Cancer Cases Research Articles

Estimating regional and national cancer incidence in Uganda: a retrospective population-based study, 2013–2017

BackgroundCancer is becoming a major health problem in Uganda. Cancer control requires accurate estimates of the cancer burden for planning and monitoring of the cancer control strategies. However, cancer estimates and trends for Uganda are mainly based on one population-based cancer registry (PBCR), located in Kampala, the capital city, due to a lack of PBCRs in other regions. This study aimed at estimating cancer incidence among the geographical regions and providing national estimates of cancer incidence in Uganda.MethodsA retrospective study, using a catchment population approach, was conducted from June 2019 to February 2020. The study registered all newly diagnosed cancer cases, in the period of 2013 to 2017, among three geographical regions: Central, Western and Eastern regions. Utilizing regions as strata, stratified random sampling was used to select the study populations. Cases were coded according to the International Classification of Diseases for Oncology (ICD-0-03). Data was analysed using CanReg5 and Microsoft Excel.Results11598 cases (5157 males and 6441 females) were recorded. The overall national age-standardized incidence rates (ASIR) were 82.9 and 87.4 per 100,000 people in males and females respectively. The regional ASIRs were: 125.4 per 100,000 in males and 134.6 per 100,000 in females in central region; 58.2 per 100,000 in males and 56.5 per 100,000 in females in Western region; and 46.5 per 100,000 in males and 53.7 per 100,000 in females in Eastern region. Overall, the most common cancers in males over the study period were cancers of the prostate, oesophagus, Kaposi’s sarcoma, stomach and liver. In females, the most frequent cancers were: cervix, breast, oesophagus, Kaposi’s sarcoma and stomach.ConclusionThe overall cancer incidence rates from this study are different from the documented national estimates for Uganda. This emphasises the need to enhance the current methodologies for describing the country’s cancer burden. Studies like this one are critical in enhancing the cancer surveillance system by estimating regional and national cancer incidence and allowing for the planning and monitoring of evidence-based cancer control strategies at all levels.

Transforming Lung Cancer Care: Advancements in Screening, Treatment, and Survivorship

Matthew Triplette, Fred Hutchinson Cancer Center and University of Washington, Seattle, USA, delivered an insightful talk at the American Thoracic Society (ATS) International Conference 2024 on how landmark studies in lung cancer screening can affect recommendations and standards of care for pulmonary medicine specialists. Triplette highlighted that lung cancer remains the leading cause of cancer-related deaths, with 85% of all lung cancer cases related to tobacco smoke worldwide.

Transition of DNA-HPV over time in HPV-infected women: a 7-year cohort study

BACKGROUND Approximately 99% of cervical cancer cases worldwide are associated with one of the high-risk human papillomavirus (HPV) types. This study aimed to determine the transition rate of DNA-HPV over time in women aged 18–69 years with HPV infection in Can Tho City, Vietnam, from 2013 to 2020. METHODS The 2-phase cohort study was conducted on 213 women between 2013 and 2020. Phase 1 involved a retrospective cohort study (2013–2018), and phase 2 included a prospective cohort study (2018–2020). HPV testing was performed using real-time polymerase chain reaction on cervical fluid. McNemar’s test was employed to compare differences in HPV transition between 2013 and 2020. RESULTS From 2013 to 2018, the transition, clearance, and non-transition rates were 17.1%, 65.8%, and 66.2%, respectively, revealing a significant difference in the number of HPV cases during this period (p = 0.007). From 2018 to 2020, the transition, clearance, and non-transition rates were 9.8%, 44.9%, and 82.2%, respectively. Overall, the DNA-HPV changes from 2013 to 2020 indicated rates of 14.3% for transition, 68.5% for clearance, and 67.1% for non-transition. A significant difference in HPV cases was found between 2013 and 2020 (p = 0.001). CONCLUSIONS The longer duration resulted in a more significant difference in the DNA-HPV transition among HPV-infected women.

