissue constraints. CONCLUSIONS: Most patients treated with standard whole breast tangential radiation in the prone position receive subtherapeutic dose to the level I and II axilla. Patients treated in the prone position who require therapeutic radiation dose to the low axilla need treatment field modification; this is feasible for many patients using tangent fields.

Diverse perspectives on the current state of genomic medicine: has the revolution begun?

A report on the Future of Genomic Medicine IV meeting held in La Jolla, California, USA, 3-4 March 2011.

Outcomes in black patients with early breast cancer treated with breast conservation therapy.

BACKGROUND: The race-specific impact of prognostic variables for early breast cancer is unknown for black patients undergoing breast conservation. METHODS AND MATERIALS: This was a retrospective study of 1,231 consecutive patients ≥40 years of age with Stage I-II invasive breast cancer treated with lumpectomy and radiation therapy at the University of Chicago Hospitals and affiliates between 1986 and 2004. Patients were classified as either black or nonblack. Cox proportional hazards regression was used to model the effects of known prognostic factors and interactions with race. RESULTS: Median follow-up for surviving patients was 82 months. Thirty-four percent of patients were black, and 66% were nonblack (Caucasian, Hispanic, and Asian). Black patients had a poorer 10-year overall survival (64.6% vs. 80.8%; adjusted hazard ratio [HR], 1.59; 95% confidence interval [CI], 1.23-2.06) and 10-year disease-free survival (58.1% vs. 75.4%; HR 1.49; 95% CI, 1.18-1.89) compared with nonblack patients. Tumor sizes were similar between nonblack and black patients with mammographically detected tumors (1.29 cm vs. 1.20 cm, p = 0.20, respectively). Tumor size was significantly associated with overall survival (HR 1.48; 95% CI, 1.12-1.96) in black patients with mammographically detected tumors but not in nonblack patients (HR 1.09; 95% CI, 0.78-1.53), suggesting that survival in black patients depends more strongly on tumor size in this subgroup. Tests for race-size method of detection interactions were statistically significant for overall survival (p = 0.049), locoregional control (p = 0.036), and distant control (p = 0.032) and borderline significant for disease-free survival (p = 0.067). CONCLUSION: Despite detection at comparable sizes, the prognostic effect of tumor size in patients with mammographically detected tumors is greater for black than in nonblack patients.

MUC1-associated proliferation signature predicts outcomes in lung adenocarcinoma patients.

BACKGROUND: MUC1 protein is highly expressed in lung cancer. The cytoplasmic domain of MUC1 (MUC1-CD) induces tumorigenesis and resistance to DNA-damaging agents. We characterized MUC1-CD-induced transcriptional changes and examined their significance in lung cancer patients. METHODS: Using DNA microarrays, we identified 254 genes that were differentially expressed in cell lines transformed by MUC1-CD compared to control cell lines. We then examined expression of these genes in 441 lung adenocarcinomas from a publicly available database. We employed statistical analyses independent of clinical outcomes, including hierarchical clustering, Student's t-tests and receiver operating characteristic (ROC) analysis, to select a seven-gene MUC1-associated proliferation signature (MAPS). We demonstrated the prognostic value of MAPS in this database using Kaplan-Meier survival analysis, log-rank tests and Cox models. The MAPS was further validated for prognostic significance in 84 lung adenocarcinoma patients from an independent database. RESULTS: MAPS genes were found to be associated with proliferation and cell cycle regulation and included CCNB1, CDC2, CDC20, CDKN3, MAD2L1, PRC1 and RRM2. MAPS expressors (MAPS+) had inferior survival compared to non-expressors (MAPS-). In the initial data set, 5-year survival was 65% (MAPS-) vs. 45% (MAPS+, p < 0.0001). Similarly, in the validation data set, 5-year survival was 57% (MAPS-) vs. 28% (MAPS+, p = 0.005). CONCLUSIONS: The MAPS signature, comprised of MUC1-CD-dependent genes involved in the control of cell cycle and proliferation, is associated with poor outcomes in patients with adenocarcinoma of the lung. These data provide potential new prognostic biomarkers and treatment targets for lung adenocarcinoma.

Tomorrow's targeted therapies in breast cancer patients: what is the risk for increased radiation-induced cardiac toxicity?

Ongoing clinical trials are now investigating the benefits of new targeted therapies, including ErbB and tyrosine kinase inhibitors (TKI) and antiangiogenics. Those may carry a potential risk for additional cardiac toxicity, particularly in association with radiotherapy. Although the risk of symptomatic cardiotoxicity is low, more subtle functional declines may increase mortality with longer follow-up and necessitate caution when assessing concurrent or sequential trastuzumab or lapatinib with radiotherapy. Potential additive toxicity encourages more conformal irradiation modalities minimizing cardiac dose, such as gating, intensity-modulated radiotherapy or Helical Tomotherapy. We recommend the collection of substantial information relevant to cardiac radiotoxicity in further clinical trials of targeted agents in breast cancer treatment, including doses delivered to cardiac structures, especially the coronary arteries. The incorporation of new biomarkers or modalities for assessment of cardiac function may also become necessary to detect cardiac toxicity at earliest stage.

