Toralf Reimer

Tumor-Infiltrating Lymphocytes and Response to Neoadjuvant Chemotherapy With or Without Carboplatin in Human Epidermal Growth Factor Receptor 2–Positive and Triple-Negative Primary Breast Cancers

PURPOSE Modulation of immunologic interactions in cancer tissue is a promising therapeutic strategy. To investigate the immunogenicity of human epidermal growth factor receptor 2 (HER2) -positive and triple-negative (TN) breast cancers (BCs), we evaluated tumor-infiltrating lymphocytes (TILs) and immunologically relevant genes in the neoadjuvant GeparSixto trial. PATIENTS AND METHODS GeparSixto investigated the effect of adding carboplatin (Cb) to an anthracycline-plus-taxane combination (PM) on pathologic complete response (pCR). A total of 580 tumors were evaluated before random assignment for stromal TILs and lymphocyte-predominant BC (LPBC). mRNA expression of immune-activating (CXCL9, CCL5, CD8A, CD80, CXCL13, IGKC, CD21) as well as immunosuppressive factors (IDO1, PD-1, PD-L1, CTLA4, FOXP3) was measured in 481 tumors. RESULTS Increased levels of stromal TILs predicted pCR in univariable (P < .001) and multivariable analyses (P < .001). pCR rate was 59.9% in LPBC and 33.8% for non-LPBC (P < .001). pCR rates ≥ 75% were observed in patients with LPBC tumors treated with PMCb, with a significant test for interaction with therapy in the complete (P = .002) and HER2-positive (P = .006), but not the TNBC, cohorts. Hierarchic clustering of mRNA markers revealed three immune subtypes with different pCR rates (P < .001). All 12 immune mRNA markers were predictive for increased pCR. The highest odds ratios (ORs) were observed for PD-L1 (OR, 1.57; 95% CI, 1.34 to 1.86; P < .001) and CCL5 (OR, 1.41; 95% CI, 1.23 to 1.62; P < .001). CONCLUSION Immunologic factors were highly significant predictors of therapy response in the GeparSixto trial, particularly in patients treated with Cb. After further standardization, they could be included in histopathologic assessment of BC.

Skin-Sparing Mastectomy with Conservation of the Nipple–Areola Complex and Autologous Reconstruction is an Oncologically Safe Procedure

Objective Is skin-sparing mastectomy (SSM) with conservation of the Nipple–Areola Complex (NAC) and immediate autologous reconstruction as safe in oncologic terms as SSM with resection of the NAC as modified radical mastectomy (MRM)? Summary Background Data The originally described technique of SSM included the removal of gland, NAC, and biopsy scar. However, the risk of tumor involvement of NAC in patients with breast cancer has been overestimated. Patients and Methods Between 1994 and 2000, 286 selected patients with an indication for MRM and tumor margins of greater than 2 cm from the nipple were presented with the alternative of a SSM. Regular follow-up data were evaluable of 112 patients with SSM and 134 patients with MRM. Immediate reconstruction was achieved by latissimus dorsi flap or TRAM flap. The mean follow-up time was 59 (18 to 92) months. Results Patients with SSM were significantly younger than those with MRM but were comparable regarding clinical data, tumor parameters, adjuvant treatment, and overall complications. After intraoperative frozen sections of the NAC-ground, the NAC could be conserved in 61 (54.5%) but was resected in 51 (45.5%) of the 112 patients with SSM. The aesthetic results after SSM were evaluated as excellent or good in 91.1% (102/112) patients and were significantly better after preservation of the NAC (P = 0.001). Six (5.4%) recurrences occurred in 112 patients with SSM compared with 11 (8.2%) cases after MRM. Only 1 recurrence in a conserved nipple was treated by wide excision of nipple with conservation of the areola. This patient is still free of disease after 52 months. Conclusion In patients who are candidates for a mastectomy and tumors distant from the nipple, SSM with intraoperative frozen section of the NAC ground offers the opportunity of NAC conservation without increasing the risk of local recurrences.