Molecular characteristics of patients with colorectal signet-ring cell carcinoma with different ABO blood groups

BACKGROUNDColorectal signet-ring cell carcinoma (SRCC) is a rare subtype of malignant adenocarcinoma, accounting for approximately 1% of colorectal cancer (CRC) cases. Its biomarkers and molecular characteristics remain controversial, and there are no specific therapeutic targets or strategies for its clinical treatment. METHODSA retrospective study was conducted between January 2010 and December 2021. 1058 colorectal cancer cases from the Sun Yat-sen University Cancer Center and 489 cases from the Tumor Genome Atlas Project were included in the analysis, of which 64 were SRCC. Data extraction included patient demographics, blood types and risk factors, including clinical variables and genomics (either a 19-gene panel NGS or 1021-gene panel NGS). Univariate analyses were performed to identify factors significantly associated with overall survival. RESULTSThe blood groups of 27 (42.2%), 18 (28.1%), 12 (18.8%), and seven (10.9%) patients were classified as O, A, B, and AB, respectively. We found that O was a unique blood group characterized by a low frequency of KRAS mutations, a high frequency of heterozygosity at each HLA class I locus, and a high tumor mutational burden (TMB). Patients in blood group A with high-frequency KRAS mutations and those in blood group B with anemia and metabolic abnormalities required targeted treatment. Furthermore, genetic alterations in SRCC differed from those in adenocarcinoma and mucinous adenocarcinoma. CONCLUSIONSOur study revealed genomic changes in SRCC patients across different blood groups, which could advance the understanding and precise treatment of colorectal SRCC.

Empirical model for a three-dimensional dose verification system and its application in volumetric-modulated arc therapy for heterogeneous and long-target tumors

PurposeTo perform commissioning of the VMAT dose verification system 3DVH from a unique perspective and investigating its clinical applications in unreported cases with heterogeneous organs or long-target tumors. MethodsInitially, the standard ArcCheck calibration process was conducted. Then, the impact of absolute dose calibration values and ArcCheck CT density settings on the accuracy of the 3DVH reconstruction model was assessed. Finally, ten lung cancer cases with heterogeneous organ-encased targets and ten cervical cancer cases with large target volumes were selected to receive VMAT treatment with a TrueBeam Linac. Finally, the performance of the 3DVH method in such radiotherapy validations was assessed. ResultsVarious calibration files had distinct impacts on ArcCheck 2D surface dosimetry and 3DVH dose reconstruction, thus requiring separate optimal calibrations files for these two purposes.The 3DVH dose reconstruction mode exhibited the highest accuracy when using the optimal ArcCheck density value of 1.1787 g/cm³ and an absolute dose calibration value of 249.96 cGy. In all test cases, deviations for target Dmean and D95% were within ±4.2% compared to the planned dose, with notable variations in critical organ doses. In structure-based 3D gamma evaluation, differences were observed compared to existing reports. ConclusionsIt's crucial to account for the ArcCheck array calibration and the interplay between CT density settings and absolute dose calibration values to identify the best combination for an optimal 3DVH dose reconstruction model. The performance of 3DVH in verifying VMAT doses for tumors in heterogeneous or longer target areas may exhibit slight variations compared to other regions.

Colorectal cancer and association with anaerobic bacteraemia: A Danish nationwide population-based cohort study

