Management of small T1a/b breast cancer by tumor subtype.

BACKGROUND: The treatment of patients with small (T1a/b) breast cancer is based on retrospective analysis. The influence of intrinsic tumor subtypes on patients' outcome and treatment decision remains unclear. PATIENTS AND METHODS: This is a prospective cohort register study including 1008 patients with small T1a/b breast cancer treated between 2003 and 2011. Tumors were grouped by biological characteristics into four different subtypes: luminal A, luminal B, human epidermal growth factor receptor 2 (HER2)-enriched, and triple-negative breast cancer (TNBC). RESULTS: The median follow-up time was 6.5 years. From 919 eligible patients, 408 (44.4%) were classified as luminal A, 246 (26.8%) as luminal B, 183 (19.9%) as HER2 enriched, and 82 (8.9%) as TNBC. A total of 305 (34.2%) patients were treated with systemic therapy. Patients receiving systemic therapy were significantly younger and had lymph node metastasis, higher tumor grade, negative HR, and positive HER2 status. Patients with luminal A tumors demonstrated the best survival rate which improved with systemic therapy. The survival rate of patients with luminal B cancer, HER2-enriched tumors, and TNBC improved by addition of systemic treatment. The effect of systemic treatment was significant in luminal B (p = 0.040) and HER2 overexpressing tumors (p = 0.016). The treatment effect of systemic therapy in HER2-enriched tumors remained significant even after adjustment of other prognostic factors (HR 0.43, CI 0.19-0.98; p = 0.047). Notably, tumor size was not associated with patients' survival and treatment decision. CONCLUSION: The treatment decision of small breast cancer should be made by biological subtype and not by tumor size or lymph node status.

Management of elderly women with endometrial cancer.

BACKGROUND: Elderly women with endometrial cancer receive less therapy in comparison with their younger counterparts. The exact reason(s) for this treatment strategy remains unclear. PATIENTS AND METHODS: We performed a multicenter, retrospective registry-based study of 1550 patients with endometrial cancer. The outcome measure was the reason for not performing the indicated treatment. RESULTS: Median follow-up was 76.8months. A total of 1550 women were eligible for analysis: 353 (22.7%) were younger than 60years, 521 (33.6%) 61-70years, 515 (33.2%) 71-80years, and 161 (10.4%) were aged 81years old and older. Elderly women were more likely to have non-endometrioid, undifferentiated endometrial cancer at an advanced stage. Patients younger than 60years were more likely to receive lymphadenectomy, brachytherapy, external-beam radiotherapy (EBRT) and systemic therapy compared with the group of patients aged older than 70years. We investigated the reason why elderly women were undertreated. The rate of indicated therapies that were not recommended by the physicians proportionally increased with an increase in patient age. Interestingly, the rate of contraindications because of performance status and/or medical disease also increased proportionally with increasing patient age. Notably, in the groups of patients older than 70years, patient refusal was a very uncommon reason for failure to perform the indicated therapy. CONCLUSIONS: Elderly women with EC are more likely undertreated because the therapy was not recommended by the physicians based on performance status and medical diseases rather than patient refusal.

The proteasome immunosubunits, PA28 and ER-aminopeptidase 1 protect melanoma cells from efficient MART-126-35 -specific T-cell recognition.

The immunodominant MART-1(26(27)-35) epitope, liberated from the differentiation antigen melanoma antigen recognized by T cells/melanoma antigen A (MART-1/Melan-A), has been frequently targeted in melanoma immunotherapy, but with limited clinical success. Previous studies suggested that this is in part due to an insufficient peptide supply and epitope presentation, since proteasomes containing the immunosubunits ß5i/LMP7 (LMP, low molecular weight protein) or ß1i/LMP2 and ß5i/LMP7 interfere with MART-1(26-35) epitope generation in tumor cells. Here, we demonstrate that in addition the IFN-γ-inducible proteasome subunit ß2i/MECL-1 (multicatalytic endopeptidase complex-like 1), proteasome activator 28 (PA28), and ER-resident aminopeptidase 1 (ERAP1) impair MART-1(26-35) epitope generation. ß2i/MECL-1 and PA28 negatively affect C- and N-terminal cleavage and therefore epitope liberation from the proteasome, whereas ERAP1 destroys the MART-1(26-35) epitope by overtrimming activity. Constitutive expression of PA28 and ERAP1 in melanoma cells indicate that both interfere with MART-1(26-35) epitope generation even in the absence of IFN-γ. In summary, our results provide first evidence that activities of different antigen-processing components contribute to an inefficient MART-1(26-35) epitope presentation, suggesting the tumor cell's proteolytic machinery might have an important impact on the outcome of epitope-specific immunotherapies.