The Oncological Safety of Skin Sparing Mastectomy with Conservation of the Nipple-Areola Complex and Autologous Reconstruction : An Extended Follow-Up Study

Objective:To find out if skin sparing mastectomy (SSM) and nipple sparing mastectomy (NSM) with immediate autologous reconstruction as safe in oncological terms as modified radical mastectomy (MRM). Summary Background:The oncological safety of less radical surgical procedures like SSM and NSM cannot be evaluated by randomized trials. A careful and long lasting follow-up of patients, treated with SSM or NSM, is urgently needed. Patients and Methods:Between 1994–2000, 246 selected patients with an indication for MRM were treated with SSM, NSM, or MRM. Short term results were published in 2003.1 After a mean follow-up of 101 months (range 32–126), 238 evaluable patients with SSM (N = 48), NSM (N = 60), or MRM (N = 130) were analyzed for local and distant recurrences, breast cancer specific death, and esthetic results. Results:Local recurrences occurred in 10.4% (SSM), 11.7% (NSM) and 11.5% (MRM) of all patients (P = 0.974). With regard to isolated DM (25.0%, 23.3%, respectively 26.2%; P = 0.916) and breast cancer specific death (20.8%, 21.7%, respectively 21.5%; P = 0.993), there were no significant differences between subgroups. The re-evaluation of esthetic results by surgeons revealed a significant shift from 78.4% excellent results after 59 months to 47.9% after 101 months follow-up (SSM; P = 0.004) and from 73.8% to 51.7% (NSM; P = 0.025). An important risk factor for decreased cosmetic score was application of adjuvant radiotherapy. Conclusion:In patients who are candidates for a mastectomy, skin sparing mastectomy or nipple sparing mastectomy with immediate autologous reconstruction are oncologically safe techniques. Adjuvant radiotherapy decreases the esthetic results even after a longer period of time.

Effect of Luteinizing Hormone–Releasing Hormone Agonist on Ovarian Function After Modern Adjuvant Breast Cancer Chemotherapy: The GBG 37 ZORO Study

PURPOSE Observational studies suggested that luteinizing hormone-releasing hormone agonists (LHRHa) might prevent premature ovarian failure resulting from adjuvant chemotherapy in premenopausal patients. We aimed to test the efficacy of ovarian function preservation with the LHRHa goserelin in patients with breast cancer. PATIENTS AND METHODS In a prospective, randomized, open-label, controlled multicenter study, 60 patients younger than age 46 years with hormone-insensitive breast cancer were allocated to receive anthracycline/cyclophosphamide (with or without taxane) -based neoadjuvant chemotherapy with or without goserelin. The first goserelin injection was administered at least 2 weeks before the first chemotherapy cycle, continuing at 3.6 mg subcutaneously every 4 weeks until the end of the last cycle. The primary objective was the reappearance of normal ovarian function, defined as two consecutive menstrual periods within 21 to 35 days at 6 months after end of chemotherapy. RESULTS Fifty-three patients (88.3%) experienced temporary amenorrhea (93.3% with v 83.3% without goserelin). No significant difference was observed regarding the reappearance of menstruation at 6 months after chemotherapy (70.0% with v 56.7% without goserelin; difference of 13.3%; 95% CI, -10.85 to 37.45; P = .284). All but one evaluable patient reported regular menses at 2 years after chemotherapy. Time to restoration of menstruation was 6.8 months (95% CI, 5.2 to 8.4) with goserelin and 6.1 months (95% CI, 5.3 to 6.8) without goserelin (P = .304). Chemotherapy resulted in a decreased ovarian reserve measured by inhibin B and anti-Müllerian hormone during follow-up, supporting the other findings. CONCLUSION Premenopausal patients with breast cancer receiving goserelin simultaneously with modern neoadjuvant chemotherapy did not experience statistically significantly less amenorrhea 6 months after end of chemotherapy compared with those receiving chemotherapy alone.

Simultaneous Immunohistochemical Detection of Tumor Cells in Lymph Nodes and Bone Marrow Aspirates in Breast Cancer and Its Correlation With Other Prognostic Factors

PURPOSE We studied the prognostic and predictive value of immunohistochemically detected occult tumor cells (OTCs) in lymph nodes and bone marrow aspirates obtained from node-negative breast cancer patients. All were classified as distant metastases-free using conventional staging methods. PATIENTS AND METHODS A total of 484 patients with pT1-2N0M0 breast cancer and 70 with pT1-2N1M0 breast cancer and a single affected lymph node participated in our trial. Ipsilateral axillary lymph nodes and intraoperatively aspirated bone marrow were examined. All samples were examined for OTCs using monoclonal antibodies to cytokeratins 8, 18, 19. Immunohistological findings were correlated with other prognostic factors. The mean follow-up was 54 +/- 24 months. RESULTS OTCs were detected in 180 (37.2%) of 484 pT1-2N0M0 patients: in the bone marrow of 126 patients (26.0%), in the lymph nodes of 31 patients (6.4%), and in bone marrow and lymph nodes of 23 (4.8%) patients. Of the 70 patients with pT1-2N1MO breast cancer and a single involved lymph node, OTCs were identified in the bone marrow of 26 (37.1%). The ability to detect tumor cells increased with the following tumor features: larger size, poor differentiation, and higher proliferation. Tumors of patients with OTCs more frequently demonstrated lymph node invasion, blood vessel invasion, higher urokinase-type plasminogen activator levels, and increased PAI-1 concentrations. Patients with detected OTCs showed reduced disease-free survival (DFS) and overall survival (OAS) rates that were comparable to those observed in patients who had one positive lymph node. Multivariate analysis of prognostic factors revealed that OTCs, histological grading, and tumor size are significant predictors of DFS; OTCs and grading of OAS. CONCLUSION OTCs detected by simultaneous immunohistochemical analysis of axillary lymph nodes and bone marrow demonstrate independent metastatic pathways. Although OTCs were significantly more frequent in patients with other unfavorable prognostic factors, they were confirmed as an independent prognostic factor for pT1-2N0M0, R0 breast cancer patients.