We aimed to identify specific anaerobic bacteria causing bacteraemia and a subsequent diagnosis of colorectal cancer. A nationwide population-based cohort study, which included all episodes of defined specific anaerobic bacteraemia from 2010 (5,534,738 inhabitants) through 2020 (5,822,763 inhabitants) and all cases of colorectal cancer diagnosed from 2010 through 2021 in Denmark. We calculated the incidence and risk of colorectal cancer after bacteraemia with specific anaerobic bacteria using Escherichia coli bacteraemia as reference. Nationwide data on colorectal cancer and specific anaerobic bacteraemia (100% complete, representing 11,124 episodes). The frequencies of colorectal cancer within one year following anaerobic bacteraemia were higher for species, which almost exclusively reside in the colon, such as Phocaeicola vulgatus/dorei (5.5%), Clostridium septicum (24.2%), and Ruminococcus gnavus (4.6%) compared to 0.6% in 50,650 E. coli bacteraemia episodes. Bacteroides spp. had a subhazard ratio for colorectal cancer of 3.9 (95% confidence interval [CI], 3.0 to 5.1) and for Clostridium spp. it was 8.9 (95% CI, 6.7 to 11.8, with C. septicum 50.0 [95% CI, 36.0 to 69.5]) compared to E. coli (reference). This nationwide study identified specific colorectal cancer-associated anaerobic bacteria, which almost exclusively reside in the colon. Bacteraemia with these bacteria could be an indicator of colorectal cancer.

Mixed Endometrioid Clear Cell Carcinoma of the Ovary: A Case Report

Background: Despite the high percentage of pure forms of epithelial ovarian cancers (EOC), mixed epithelial cancer of the ovary is extremely rare and accounts for less than 1% percent of all epithelial ovarian cancers. Because of the low prevalence; there are only a few cases of mixed epithelial cancers published in the literature. This study presents the case of a mixed endometrioid (EC)/clear cell carcinoma (CCC), diagnosed in a woman with a complaint of low back pain and a history of infertility. Case Report: We report the case of a 35-year-old woman who came to our clinic complaining of progressive back pain and a history of infertility. Imaging showed a left ovarian mass that was compatible with malignant tumors. The patient underwent open surgery and a frozen section evaluation of the tumor was done during the operation. The pathology result demonstrated mixed CCC/EC histology in the left ovary. We decided to perform a total abdominal hysterectomy as well as right salpingooophorectomy, omentectomy, bilateral pelvic lymphadenectomy, and para-aortic lymphadenectomy. Adjuvant chemotherapy was administrated postoperatively. Conclusion: Although epithelial cancers account for more than 90% of all ovarian cancers (OC), developing mixed forms of epithelial cancers is extremely rare, and there are little data available in the literature about their presentation and histopathological features. The main purpose of this article was to report a mixed CCC/EC and to discuss different aspects of this rare histologic type of OC. More research is needed to determine metastatic potential as well as the likelihood of recurrence of these unique neoplasms.

Successful Management of Upper Gastrointestinal Obstruction With Primary Advanced Ovarian Cancer.

Upper gastrointestinal obstruction is an extremely rare complication of primary ovarian cancer. We present a case of primary advanced ovarian cancer with gastroduodenal obstruction successfully managed with neoadjuvant chemotherapy (NAC) and conservative treatment. A 60-year-old woman was referred to our hospital for advanced ovarian cancer with upper gastrointestinal obstruction. Computed tomography and endoscopy revealed severe duodenal obstruction caused by dissemination. NAC was initiated with conservative management using a nasogastric tube and total parenteral nutrition (TPN). She was able to eat and TPN was stopped after three months. Complete resection was achieved with interval debulking surgery (IDS) not involving pancreatoduodenectomy, which would have been necessary for primary debulking surgery. There were no serious postoperative complications. NAC with conservative management can improve upper gastrointestinal obstruction in patients with primary advanced ovarian cancer. Furthermore, IDS is expected to allow complete resection, avoiding highly invasive surgeries.

Colposcopically Directed Biopsy Before Ablative Treatment Versus Direct Ablative Treatment in Patients With Cervical Oncogenic HPV.

