Sacituzumab govitecan response in extensive leptomeningeal carcinomatosis from triple-negative breast cancer: a case report.

Sacituzumab govitecan (SG), a Trop-2-directed antibody-drug conjugate (ADC), was the first ADC approved for patients with metastatic triple-negative breast cancer (mTNBC) who had received at least two prior lines of therapy for advanced disease. Although SG has shown promising clinical activity in treating brain metastases in both ASCENT randomized trials and real-world analysis, its utility in leptomeningeal carcinomatosis (LC) remains underexplored. We report the diagnostic and therapeutic process of a patient who develops extensive LC from TNBC treated with SG. She presented a clinical response after the first cycle of SG with a PFS of 6 months. This case report highlights the need for further inquiry into the use of SG in LC.

Olaparib plus trastuzumab in HER2-positive advanced breast cancer patients with germline BRCA1/2 mutations: The OPHELIA phase 2 study.

PURPOSE: To evaluate the efficacy and safety of the combination of olaparib plus trastuzumab in patients with HER2-positive advanced breast cancer (ABC) and germinal BRCA mutations (gBRCAm). METHODS: OPHELIA (NCT03931551) was a single-arm, open-label, phase 2 clinical trial. Patients aged ≥18 years diagnosed with HER2-positive ABC with germinal deleterious mutations in BRCA1 or BRCA2 who had received at least one prior systemic regimen for advanced disease were enrolled. Patients received olaparib plus trastuzumab until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was investigator-assessed clinical benefit rate for at least 24 weeks as per RECIST v.1.1. Key secondary endpoints included overall response rate (ORR) and safety profile. RESULTS: A total of 68 pre-treated HER2-positive ABC patients were screened. Due to slow accrual the trial was stopped after enrolling 5 patients instead of the planned sample size of 20. Four patients achieved clinical benefit (80.0 %, 95 % CI; 28.4-99.5, p < 0.001) and the primary endpoint was met. The ORR was 60.0 % (95 % CI; 14.7-94.7), including one complete response. Four (80.0 %) patients experienced at least one treatment-related treatment-emergent adverse event (TEAE). Most TEAEs were grade 1 or 2. There were no treatment-related deaths and no new safety signals were identified. CONCLUSIONS: This study suggests that the combination of olaparib plus trastuzumab may be effective and safe in pre-treated patients with HER2-positive gBRCAm ABC. This ABC patient population should be further studied and not be pre-emptively excluded from clinical trials of targeted therapy for BRCA1/2-driven cancers.

Body composition and endometrial cancer outcomes.

BACKGROUND: Obesity is a known risk factor for developing endometrial cancer. However, the association of obesity with endometrial cancer (EC) outcomes has not been clearly established. This study examined how outcomes in women with early stage EC vary with body composition measured via computed tomography (CT). METHODS: In this retrospective study, patients diagnosed with EC international Federation of Gynecology and Obstetrics stages I-III and available CT scans were included. Automatica software was used to assess the areas of visceral adipose tissue, subcutaneous adipose tissue (SAT), and intermuscular adipose tissue (IMAT) and skeletal muscle area. RESULTS: Of 293 patient charts assessed, 199 met eligibility criteria. Median body mass index (BMI) was 32.8 kg/m2 (interquartile range [IQ] = 26.8-38.9); 61.8% had histologic subtype endometrioid carcinoma. Adjusted for age, international Federation of Gynecology and Obstetrics stage, and histologic subtype, a BMI of at least 30 vs less than 30 kg/m2 was associated with lower endometrial cancer-specific survival (ECSS) (hazard ratio [HR] = 2.32, 95% confidence interval [CI] = 1.27 to 4.25) and overall survival (OS) (HR = 2.7, 95% CI = 1.35 to 5.39). Higher IMAT 75th vs 25th percentile and SAT of at least 225.6 vs less than 225.6 cm2 were associated with lower ECSS (HR = 1.53, 95% CI = 1.1 to 2.13, and HR = 2.57, 95% CI = 1.13 to 5.88) and OS (HR = 1.50, 95% CI = 1.11 to 2.02, and HR = 2.46, 95% CI = 1.2 to 5.01), respectively. The association of visceral adipose tissue (75th vs 25th percentile) with ECSS and OS was not statistically significant (HR = 1.42, 95% CI = 0.91 to 2.22, and HR = 1.24, 95% CI = 0.81 to 1.89). CONCLUSION: Higher BMI, IMAT, and SAT were associated with higher mortality from EC and lower OS. A better understanding of the mechanisms underlying these relationships could inform strategies to improve patient outcomes.