Primary tumor necrosis predicts distant control in locally advanced soft-tissue sarcomas after preoperative concurrent chemoradiotherapy.

PURPOSE: Various neoadjuvant approaches have been evaluated for the treatment of locally advanced soft-tissue sarcomas. This retrospective study describes a uniquely modified version of the Eilber regimen developed at the University of Chicago. METHODS AND MATERIALS: We treated 34 patients (28 Stage III and 6 Stage IV) with locally advanced soft-tissue sarcomas of an extremity between 1995 and 2008. All patients received preoperative therapy including ifosfamide (2.5 g/m2 per day for 5 days) with concurrent radiation (28 Gy in 3.5-Gy daily fractions), sandwiched between various chemotherapy regimens. Postoperatively, 47% received further adjuvant chemotherapy. RESULTS: Most tumors (94%) were Grade 3, and all were T2b, with a median size of 10.3 cm. Wide excision was performed in 29 patients (85%), and 5 required amputation. Of the resected tumor specimens, 50% exhibited high (> or =90%) treatment-induced necrosis and 11.8% had a complete pathologic response. Surgical margins were negative in all patients. The 5-year survival rate was 42.3% for all patients and 45.2% for Stage III patients. For limb-preservation patients, the 5-year local control rate was 89.0% and reoperation was required for wound complications in 17.2%. The 5-year freedom-from-distant metastasis rate was 53.4% (Stage IV patients excluded), and freedom from distant metastasis was superior if treatment-induced tumor necrosis was 90% or greater (84.6% vs. 19.9%, p = 0.02). CONCLUSIONS: This well-tolerated concurrent chemoradiotherapy approach yields excellent rates of limb preservation and local control. The resulting treatment-induced necrosis rates are predictive of subsequent metastatic risk, and this information may provide an opportunity to guide postoperative systemic therapies.

Internal mammary lymph node irradiation contributes to heart dose in breast cancer.

We assessed the impact of internal mammary chain radiotherapy (IMC RT) to the radiation dose received by the heart in terms of heart dose-volume histogram (DVH). Thirty-six consecutive breast cancer patients presenting with indications for IMC RT were enrolled in a prospective study. The IMC was treated by a standard conformal RT technique (50 Gy). For each patient, a cardiac DVH was generated by taking into account the sole contribution of IMC RT. Cardiac HDV were compared according to breast cancer laterality and the type of previous surgical procedure, simple mastectomy or breast conservative therapy (BCT). The contribution of IMC RT to the heart dose was significantly greater for patients with left-sided versus right-sided tumors (13.8% and 12.8% for left-sided tumors versus 3.9% and 4.2% for right-sided tumors in the BCT group and the mastectomy group, respectively; p < 0.0001). There was no statistically significant difference in IMC contribution depending on the initial surgical procedure. IMC RT contributes to cardiac dose for both left-sided and right-sided breast cancers, although the relative contribution is greater in patients with left-sided tumors.

STAT1-dependent expression of energy metabolic pathways links tumour growth and radioresistance to the Warburg effect.

BACKGROUND: The Signal Transducer and Activator of Transcription 1 (STAT1) has traditionally been regarded as a transmitter of interferon signaling and a pro-apoptotic tumour suppressor. Recent data have identified new functions of STAT1 associated with tumourigenesis and resistance to genotoxic stress, including ionizing radiation (IR) and chemotherapy. To investigate the mechanisms contributing to the tumourigenic functions of STAT1, we performed a combined transcriptomic-proteomic expressional analysis and found that STAT1 is associated with regulation of energy metabolism with potential implication in the Warburg effect. METHODS: We generated a stable knockdown of STAT1 in the SCC61 human squamous cell carcinoma cell line, established tumour xenografts in athymic mice, and compared transcriptomic and proteomic profiles of STAT1 wild-type (WT) and knockdown (KD) untreated or irradiated (IR) tumours. Transcriptional profiling was based on Affymetrix Human GeneChip(R) Gene 1.0 ST microarrays. Proteomes were determined from the tandem mass spectrometry (MS/MS) data by searching against the human subset of the UniProt database. Data were analysed using Significance Analysis of Microarrays for ribonucleic acid and Visualize software for proteins. Functional analysis was performed with Ingenuity Pathway Analysis with statistical significance measured by Fisher's exact test. RESULTS: Knockdown of STAT1 led to significant growth suppression in untreated tumours and radio sensitization of irradiated tumours. These changes were accompanied by alterations in the expression of genes and proteins of glycolysis/gluconeogenesis (GG), the citrate cycle (CC) and oxidative phosphorylation (OP). Of these pathways, GG had the most concordant changes in gene and protein expression and demonstrated a STAT1-dependent expression of genes and proteins consistent with tumour-specific glycolysis. In addition, IR drastically suppressed the GG pathway in STAT1 KD tumours without significant change in STAT1 WT tumours. CONCLUSION: Our results identify a previously uncharacterized function of STAT1 in tumours: expressional regulation of genes encoding proteins involved in glycolysis, the citrate cycle and mitochondrial oxidative phosphorylation, with predominant regulation of glycolytic genes. STAT1-dependent expressional regulation of glycolysis suggests a potential role for STAT1 as a transcriptional modulator of genes responsible for the Warburg effect.