In the past, the standard of care for women with abnormal cervical cytology has been the performance of colposcopically guided biopsy, followed by conization or large loop excision of the transition zone (LLETZ) where biopsy revealed pre-cancerous or cancerous areas. More straightforward protocols are emerging which advocate performing LLETZ in all women with highly suspicious cytology, suspicious colposcopic impression, or the presence of high-risk oncogenic human papilloma virus (HPV) strains in their cervical swabs. This, theoretically, would reduce the rate of false-negative diagnoses, but at the price of overtreating a significant number of healthy women. We retrospectively analyzed cervical cancer screening protocols in two large cohorts of women with high-risk HPV. The study compared outcomes between patients undergoing a colposcopically directed biopsy before LLETZ (n=683) and those proceeding directly to LLETZ without a biopsy (n=136). The primary focus was to assess whether intervening biopsies would reduce unnecessary ablative procedures without compromising the detection of high-grade lesions. The biopsy group had a high false-negative rate, with several high-grade lesions (CIN3) and a case of invasive cancer initially underdiagnosed. Conversely, the direct-to-LLETZ approach, while ensuring no high-grade lesions were missed, led to overtreatment of lower grade lesions. These findings raise concern about the reliance on biopsy results for treatment decisions. Neither protocol was entirely satisfactory, although the more aggressive one avoided the potentially life-threatening consequence of false-negative results. Further research is mandatory to accurately diagnose all cases requiring aggressive treatment, without subjecting healthy women to ablative treatments they do not need.

A Long-term Evaluation of Acellular Dermal Matrix for Immediate Implant-based Breast Reconstruction following Risk-reducing Mastectomy.

Acellular dermal matrices (ADMs) are sometimes used in implant-based breast reconstructions (IBR), but long-term ADM-related evaluations are scarce. In this study, we evaluated early and late complications and patient-related outcomes (PROs) over an 8-year postoperative period in women who had undergone immediate IBR following risk-reducing mastectomy with bovine ADM (SurgiMend). This prospective observational single-center analysis involved 34 women at high risk for breast carcinoma. Complications were prospectively recorded during the first year, followed by 4 years of postoperative retrospective chart reviews. Long-term evaluations were done using a questionnaire. Preoperative, 1 year, and 5- to 8-year postoperative PRO assessments were obtained based on results from the BREAST-Q questionnaire. In 56 breasts, complications after a mean of 12.4 months follow-up included implant loss (7.1%), implant change (1.8%), hematoma (7.1%), breast redness (41.1%), and seroma (8.9%). Most breasts (80.3%) were graded Baker I/II, which indicated a low capsular contracture incidence. After a mean of 6.9 years, the total implant explantation rate was 33.9%, and the revision surgery rate was 21.4%. Two cases of breast cancer were reported during the long-term evaluation. BREAST-Q results indicated significantly decreased satisfaction with outcome (P = 0.024). A positive trend regarding psychosocial well-being and declining trend regarding satisfaction with both breast physical- and sexual well-being parameters were reported. The observed complication rates agree with previous findings concerning ADM-assisted IBR. A high demand for revision surgery exists, and PROs remain relatively stable over time.

Risk prediction model for gastric cancer within 5 years in healthy Korean adults.

Although endoscopy is commonly used for gastric cancer screening in South Korea, predictive models that integrate endoscopy results are scarce. We aimed to develop a 5-year gastric cancer risk prediction model using endoscopy results as a predictor. We developed a predictive model using the cohort data of the Kangbuk Samsung Health Study from 2011 to 2019. Among the 260,407 participants aged ≥20years who did not have any previous history of cancer, 435 cases of gastric cancer were observed. A Cox proportional hazard regression model was used to evaluate the predictors and calculate the 5-year risk of gastric cancer. Harrell's C-statistics and Nam-D'Agostino χ2 test were used to measure the quality of discrimination and calibration ability, respectively. We included age, sex, smoking status, alcohol consumption, family history of cancer, and previous results for endoscopy in the risk prediction model. This model showed sufficient discrimination ability [development cohort: C-Statistics: 0.800, 95% confidence interval (CI) 0.770-0.829; validation cohort: C-Statistics: 0.799, 95% CI 0.743-0.856]. It also performed well with effective calibration (development cohort: χ2=13.65, P=0.135; validation cohort: χ2=15.57, P=0.056). Our prediction model, including young adults, showed good discrimination and calibration. Furthermore, this model considered a fixed time interval of 5years to predict the risk of developing gastric cancer, considering endoscopic results. Thus, it could be clinically useful, especially for adults with endoscopic results.