Pandemic Phase-Adjusted Analysis of COVID-19 Outcomes Reveals Reduced Intrinsic Vulnerability and Substantial Vaccine Protection From Severe Acute Respiratory Syndrome Coronavirus 2 in Patients With Breast Cancer.

PURPOSE: Although representing the majority of newly diagnosed cancers, patients with breast cancer appear less vulnerable to COVID-19 mortality compared with other malignancies. In the absence of patients on active cancer therapy included in vaccination trials, a contemporary real-world evaluation of outcomes during the various pandemic phases, as well as of the impact of vaccination, is needed to better inform clinical practice. METHODS: We compared COVID-19 morbidity and mortality among patients with breast cancer across prevaccination (February 27, 2020-November 30, 2020), Alpha-Delta (December 1, 2020-December 14, 2021), and Omicron (December 15, 2021-January 31, 2022) phases using OnCovid registry participants (ClinicalTrials.gov identifier: NCT04393974). Twenty-eight-day case fatality rate (CFR28) and COVID-19 severity were compared in unvaccinated versus double-dosed/boosted patients (vaccinated) with inverse probability of treatment weighting models adjusted for country of origin, age, number of comorbidities, tumor stage, and receipt of systemic anticancer therapy within 1 month of COVID-19 diagnosis. RESULTS: By the data lock of February 4, 2022, the registry counted 613 eligible patients with breast cancer: 60.1% (n = 312) hormone receptor-positive, 25.2% (n = 131) human epidermal growth factor receptor 2-positive, and 14.6% (n = 76) triple-negative. The majority (61%; n = 374) had localized/locally advanced disease. Median age was 62 years (interquartile range, 51-74 years). A total of 193 patients (31.5%) presented ≥ 2 comorbidities and 69% (n = 330) were never smokers. In total, 392 (63.9%), 164 (26.8%), and 57 (9.3%) were diagnosed during the prevaccination, Alpha-Delta, and Omicron phases, respectively. Analysis of CFR28 demonstrates comparable estimates of mortality across the three pandemic phases (13.9%, 12.2%, 5.3%, respectively; P = .182). Nevertheless, a significant improvement in outcome measures of COVID-19 severity across the three pandemic time periods was observed. Importantly, when reported separately, unvaccinated patients from the Alpha-Delta and Omicron phases achieved comparable outcomes to those from the prevaccination phase. Of 566 patients eligible for the vaccination analysis, 72 (12.7%) were fully vaccinated and 494 (87.3%) were unvaccinated. We confirmed with inverse probability of treatment weighting multivariable analysis and following a clustered robust correction for participating center that vaccinated patients achieved improved CFR28 (odds ratio [OR], 0.19; 95% CI, 0.09 to 0.40), hospitalization (OR, 0.28; 95% CI, 0.11 to 0.69), COVID-19 complications (OR, 0.16; 95% CI, 0.06 to 0.45), and reduced requirement of COVID-19-specific therapy (OR, 0.24; 95% CI, 0.09 to 0.63) and oxygen therapy (OR, 0.24; 95% CI, 0.09 to 0.67) compared with unvaccinated controls. CONCLUSION: Our findings highlight a consistent reduction of COVID-19 severity in patients with breast cancer during the Omicron outbreak in Europe. We also demonstrate that even in this population, a complete severe acute respiratory syndrome coronavirus 2 vaccination course is a strong determinant of improved morbidity and mortality from COVID-19.

Current Systemic Treatments for the Hereditary Cancer Syndromes: Drug Development in Light of Genomic Defects.

Advances in the genetic basis of different tumors have led to identification of tumor vulnerabilities that can be turn into targeted therapies. In this regard, PARP inhibitors cause synthetic lethality with tumors harboring BRCA1 or BRCA2 genetic alterations. On the other hand, tumors with microsatellite instability, either due to germline or sporadic alterations, are candidates for immune checkpoint inhibitors. Finally, patients with von Hippel-Lindau disease who carry a germline alteration in the VHL gene may benefit form belzutifan, a hypoxia-inducible factor 2 alpha inhibitor. Overall, research on the underlying pathological mechanisms of these tumors has provided new therapeutic opportunities that might be expanded to other sporadic tumors with similar biology.