Tumour stage distribution and survival of malignant melanoma in Germany 2002-2011.

BACKGROUND: Over the past two decades, there has been a rising trend in malignant melanoma incidence worldwide. In 2008, Germany introduced a nationwide skin cancer screening program starting at age 35. The aims of this study were to analyse the distribution of malignant melanoma tumour stages over time, as well as demographic and regional differences in stage distribution and survival of melanoma patients. METHODS: Pooled data from 61 895 malignant melanoma patients diagnosed between 2002 and 2011 and documented in 28 German population-based and hospital-based clinical cancer registries were analysed using descriptive methods, joinpoint regression, logistic regression and relative survival. RESULTS: The number of annually documented cases increased by 53.2% between 2002 (N = 4 779) and 2011 (N = 7 320). There was a statistically significant continuous positive trend in the proportion of stage UICC I cases diagnosed between 2002 and 2011, compared to a negative trend for stage UICC II. No trends were found for stages UICC III and IV respectively. Age (OR 0.97, 95% CI 0.97-0.97), sex (OR 1.18, 95% CI 1.11-1.25), date of diagnosis (OR 1.05, 95% CI 1.04-1.06), 'diagnosis during screening' (OR 3.24, 95% CI 2.50-4.19) and place of residence (OR 1.23, 95% CI 1.16-1.30) had a statistically significant influence on the tumour stage at diagnosis. The overall 5-year relative survival for invasive cases was 83.4% (95% CI 82.8-83.9%). CONCLUSIONS: No distinct changes in the distribution of malignant melanoma tumour stages among those aged 35 and older were seen that could be directly attributed to the introduction of skin cancer screening in 2008.

Moderate level of HER2 expression and its prognostic significance in breast cancer with intermediate grade.

Overexpression of human epidermal growth factor receptor 2 (HER2) is an important prognostic and predictive marker of response to anti-HER2 therapy in breast cancer. Our goal was to analyze the prognostic significance of moderate expression of HER2 in breast cancer with intermediate differentiation grade. We performed a multicenter retrospective register study of 8494 patients with primary non-metastatic breast cancer admitted between 2000 and 2011 to eight Clinics in Saxony-Anhalt, federal state of Germany. Patients were divided into three groups according to their HER2 score: 4073 were classified as HER2 negative (HER2 0 and 1+), 822 HER2 moderate (HER2 2+/HER2), and 1238 HER2 positive (HER2 3+ or HER2 2+/HER2+). HER2-positive cases were excluded from analysis. Tumors with moderate HER2 (HER2 2+) expression demonstrated an aggressive behavior and worse patient survival compared with HER2 0 and 1+ status. HER2 2+ status was associated with shorter median overall survival (OS) (P < 0.0001) in breast cancer patients with an intermediate grade of differentiation. Comparing low-grade and high-grade tumors, HER2 moderate expression did not significantly influence patient survival. In multivariate analysis after adjustment for other prognostic factors HER2 2+ status remained an unfavorable prognostic factor for OS (HR 1.224, 95 % CI 1.059-1.415, P = 0.006) in breast cancer patients with an intermediate grade of differentiation. HER2 2+ status is an unfavorable prognostic factor regarding the OS of breast cancer patients with intermediate grade of differentiation and could be used to identify patients, who may benefit from adjuvant therapy.

Tumor characteristics, therapy, and prognosis in young breast cancer patients ≤ 35 years.