Once-daily upadacitinib versus placebo in adults with extensive non-segmental vitiligo: a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-ranging study

Janus kinase (JAK) inhibition is a promising approach for treating vitiligo. We aimed to assess the efficacy and safety of upadacitinib, an oral selective JAK inhibitor, in adults with non-segmental vitiligo. This was a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-ranging study completed at 33 clinical centres in the United States, Canada, France, and Japan. Eligible patients were aged 18-65 years with non-segmental vitiligo and had a Facial Vitiligo Area Scoring Index (F-VASI) ≥0.5 and a Total Vitiligo Area Scoring Index (T-VASI) ≥5. Patients were randomly assigned (2:2:2:1:1) using an interactive response technology to receive upadacitinib 6mg (UPA6), upadacitinib 11mg (UPA11), upadacitinib 22mg (UPA22), or placebo (PBO; preassigned to switch to either UPA11 or UPA22 in period 2) once daily for 24 weeks (period 1). For weeks 24-52 (period 2), patients randomly assigned to upadacitinib continued their treatment, and patients receiving PBO switched to their preassigned upadacitinib dose in a blinded fashion. The primary endpoint was the percent change from baseline in F-VASI at week 24. Efficacy was analysed in the intention-to-treat population, and safety was examined in all randomly assigned patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT04927975. Between June 16, 2021, and June 27, 2022, 185 patients (including 115 [62%] who were female and 70 [38%] who were male) were randomly assigned to UPA6 (n=49), UPA11 (n=47), UPA22 (n=43), or PBO (n=46). At week 24, the LS mean difference versus PBO in the percent change from baseline in F-VASI was-7.60 (95% CI-22.18 to 6.97; p=0.3037) for UPA6,-21.27 (95% CI-36.02 to-6.52; p=0.0051) for UPA11, and-19.60 (95% CI-35.04 to-4.16; p=0.0132) for UPA22. The LS mean difference versus PBO in the percent change from baseline in T-VASI was-7.45 (95% CI-16.86 to 1.96; p=0.1198) for UPA6,-10.84 (95% CI-20.37 to-1.32; p=0.0259) for UPA11 and-14.27 (95% CI-24.24 to-4.30; p=0.0053) for UPA22. Ongoing treatment with upadacitinib induced continuous skin repigmentation over time without reaching a plateau through week 52. The rates for study drug discontinuation and serious treatment-emergent adverse events (TEAEs) were higher in the UPA22 group than in the UPA11 and UPA6 groups. Eight serious TEAEs, including one death of unknown cause and one case of infiltrating lobular breast carcinoma, were reported through 52 weeks; only two serious TEAEs (coronary artery arteriosclerosis [UPA6 (n=1)] and non-fatal ischemic stroke [UPA11 (n=1)]) were deemed by the investigator to have a reasonable possibility of being related to study drug. The one case of breast cancer in the UPA11 group was deemed unrelated to study drug, and the one death of unknown cause in the UPA22 group was reviewed and adjudicated and was deemed to be unrelated to study drug. The most common TEAEs were COVID-19, headache, acne, and fatigue. No new safety signals were observed. Upadacitinib monotherapy led to substantial repigmentation of both facial and total body vitiligo lesions and may offer an effective treatment option for adults with extensive non-segmental vitiligo. Based on these findings, upadacitinib 15mg is being investigated in adults and adolescents with non-segmental vitiligo in an ongoing phase 3 randomised controlled trial. AbbVie Inc.

Advances in chitosan-based drug delivery systems in melanoma: A narrative review.