MUC1-induced transcriptional programs associated with tumorigenesis predict outcome in breast and lung cancer.

The Mucin 1 (MUC1) oncoprotein is aberrantly overexpressed in diverse human malignancies including breast and lung cancer. Although MUC1 modulates the activity of several transcription factors, there is no information regarding the effects of MUC1 on global gene expression patterns and the potential role of MUC1-induced genes in predicting outcome for cancer patients. We have developed an experimental model of MUC1-induced transformation that has identified the activation of gene families involved in oncogenesis, angiogenesis, and extracellular matrix remodeling. A set of experimentally derived MUC1-induced genes associated with tumorigenesis was applied to the analysis of breast and lung adenocarcinoma cancer databases. A 35-gene MUC1-induced tumorigenesis signature predicts significant decreases in both disease-free and overall survival in patients with breast (n=295) and lung (n=442) cancers. The data show that the MUC1 oncoprotein contributes to the regulation of genes that are highly predictive of clinical outcome in breast and lung cancer patients.

Concurrent hormone and radiation therapy in patients with breast cancer: what is the rationale?

Endocrine therapy is often given together with postoperative radiotherapy in patients with breast cancer and positive hormone-receptor status. However, few experimental or clinical studies address the combined effects of hormone and radiation therapy. Preclinical models have shown changes in tumour cell kinetics with the addition of tamoxifen, and some show reduced tumour cell death with concurrent anti-oestrogen treatment and radiotherapy. Although data from in-vitro studies support the notion of antagonistic effects of concurrent tamoxifen and radiotherapy on tumour cells, in-vivo research suggests a synergistic effect that could be attributable to micro-environmental changes in tumour responsiveness to ionising radiation and hormone therapy. Retrospective studies suggest that in practical application, concurrent administration of tamoxifen with radiotherapy does not compromise local control but might increase toxicity. Preliminary results from simultaneous treatment with aromatase inhibitors and radiation indicate that this combination of endocrine and radiation therapy could enhance cytotoxicity and improve tumour response. Further studies are needed to clarify the physiological mechanisms activated by oestrogens, which will allow a more thorough understanding of the complex interactions between 17beta-oestradiol and P53/P21(WAF1/CIP1)/Rb pathways and of the interaction between endocrine therapy and radiotherapy.

A rationale for the targeted treatment of oligometastases with radiotherapy.

An oligometastatic state has been proposed wherein patients with metastases limited in number and location may benefit from local therapy directed at all known sites of metastases. We describe here the clinical and biological basis for the oligometastatic state. We present evidence for a potentially curative approach to patients with oligometastases using stereotactic body radiotherapy (SBRT) and we review the literature for SBRT directed at specific metastatic sites in the lungs, liver and multiple organs.

Extranodal nonorbital indolent lymphomas of the head and neck: relationship between tumor control and radiotherapy.

PURPOSE: To review our experience managing extranodal nonorbital indolent lymphomas of the head and neck. PATIENTS AND METHODS: A retrospective review was made of 40 patients with indolent lymphomas of the head and neck evaluated at Stanford. The tumor head-and-neck location was Waldeyer's ring, 14; salivary glands, 16; thyroid, 4; and other sites, 6. Twenty-five were Stage I-IIE. Pathology was re-reviewed in 37. The most common histologies were marginal zone lymphoma and follicular grade 2. Patients received combinations of surgery, chemotherapy, and radiotherapy. Local therapy included surgery alone in 6 patients, radiotherapy alone in 7, and surgery plus radiotherapy in 12. Median follow-up was 70.5 months. RESULTS: Freedom from local progression was 86%, and freedom from progression was 61% at 5 years. Patients with radiotherapy had significantly better freedom from local progression (5-year, 100% vs. 72% for patients without radiotherapy, p = 0.006) and freedom from progression (5-year, 90% vs. 34% for patients without radiotherapy, p = 0.001). Improvement in freedom from progression with radiotherapy was statistically significant for Stage I-II patients (88% vs. 50%, p = 0.02) and of borderline significance in Stage III-IV patients (100% vs. 23%, p = 0.07). Overall survival at 10 years was 70%. Multivariate analysis revealed that significant prognostic factors for survival were tumor site (favoring salivary and thyroid, p = 0.02) and age (favoring younger, p = 0.04). CONCLUSION: Survival is excellent in patients with indolent lymphomas of the head and neck. Patients with salivary and thyroid primary tumors had better survival compared with others. Early use of radiotherapy resulted in significantly higher rates of freedom from progression and freedom from local progression in early-stage patients.