The conundrum of breast cancer and microbiome - A comprehensive review of the current evidence.

Disturbance of the microbial balance of a habitat can have detrimental effects on the health of the individual and, in addition, polymorphic microbiomes were recently suggested as emerging cancer hallmarks. Modern sequencing and metagenomics techniques have allowed characterization of intratumoral microbiome composition even in tissues such as the breast. We conducted a comprehensive literature review on different aspects related to the microbial landscape of the breast tissue and breast tumors, as well as its relation to systemic therapy. Emerging data suggest varying microbiome composition intratumorally compared to the normal breast tissue and other tumor types. Differences in the microbes present in normal breast and cancerous lesions of the breast have also been described, as well as potential correlation between microbiome composition and breast cancer subtype and stage. The interplay between gut and breast microbiome is not well understood although bacterial allocation through mesenteric lymph nodes has been suggested as a possible pathway. Moreover, gut bacteria with estrogen metabolizing properties are of special interest in the context of breast cancer and available knowledge and reported studies are hereby described. The relationship of gut microbiome and cancer therapy is another aspect of interest and available data are presented. Notwithstanding, the field of microbiome in the context of breast cancer is starting to evolve and a number of questions arise, with the gut-breast-cancer therapy axis in the center.

Genetic and functional homologous repair deficiency as biomarkers for platinum sensitivity in TNBC: A case report.

Triple-negative breast cancer is the most aggressive subtype of mammary carcinoma. In the early stage, neoadjuvant chemotherapy (NAC) is the standard of care for prognostic stratification and the best adjuvant treatment strategy. A 30-year-old female presented in the emergency room because of a gigantic right breast associated with an ulcerated lump at the upper quadrants. The right axillary nodes were palpable. An ultrasound was performed, showing the ulcerated neoformation with enlarged right axillary lymph nodes observed to level III. A core biopsy of the breast lesion was performed, and the pathological examination revealed a nonspecial type, grade 3, invasive, triple-negative breast cancer. No distant disease was found in the PET-CT scan. A germline genetic panel by next-generation sequencing identified a likely pathogenic variant in RAD51D (c.898C>T). Assessment of the functionality of the DNA homologous recombination repair pathway by RAD51 foci in the tumor revealed a profile of homologous recombination deficiency. NAC consisting of weekly carboplatin and paclitaxel followed by dose-dense doxorubicin/cyclophosphamide was performed with a complete metabolic response achieved in the PET-CT scan. The patient underwent a modified radical mastectomy plus axillary lymphadenectomy with a pathological complete response in the breast and axilla and remains disease-free after 2 years of follow-up. We report a young female with a triple-negative breast cancer stage cT4bN3M0 and a hereditary pathogenic mutation in RAD51D. The tumor was highly proliferative and homologous recombination-deficient by RAD51. The patient received platinum-based NAC, achieving a pathologic complete response. More effort should be made to identify predictive functional biomarkers of treatment response, such as RAD51 foci, for platinum sensitivity.

Prognostic value of ctDNA detection in patients with early breast cancer undergoing neoadjuvant therapy: A systematic review and meta-analysis.

Circulating tumor DNA (ctDNA) is increasingly being used as a biomarker in early breast cancer (EBC). We performed a systematic review and meta-analysis to investigate the prognostic value of ctDNA in patients with EBC treated with neoadjuvant therapy (NAT). We searched Medline, Web of Science and Embase for observational or interventional studies that included patients with EBC undergoing NAT, reported outcomes related to the predefined endpoints, and had full text articles available. Study selection followed the PRISMA guidelines and quality assessment the REMARK tool for biomarker studies. Primary endpoint was impact of ctDNA detection in different time points (baseline, on-treatment, and after NAT) on relapse-free survival (RFS) and overall survival (OS). Secondary endpoints included the association of ctDNA detection with pathologic complete response (pCR), and the positive and negative predictive value of ctDNA detection in predicting residual disease after NAT. From the 2908 studies initially identified, 11 met the eligibility criteria and were included in the meta-analysis. Detection of ctDNA, both at baseline and after completion of NAT, significantly associated to worse RFS (HR 4.22, 95% CI: 1.29-13.82 and HR 5.67, 95% CI: 2.73-11.75, respectively) and worse OS (HR 19.1, 95% CI: 6.9-53.04 and HR 4.00, 95% CI: 1.90-8.42, respectively). In contrast, detection of ctDNA did not associate with the probability of achieving a pCR. Our results suggest that ctDNA assessment during NAT for EBC merits further evaluation as a stratification risk factor in prospective trials, in order to better individualize patient's treatment.