Melanoma accounts for the minority of skin cancer cases. However, it has the highest mortality rate among the subtypes of skin cancer. At the early stages of the disease, patients show a good prognosis after the surgery, but developing metastases leads to a remarkable drop in patients' 5-year survival rate. Despite the advances made in the therapeutic approaches to this disease, melanoma treatment is still facing several obstacles. Systemic toxicity, water insolubility, instability, lack of proper biodistribution, inadequate cellular penetration, and rapid clearance are some of the challenges that should be addressed in the field of melanoma treatment. While various delivery systems have been developed to circumvent these challenges, chitosan-based delivery platforms have indicated significant success. Chitosan that is produced by the deacetylation of chitin can be formulated into different materials (e.g., nanoparticle, film, and hydrogel) due to its characteristics. Both in vitro and in vivo studies have reported that chitosan-based materials can be used in drug delivery systems while offering a solution for the common problems in this area, such as enhancing biodistribution and skin penetration as well as the sustained release of the drugs. Herein, we reviewed the studies concerning the role of chitosan as a drug delivery system in melanoma and discussed how these drug systems are used for delivering chemotherapeutic drugs (e.g., doxorubicin and paclitaxel), genes (e.g., TRAIL), and RNAs (e.g., miRNA199a and STAT3 siRNA) successfully. Furthermore, we take a look into the role of chitosan-based nanoparticles in neutron capture therapy.

Improved efficacy of cisplatin delivery by peanut agglutinin‑modified liposomes in non‑small cell lung cancer.

Globally, non‑small cell lung cancer (NSCLC) is a significant threat to human health, and constitutes >80% of lung cancer cases. Cisplatin (CDDP), a commonly used drug in clinical treatment, has been the focus of research aiming to mitigate its potent toxicity through encapsulation within liposomes. However, challenges, such as a reduced drug loading efficiency and nonspecific release, have emerged as obstacles. The present study aimed to improve the encapsulation efficiency of CDDP within liposomes by pre‑preparation of CDDP and modifying the liposome surface through the incorporation of peanut agglutinin (PNA) as a ligand [CDDP‑loaded PNA‑modified liposomes (CDDP‑PNA‑Lip)]. This strategy was designed to enhance the delivery of CDDP to tumour tissues, thereby reducing associated side effects. The effect of CDDP‑PNA‑Lip on the proliferation and migration of NSCLC cell lines with high MUC1 expression was elucidated through in vitro studies. Additionally, the capacity of PNA modification to augment the targeted anti‑tumour efficacy of liposomes was assessed through xenograft tumour experiments. The results indicated that in an in vitro uptake assay Rhodamine B (RhB)‑loaded PNA‑modified liposomes were taken up by cells with ~50% higher efficiency compared with free RhB. In addition, CDDP‑PNA‑Lip resulted in a 2.65‑fold enhancement of tumour suppression in vivo compared with free CDDP. These findings suggested that the encapsulation of CDDP within ligand‑modified liposomes may significantly improve its tumour‑targeting capabilities, providing valuable insights for clinical drug development.

Quality of ChatGPT-Generated Therapy Recommendations for Breast Cancer Treatment in Gynecology

Introduction: Artificial intelligence (AI) is revolutionizing medical workflows, with self-learning systems like ChatGPT showing promise in therapy recommendations. Our study evaluated ChatGPT’s performance in suggesting treatments for 30 breast cancer cases. AI’s role in healthcare is expanding, particularly with tools like ChatGPT becoming accessible. However, understanding its limitations is vital for safe implementation. Material and Methods: We used 30 breast cancer cases from our medical board, assessing ChatGPT’s suggestions. The input was standardized, incorporating relevant patient details and treatment options. ChatGPT’s output was evaluated by oncologists based on a given questionnaire. Results: Treatment recommendations by ChatGPT were overall rated sufficient with minor limitations by the oncologists. The HER2 treatment category was the best-rated therapy option, with the most accurate recommendations. Primary cases received more accurate recommendations, especially regarding chemotherapy. Conclusions: While ChatGPT demonstrated potential, difficulties were shown in intricate cases and postoperative scenarios. Challenges arose in offering chronological treatment sequences and partially lacked precision. Refining inputs, addressing ethical intricacies, and ensuring chronological treatment suggestions are essential. Ongoing research is vital to improving AI’s accuracy, balancing AI-driven suggestions with expert insights and ensuring safe and reliable AI integration into patient care.

