Update Breast Cancer 2022 Part 5 – Early Stage Breast Cancer

The treatment of patients with early stage breast cancer has changed in recent years due to the introduction of pembrolizumab, olaparib, and abemaciclib. These and other drugs with the same class of active ingredient are currently in trial for various indications. This review article summarizes the latest results that have either been presented at major conferences such as the ESMO 2022 or published recently in international journals. This includes reports on newly discovered breast cancer genes, atezolizumab in neoadjuvant therapy in HER2-positive patients, long-term data from the APHINITY study, and on how preoperative peritumoral application of local anesthetics can influence the prognosis. We also present solid data on dynamic Ki-67 from the ADAPT studies.Key words: breast cancer, surgery, chemotherapy, therapy standard     

Exome sequencing in individuals with cardiovascular laterality defects identifies potential candidate genes

The birth prevalence of laterality defects is about 1.1/10,000 comprising different phenotypes ranging from situs inversus totalis to heterotaxy, mostly associated with complex congenital heart defects (CHD) and situs abnormalities such as intestinal malrotation, biliary atresia, asplenia, or polysplenia. A proportion of laterality defects arise in the context of primary ciliary dyskinesia (PCD) accompanied by respiratory symptoms or infertility. In this study, exome sequencing (ES) was performed in 14 case-parent trios/quattros with clinical exclusion of PCD prior to analysis. Moreover, all cases and parents underwent detailed clinical phenotyping including physical examination, echocardiography by a skilled paediatric cardiologist and abdominal ultrasound examinations not to miss mildly affected individuals. Subsequent survey of the exome data comprised filtering for monoallelic de novo, rare biallelic, and X-linked recessive variants. In two families, rare variants of uncertain significance (VUS) in PKD1L1 and ZIC3 were identified. Both genes have been associated with laterality defects. In two of the remaining families, biallelic variants in LMBRD1 and DNAH17, respectively, were prioritized. In another family, an ultra-rare de novo variant in WDR47 was found. Extensive exome survey of 2,109 single exomes of individuals with situs inversus totalis, heterotaxy, or isolated CHD identified two individuals with novel monoallelic variants in WDR47, but no further individuals with biallelic variants in DNAH17 or LMBRD1. Overall, ES of 14 case-parent trios/quattros with cardiovascular laterality defects identified rare VUS in two families in known disease-associated genes PKD1L1 and ZIC3 and suggests DNAH17, LMBRD1, and WDR47 as potential genes involved in laterality defects.Subject terms: Disease genetics, Genetic counselling, Biological sciences     

Toxicity and response to high-dose ifosfamide+mesna as salvage therapy for advanced breast cancer

Summary Twenty-six cycles of high-dose ifosfamide+mesna (HD-IFO+M) were applied to seven female patients with advanced breast cancer refractory to prior treatment, using three different durations of continuous infusion (4, 24, and 48 h) every 3 weeks. To evaluate the most tolerable time schedule, the duration of the infusions was changed periodically in each patient. Toxicity was low in general, but continuous infusion of HD-IFO+M over 24 h appeared to be the best tolerated. On partial response lasting 27 weeks was achieved and four patients achieved stable disease lasting from 9 to 12 weeks.     

Freezing of human ovarian tissue--not the oocytes but the granulosa is the problem

The freezing of human ovarian tissue may be the key for restoring fertility after systemic therapy of cancer. In contrast to others we investigated the survival rate of whole follicles, and had a special look at the granulosa cells. Ovarian tissue was collected laparoscopically (n = 10) and divided into equal parts for freezing (n = 1570) or as control (n = 1660). The cryopreservation was done slowly, or as a ultrarapid freezing. After thawing the number of follicles, oocytes and granulosa cells surviving was counted and corrected for equal volumina of the samples. While 84.5% of the oocytes survived freezing, only 40.4% of the follicles were intact after thawing. The data show that the procedure damaged follicles, which mainly affected the granulosa cells. As the intactness of follicles may play a critical role for the maturation of the oocytes after thawing the protocols should be optimised to meet the needs of oocytes and granulosa cells.     