Effects of Adjuvant Tamoxifen on the Endometrium in Postmenopausal Women With Breast Cancer: A Prospective Long-Term Study Using Transvaginal Ultrasound

PURPOSE To study the value of transvaginal ultrasound (TVS) in endometrial screening of postmenopausal breast cancer patients treated with tamoxifen. PATIENTS AND METHODS In 247 tamoxifen-treated (20 to 30 mg/d for >/= 2 years) women and 98 controls, the endometrium was prospectively followed-up by means of TVS every 6 months for up to 5 years. Patients with homogeneous endometrium of more than 10-mm thickness were then scanned repeatedly every 3 months. RESULTS The mean endometrial thickness was 3.5 +/- 1.1 mm before treatment and increased to a maximum of 9. 2 +/- 5.1 mm after 3 years of tamoxifen application (P: <.0001), which was significantly (P: <.0001) thicker compared with controls. Fifty-two asymptomatic patients with thickened or morphologically suspect endometrium underwent hysteroscopy and dilatation and curettage (D&C), resulting in four uterine perforations. Histopathologically, atrophy was found in 38 patients (73.1%), polyps in nine, hyperplasia in four, and endometrial cancer in one case. In 20 screened patients who reported vaginal bleeding, five atrophies (25%), five polyps, four hyperplasias, and two endometrial cancers were found. Before hysteroscopy and D&C were performed, 36 (69.2%) of 52 asymptomatic and four (20%) of 20 symptomatic patients were scanned by repeated TVS over 2 to 30 months. Invasive diagnostic procedures were significantly (P: <.05) more frequent in younger and obese patients. In the controls, one asymptomatic polyp and one symptomatic hyperplasia were found. CONCLUSION In tamoxifen-treated patients, TVS offered a high false-positive rate, even with a cutoff value of 10 mm for endometrial thickness and repeated TVS scans. Increased iatrogenic morbidity and only one asymptomatic endometrial carcinoma do not warrant endometrial screening by TVS in tamoxifen-treated patients.

Ultrasonographic detection of asymptomatic endometrial cancer in postmenopausal patients offers no prognostic advantage over symptomatic disease discovered by uterine bleeding

The aim of this study was to investigate whether endometrial carcinoma (EC) screening by transvaginal sonography (TVS) has a prognostic advantage over symptomatic EC. In a retrospective study, 190 postmenopausal patients with symptomatic EC and 123 asymptomatic patients with suspicious endometrium detected by TVS were analysed regarding clinical, socio-economic and histopathological findings. Total bleeding time and the International Federation of Gynecology and Obstetrics (FIGO) tumour stage were evaluated with respect to their effect on survival. In 123 asymptomatic patients with suspicious endometrium, 16 (13%) EC, 61 (50%) polyps, 21 (17%) hyperplasias, 23 (19%) atrophias, 1 (0.8%) myoma and 1 (0.8%) metastasis were found. TVS findings in asymptomatic patients resulted in unnecessary operations, which were associated with considerable costs totalling at least 116256. Compared with screened asymptomatic patients, symptomatic patients were significantly (P<0.05) older, more frequently obese, and hypertensive, had a larger proportion of cases living in rural areas and visited their gynaecologists rarely. The bleeding time of symptomatic patients strongly correlated with the tumour stage (P<0.0001). Depending on the bleeding time, the 5-year disease-free survival and overall survival rates were 77% and 86% (no bleeding), 83% and 98% (<8 weeks), 74% and 90% (8-16 weeks), and 62% and 69% (>16 weeks), respectively. The corresponding tumour stage-related data for disease-free and overall survival were 100% (Ia; both rates), 87% and 95% (Ib), 66% and 93% (Ic), 63% and 78% (II) and 36% (III/IV; both rates), respectively. Postmenopausal vaginal bleeding represents an early symptom of EC, but it is not always perceived as problematic by the patients. There is no prognostic advantage for screened compared with symptomatic patients, who had bleeding of shorter than 8 weeks. Moreover, patients who are at a high risk for EC tend to avoid TVS screening. Finally, endometrial screening often results in unnecessary operations, which are associated with increased morbidity and costs.