[Synchronous revascularization surgery of supraaortic trunks and abdominal visceral arteries. Case report]. / Revascularização simultânea dos troncos supraórticos e das artérias viscerais do abdómen. Caso clínico.

The clinical case of a 50 years old female is reported, who was admitted at our hospital in very poor general condition, in a physical and psychologic state of exhaustion, due to a mesenteric vascular insufficiency syndrome (abdominal angina), for the last three years. She underwent a conventional angiographic evaluation, disclosing an occlusion of both the celiac axis and superior mesenteric artery and at the level of the aortic arch, an occlusion of the innominate artery associated to an ostial stenosis of the left common carotid artery was also found. The coronary circulation was normal. The patient underwent surgical management consisting in the bowel revascularization trough a supraceliac aortic bypass to both the hepatic and superior mesenteric arteries, followed by a supraaortic trunks revascularization by means of a bypass graft from the ascending aorta to both common carotid arteries. The extensive procedure was well tolerated by the patient and the post-operative course was normal, with the exception of an acute respiratory insufficiency promptly managed with intensive and non-invasive care and she was discharged on day 14th, asymptomatic and with a gain weight of 7 kilos. The unusual and eventually unique character of this simultaneous surgery justifies its presentation, as well as a discussion on the advantages and contraindications of such approach, that revealed itself as an efficient and extremely well succeeded procedure.

Association of Obesity With Breast Cancer Outcome in Relation to Cancer Subtypes: A Meta-Analysis.

BACKGROUND: Obesity at breast cancer (BC) diagnosis has been associated with poor outcome, although the magnitude of effect in different BC subtypes is uncertain. We report on the association of obesity or overweight at diagnosis of nonmetastatic BC with disease-free (DFS) and overall survival (OS) in the following defined subtypes: hormone receptor positive/HER2 negative (HR+HER2-), HER2 positive (HER2+), and triple negative (TNBC). METHODS: We searched MEDLINE, EMBASE, and COCHRANE databases up to January 1, 2019. Study eligibility was performed independently by 2 authors. Studies reporting hazard ratios (HRs) of OS and/or DFS for obesity or overweight in BC subtypes were included. The pooled hazard ratio was computed and weighted using generic inverse variance and random effects models. RESULTS: Twenty-seven studies were included. Obese compared with nonobese women had worse DFS in all subtypes: the hazard ratios were 1.26 (95% confidence interval [CI] = 1.13 to 1.41, P < .001) for HR+HER2- BC, 1.16 (95% CI = 1.06 to 1.26, P < .001) for HER2+ BC, and 1.17 (95% CI = 1.06 to 1.29, P = .001) for TNBC. OS was also worse in obese vs nonobese women (HR+HER2- BC HR = 1.39, 95% CI = 1.20 to 1.62, P < .001; HER2+ BC HR = 1.18, 95% CI = 1.05 to 1.33, P = .006; and TNBC HR = 1.32, 95% CI = 1.13 to 1.53, P < .001). As opposed to obesity, overweight was not associated with either DFS or OS in HER2+ BC (HR = 1.02, 95% CI = 0.81 to 1.28, P = .85; and HR = 0.96, 95% CI = 0.76 to 1.21, P = .99, respectively) or TNBC (HR = 1.04, 95% CI = 0.93 to 1.18, P = .49; and HR = 1.08, 95% CI = 0.81 to 1.44, P = .17), respectively. In HR+HER2- BC, being overweight was associated with worse OS (HR = 1.14, 95% CI = 1.07 to 1.22, P < .001). CONCLUSIONS: Obesity was associated with modestly worse DFS and OS in all BC subtypes.