Expression of the novel adrenocorticotropin-responsive gene selective Alzheimer's disease indicator-1 in the normal adrenal cortex and in adrenocortical adenomas and carcinomas

Selective Alzheimer's disease indicator-1 (seladin-1) is a novel gene with antiapoptotic activity that is down-regulated in vulnerable brain regions in Alzheimer's disease. This gene encodes 3-beta-hydroxysterol Delta-24-reductase (DHCR24), which converts desmosterol into cholesterol. In the adrenal cortex, increased expression of seladin-1/DHCR24, which appears to be modulated by ACTH, has been recently reported in cortisol-secreting adenomas, compared with the adjacent atrophic tissue. In our study, we measured the expression level of seladin-1/DHCR24 in cortisol- (n = 18) and aldosterone-secreting (n = 16) adrenocortical adenomas, in carcinomas (n = 17), and in normal adrenal glands (n = 8) by quantitative real-time RT-PCR. The amount of seladin-1/DHCR24 mRNA was significantly reduced in carcinomas (total RNA, 2.5 +/- 0.8 pg/ micro g) compared with the other groups (P < 0.01). Western blot analysis confirmed the mRNA results. Similarly, in adrenal malignancies, significantly reduced levels of expression of the ACTH receptor gene were found. In the adrenal cancer cell line H295R and in primary cultures from adrenocortical cells, ACTH (1 nM) and forskolin (10 micro M) effectively increased seladin-1/DHCR24 expression, confirming that seladin-1/DHCR24 is modulated by the ACTH/cAMP-driven pathway. In summary, this is the first demonstration that seladin-1/DHCR24 expression is reduced in adrenal cancer, suggesting that it might be viewed as a new potential marker of adrenal malignancies.     

Role of gonadotropins in malignant progression of sex cord stromal tumors produced by sequential auto- and isogenic transplantation of ovarian tissue in ovariectomized rats

Purpose: In this study the effect of continuous stimulation of gonadotropins on sex cord stromal tumors in the rat was examined. Methods: Sex cord stromal tumors were induced by transplantation of ovaries under the splenic capsule of ovariectomized rats. Beginning 180 days after transplantation, these tumors were taken out and cut into several pieces, which were then retransplanted (by isotransplantation) under the splenic capsule of 80 either intact or ovariectomized rats. Results: Most of the tumor grafts grew up to a median size of 0.7 cm in ovariectomized rats. However, some of the tumors recovered from recipient rats that were retransplanted with donor tumors differed significantly from the others. Characterized by a high mitotic rate, nuclear atypia, size (up to 3.8 cm) as well as growth in intact animals, these tumors were defined as malignant. They could be kept in culture and always led to the development of metastases after retransplantation into other rats. Conclusion: Benign sex cord stromal tumors can show malignant growth after transplantation. This study for the first time demonstrates that gonadotropins are involved in the induction of ovarian malignancies. Received: 15 December 2000 / Accepted: 15 February 2001     

Comparison of transthoracic three dimensional echocardiography with magnetic resonance imaging in the assessment of right ventricular volume and mass.

OBJECTIVE: Assessment of right ventricular volume and mass with three dimensional echocardiography and comparison with magnetic resonance imaging. METHODS: Measurements of right ventricular volumes performed on three dimensional datasets acquired by transthoracic echocardiography were compared to those obtained from magnetic resonance imaging performed on the same day. Volumes were measured in end systole and end diastole and ejection fraction calculated. Right ventricular mass was assessed in end systole. With both methods, the areas of a 2 mm thick slice of the ventricle were manually outlined and multiplied by the slice thickness to obtain slice volume. Slice volumes were multiplied by the number of measured slices to obtain the ventricular volume. PATIENTS: 16 patients were studied: three with normal hearts, three after surgical repair of coarctation of the aorta, nine following repair of tetralogy of Fallot, and one with Mustard atrial repair of complete transposition of the great arteries. RESULTS: Correlation between end diastolic volumes measured by both methods was r = 0.95 with limits of agreement ranging from -3.5 to 12.5 ml; correlation for end systolic volumes was r = 0.87 with limits of agreement between -4.0 and 16.4 ml; correlation for end systolic right ventricular mass was r = 0.81 with limits of agreement between -7.0 and 20.6 g. Interobserver variability ranged from 4.3% (range 0.2% to 9.3%) for end diastolic volume to 7.6% (1.8% to 15.4%) for mass measurements. CONCLUSIONS: With transthoracic three dimensional echocardiography, end diastolic right ventricular volumes can be assessed with acceptable accuracy in normal hearts and those with enlarged right ventricles, whereas the current method of three dimensional echocardiography is less good for end systolic volumes and not satisfactory for right ventricular mass measurements.