Complementary and alternative therapeutic approaches in patients with early breast cancer: a systematic review

SummaryComplementary and alternative medicine (CAM) is becoming increasingly popular, particularly among patients with breast cancer. We have done a systematic review of studies published between 1995 and February 2005, identified through a comprehensive search. CAM encompasses a wide range of treatment modalities, including dietary and vitamin supplements, mind-body approaches, acupuncture, and herbal medicines. The objectives of CAM treatments are diverse: reduction of therapy-associated toxicity, improvement of cancer-related symptoms, fostering of the immune system and even direct anticancer effects. Clinical trials have generated few or no data on the efficacy of CAM, whether regarding disease recurrence, survival, overall quality of life or safety. Some CAM methods may even have adverse effects or reduce the efficacy of conventional treatment. The primary justification for CAM is based on empirical evidence, case studies, and hypothetical physiological effects. We conclude that␣available data on CAM modalities in the treatment of early-stage breast cancer does not support their application.

Perioperative screening for metastatic disease is not indicated in patients with primary breast cancer and no clinical signs of tumor spread

AbstractBackground. Is a perioperative metastatic screening program indicated in patients presenting with primary operable breast cancer and no signs of distant metastases? Patients and methods. The impact of staging results (chest X-ray, bone scanning, liver ultrasound) for prognosis, treatment, quality of life and costs was retrospectively analyzed in 1076 patients with an operable breast cancer and no clinical signs of metastases. Results. Staging examinations revealed 30 (2.8%) distant metastases, 130 (12.1%) suspect findings and excluded metastases in 916 (85.1%) patients. Further diagnostic procedures confirmed distant metastases in 7 (5.4%) and excluded them in 123 (94.6%) out of 130 patients with suspect findings. Distant metastases were detected more frequently with increasing pathological tumor size (pT ≤q 2.0 cm: 1.6%, pT 2.1–5.0 cm: 3.0%, respectively pT > 5.0 cm: 15.1%; p < 0.001) and increasing number of involved axillary lymph nodes (pN0: 1.9%, pN1–3+: 1.8%, pN4–9+: 4.0%, pN ≥ 10+: 18.7%; p < 0.001). Due to false positive findings 123 (11.4%) patients had to live for a significant period of time with the psychological distress of suspected metastatic disease. The abandonment of a perioperative screening in 1076 patients saves costs of at least Euro 259,367.68. Conclusions. In breast cancer patients without clinical signs of tumor spread perioperative screening for metastases is not warranted because of low frequency of metastases, false positive findings, missing therapeutic consequences and high costs.

Standardized evaluation of tumor-infiltrating lymphocytes in breast cancer : results of the ring studies of the international immuno-oncology biomarker working group

Multiple independent studies have shown that tumor-infiltrating lymphocytes (TIL) are prognostic in breast cancer with potential relevance for response to immune-checkpoint inhibitor therapy. Although many groups are currently evaluating TIL, there is no standardized system for diagnostic applications. This study reports the results of two ring studies investigating TIL conducted by the International Working Group on Immuno-oncology Biomarkers. The study aim was to determine the intraclass correlation coefficient (ICC) for evaluation of TIL by different pathologists. A total of 120 slides were evaluated by a large group of pathologists with a web-based system in ring study 1 and a more advanced software-system in ring study 2 that included an integrated feedback with standardized reference images. The predefined aim for successful ring studies 1 and 2 was an ICC above 0.7 (lower limit of 95% confidence interval (CI)). In ring study 1 the prespecified endpoint was not reached (ICC: 0.70; 95% CI: 0.62–0.78). On the basis of an analysis of sources of variation, we developed a more advanced digital image evaluation system for ring study 2, which improved the ICC to 0.89 (95% CI: 0.85–0.92). The Fleiss’ kappa value for <60 vs ≥60% TIL improved from 0.45 (ring study 1) to 0.63 in RS2 and the mean concordance improved from 88 to 92%. This large international standardization project shows that reproducible evaluation of TIL is feasible in breast cancer. This opens the way for standardized reporting of tumor immunological parameters in clinical studies and diagnostic practice. The software-guided image evaluation approach used in ring study 2 may be of value as a tool for evaluation of TIL in clinical trials and diagnostic practice. The experience gained from this approach might be applicable to the standardization of other diagnostic parameters in histopathology.