The Effect of Metformin vs Placebo on Sex Hormones in Canadian Cancer Trials Group MA.32.

BACKGROUND: Metformin has been associated with lower breast cancer (BC) risk and improved outcomes in observational studies. Multiple biologic mechanisms have been proposed, including a recent report of altered sex hormones. We evaluated the effect of metformin on sex hormones in MA.32, a phase III trial of nondiabetic BC subjects who were randomly assigned to metformin or placebo. METHODS: We studied the subgroup of postmenopausal hormone receptor-negative BC subjects not receiving endocrine treatment who provided fasting blood at baseline and at 6 months after being randomly assigned. Sex hormone-binding globulin, bioavailable testosterone, and estradiol levels were assayed using electrochemiluminescence immunoassay. Change from baseline to 6 months between study arms was compared using Wilcoxon sum rank tests and regression models. RESULTS: 312 women were eligible (141 metformin vs 171 placebo); the majority of subjects in each arm had T1/2, N0, HER2-negative BC and had received (neo)adjuvant chemotherapy. Mean age was 58.1 (SD=6.9) vs 57.5 (SD=7.9) years, mean body mass index (BMI) was 27.3 (SD=5.5) vs 28.9 (SD=6.4) kg/m2 for metformin vs placebo, respectively. Median estradiol decreased between baseline and 6 months on metformin vs placebo (-5.7 vs 0 pmol/L; P < .001) in univariable analysis and after controlling for baseline BMI and BMI change (P < .001). There was no change in sex hormone-binding globulin or bioavailable testosterone. CONCLUSION: Metformin lowered estradiol levels, independent of BMI. This observation suggests a new metformin effect that has potential relevance to estrogen sensitive cancers.

A phase II randomized clinical trial of the effect of metformin versus placebo on progression-free survival in women with metastatic breast cancer receiving standard chemotherapy.

OBJECTIVES: Pre-clinical data suggest metformin might enhance the effect of chemotherapy in breast cancer (BC). We conducted a Phase II randomized trial of chemotherapy plus metformin versus placebo in metastatic breast cancer (MBC). MATERIAL AND METHODS: In this double blind phase II trial we randomly assigned non-diabetic MBC patients on 1st to 4th line chemotherapy to receive metformin 850 mg po bid or placebo bid. Primary outcome was progression-free survival (PFS); secondary outcomes included overall survival (OS), response rate (RR), toxicity and quality of life (QOL). With 40 subjects and a type-one error of 0.2 (one-sided), a PFS hazard ratio (HR) of 0.58 could be detected with 80% power. RESULTS: 40 patients were randomized (22 metformin, 18 placebo) with a mean age of 55 vs 57 years and ER/PR positive BC in 86.4% vs 83.3% off metformin vs placebo, respectively. Mean BMI was 27kg/m2 in both arms. The majority of patients were on 1st line chemotherapy. Grade 3-4 toxicity occurred in 31.8% (metformin) vs 58.8% (placebo). Best response: Partial response 18.2% metformin vs 25% placebo, stable disease 36.4% metformin vs 18.8% placebo, progressive disease 45.4% metformin vs 56.2% placebo. Mean PFS was 5.4 vs 6.3 months (metformin vs placebo), HR 1.2 (95% CI 0.63-2.31). Mean OS was 20.2 (metformin) vs 24.2 months (placebo), HR 1.68 (95% CI 0.79-3.55). CONCLUSION: In this population metformin showed no significant effect on RR, PFS or OS. These results do not support the use of metformin with chemotherapy in non-diabetic MBC patients.

Effects of acupuncture on leucopenia, neutropenia, NK, and B cells in cancer patients: a randomized pilot study.

Chemotherapy is one of most significant therapeutic approaches to cancer. Immune system functional state is considered a major prognostic and predictive impact on the success of chemotherapy and it has an important role on patients' psychoemotional state and quality of life. In Chinese medicine, chemotherapy is understood as "toxic cold" that may induce a progressive hypofunctional state of immune system, thus compromising the fast recovery of immunity during chemotherapy. In this study, we performed a standardized acupuncture and moxibustion protocol to enhance immunity in cancer patients undergoing chemotherapy and to assess if the improvement of immunity status correlates with a better psychoemotional state and quality of life.