The use of mixed reality in the preoperative planning of colorectal surgery: Preliminary experience with a narrative review

New advanced technologies have recently been developed and preliminarily applied to surgery, including virtual reality (VR), augmented reality (AR) and mixed reality (MR). We retrospectively review all colorectal cases in which we used holographic 3D reconstruction from February 2020 to December 2022. This innovative approach was used to identify vascular anomalies, pinpoint tumor locations, evaluate infiltration into neighboring organs and devise surgical plans for both training and educating trainee assistants. We have also provided a state-of-the-art analysis, briefly highlighting what has been stated by the scientific literature to date. VR facilitates training and anatomical assessments, while AR enhances training and laparoscopic performance evaluations. MR, powered by HoloLens, enriches anatomic recognition, navigation, and visualization. Successful implementation was observed in 10 colorectal cancer cases, showcasing the effectiveness of MR in improving preoperative planning and its intraoperative application. This technology holds significant promise for advancing colorectal surgery by elevating safety and reliability standards.

Functional exploration of copy number alterations in a Drosophila model of triple-negative breast cancer.

Accounting for 10-20% of breast cancer cases, triple-negative breast cancer (TNBC) is associated with a disproportionate number of breast cancer deaths. One challenge in studying TNBC is its genomic profile: with the exception of TP53 loss, most breast cancer tumors are characterized by a high number of copy number alterations (CNAs), making modeling the disease in whole animals challenging. We computationally analyzed 186 CNA regions previously identified in breast cancer tumors to rank genes within each region by likelihood of acting as a tumor driver. We then used a Drosophila p53-Myc TNBC model to identify 48 genes as functional drivers. To demonstrate the utility of this functional database, we established six 3-hit models; altering candidate genes led to increased aspects of transformation as well as resistance to the chemotherapeutic drug fluorouracil. Our work provides a functional database of CNA-associated TNBC drivers, and a template for an integrated computational/whole-animal approach to identify functional drivers of transformation and drug resistance within CNAs in other tumor types.

Quantitative Measurement of HER2 Expression in Non-Small Cell Lung Cancer with a High Sensitivity Assay

Recently, low HER2 protein expression has been proposed as a predictive biomarker for response to antibody-drug conjugate trastuzumab deruxtecan (T-DXd) in metastatic breast cancer. HER2 expression in non-small cell lung cancer (NSCLC) patients has never been carefully measured, and little is known about the frequency of cases with unamplified but detectable levels of the protein. Although some HER2-targeted therapies have been studied in NSCLC patients, they have been restricted to those with genomic ERBB2 gene alterations, which only represent relatively rare cases of NSCLC. Still, emerging investigations of T-DXd in NSCLC have shown promise in patients with unamplified HER2. Taken together, we hypothesize that there may be many cases of NSCLC with levels of HER2 protein expression comparable to levels seen in breast cancer who benefit from T-DXd. Here, we used a previously validated, analytic, quantitative immunofluorescence (QIF) assay that is more sensitive than legacy clinical HER2 immunohistochemistry assays. We measured HER2 protein levels in NSCLC cases to determine the proportion of cases with detectable HER2 expression. Using cell line calibration microarrays alongside our QIF method enabled us to convert HER2 signal into units of attomoles per mm2. We found that over 63% of the 741 analyzed NSCLC cases exhibited HER2 expression above the limit of detection, with more than 17% of them exceeding the lower limit of quantification. While the threshold for response to T-DXd in breast cancer is still unknown, many cases of NSCLC have expression in a range comparable to breast cancer cases with immunohistochemistry scores of 1+ or 2+. Our assay could potentially select NSCLC cases with detectable target (i.e., HER2) that might benefit from HER2 antibody-drug conjugates, irrespective of ERBB2 genomic alterations.

Fraction of cancers attributable to and prevented by reproductive factors and exogenous hormones use in Italy

ObjectiveEndogenous and exogenous hormonal factors have been associated with female breast, genital, and colorectal cancer risk. The aim of the present study is to conduct an evidence-based evaluation of the fraction of cancers attributable to and prevented by exogenous hormonal (i.e., combined oral contraceptives [COC] and combined estrogen-progestogen menopausal therapy [CEPMT]) and reproductive factors (i.e., parity and breastfeeding) in Italy. Study designWe calculated the population attributable and prevented fractions combining relative risks and prevalence of exposure in Italian women. Italian cancer incidence and mortality data were extracted from national sources and used to estimate the number of cancer cases and deaths attributable to reproductive factors and exogenous hormones in Italy in 2020. For long-term effects, a 20-year latency period was considered. ResultsCOC were responsible for 4.4 % of breast and 10.9 % of cervical cancers in women aged 15–44, but also avoided 6.4 % of endometrial, 5.6 % of ovarian and 2.9 % of colorectal cancers in women of all ages. Overall, COC use prevented 1174 cancer diagnoses and 577 cancer deaths. CEPMT caused 0.4 % of breast cancers at age 45–69. Low parity accounted for 8.1 %, 11.8 % and 15.5 % of breast, endometrial and ovarian cancers, respectively (6267 cases, 1796 deaths). Breastfeeding avoided 6.4 % of breast cancers (3775 cases, 897 deaths). ConclusionsOur analysis quantified the complex effects of hormonal and reproductive factors on cancer burden in Italian women.

Population-based germline breast cancer gene association studies and meta-analysis to inform wider mainstream testing.

BackgroundGermline genetic testing, previously restricted to familial and young-onset breast cancer, is now offered increasingly broadly to ‘population-type’ breast cancer patients in mainstream oncology clinics, with wide variation in the genes included. MethodsWeighted meta-analysis was performed for three population-based case-control studies (BRIDGES, CARRIERS and UK Biobank) comprising in total 101,397 women with breast cancer and 312,944 women without breast cancer, to quantify for 37 putative breast cancer susceptibility genes (BCSGs) the frequency of pathogenic variants (PVs) in unselected, ‘population-type’ breast cancer cases and their association with breast cancer and its subtypes. ResultsMeta-analysed odds ratios (ORs) and frequencies of PVs in population-type breast cancer cases were generated for BRCA1 (OR= 8.73 (95% CI 7.47-10.20), 1 in 101), BRCA2 (OR=5.68 (5.13-6.30), 1 in 68) and PALB2 (OR= 4.30 (95% CI 3.68-5.03), 1 in 187). For both CHEK2 (OR=2.40 (95% CI 2.21-2.62), 1 in 73) and ATM (OR=2.16 (95%CI 1.93-2.41), 1 in 132) subgroup analysis showed stronger association with ER-positive disease. Magnitude of association and frequency of PVs were low for RAD51C (OR=1.53 (95%CI 1.15-2.04), 1 in 913), RAD51D (OR=1.76, (95%CI 1.15-2.41, 1 in 1079) and BARD1 (OR=2.34 (1.85-2.97), 1 in 672); frequencies and associations were moderately higher restricting to triple-negative breast cancersThe PV-frequency in ‘population-type’ breast cancer cases was very low for ‘syndromic’ BCSGs TP53 (1 in 1844), STK11 (1 in 11,525), CDH1 (1 in 2668), PTEN (1 in 3755) and NF1 (1 in 1470), with metrics of association also modest ranging from OR=3.62 (95%CI 1.98-6.61) for TP53 down to OR=1.60 (95%CI 0.48-5.30) for STK11. ConclusionsThese metrics reflecting ‘population-type’ breast cancer will be informative to defining the appropriate gene set as we continue to expand to germline testing out to more unselected population-type breast cancer cases.