PURPOSES: Young breast cancer patients aged 35 years and younger are a small group of women who tend to present at high-risk form of the disease. More analysis of the data on tumor characteristics, treatment, and survival is necessary to help improving treatment and outcome. METHODS: In this retrospective study, we compared the clinical and tumor characteristics, the treatments, and the survival of 257 women aged ≤ 35 years, with 6566 women aged 50-69 years. We used a registry-based data of patients with invasive, non-metastatic breast cancer diagnosed between 2000 and 2015. RESULTS: Young women showed lower rate of hormone receptor (HR) positivity. Their tumors were more often HER2-positive, which showed lower rate of differentiation and higher rate of Ki-67 expression compared to their older counterparts. Women aged 35 years and younger were more likely to undergo neoadjuvant therapy and mastectomy. Endocrine therapy was underrepresented in young patients. 5-Year disease-free survival (DFS) was significantly lower in the younger patient group (81.7% vs. 91.3%, p < 0.001), while 5-year overall survival (OS) was not impaired (91.4% vs. 91.1%, p = 0.847). CONCLUSION: The unfavorable disease-free survival in the group of younger patients might be explained by their unfavorable tumor characteristics. The surgical treatment appears to be more aggressive in young breast cancer patients and is more frequently combined with chemotherapy and immunotherapy, either in a neoadjuvant or in an adjuvant setting.

Patterns of breast cancer relapse in accordance to biological subtype.

PURPOSE: To evaluate the pattern of recurrence of breast cancer according to its biological subtype in a large cohort of patients treated with therapy representative of current practice. PATIENTS AND METHODS: Patients treated between 2000 and 2016 with known biological subtype were eligible. Data were prospectively collected. Primary endpoint was the subtype-dependent pattern and time of recurrence. Loco-regional and distant site and time of recurrence were assessed. RESULTS: Median follow-up time was 80.8 months. For 12,053 (82.5%) of 14,595 patients with primary non-metastatic invasive breast cancer a subtype classification was possible. The luminal A subtype had the highest 10-year survival followed by luminal B and luminal/HER2. The worst survival demonstrated HER2 enriched and TNBC. HER2 and TNBC had the highest rate of recurrence in the first 5 years, whereas the rate of recurrence for luminal A and luminal B tumors was initially low, but remained continuously even after 10 years of follow-up. Luminal A tumors demonstrated the lowest rate of distant metastases predominantly in bone. So did luminal B tumors. HER2 enriched subtype was characterized with increased rate of loco-regional recurrence and distant metastases in bone, liver and brain. Luminal/HER2 had pattern of relapse similar to HER2 enriched tumors, with exception of loco-regional relapse and brain metastases. TNBC had higher rate of lung, bone and brain metastases as well as loco-regional relapse. CONCLUSION: Breast cancer subtypes are associated with different time and pattern of recurrence and it should be considered during treatment decision.

Ovarian metastasis in patients with endometrial cancer: risk factors and impact on survival.

BACKGROUND: Oophorectomy is generally performed in patients with endometrial cancer despite the rate of ovarian metastasis being relatively low. PATIENTS AND METHODS: A multicenter retrospective registry-based study was performed in 2329 patients with endometrial cancer. The outcome measures were the incidence of ovarian metastasis and the impact on overall survival. RESULTS: Median follow-up was performed at 84 months. A total of 2158 women were eligible for analysis, of which 131 (6.1%) had ovarian metastasis. Women with ovarian metastasis were more likely to have > 50% myometrial invasion, undifferentiated nonendometrioid tumors, and lymph and vascular space invasion. The presence of < 50% myometrial invasion, endometrioid histology, well-differentiated cancer, and negative lymph and vascular space invasion were associated with a very low rate (0.5%) of ovarian metastasis. Notably, after matching for tumor histology and grade, myometrial invasion, and lymph and vascular space invasion, ovarian metastasis was not associated with a reduced median overall survival. CONCLUSIONS: Ovarian preservation should be offered to premenopausal women with endometrial cancer in whom myometrial invasion is less than 50%, the histological type is endometrioid and well-differentiated, and lymph and vascular space invasion is not involved.

Hormone receptor status does not alter the effect of trastuzumab in breast cancer.

Overexpression of human epidermal growth factor receptor 2 (HER2) predicts response to anti-HER2 therapy in breast cancer. We investigated whether hormone receptor (HR) status influences the treatment benefit of trastuzumab in patients with breast cancer. Data from 8338 patients with primary nonmetastatic breast cancer from the cancer registry of Saxony-Anhalt Germany were analyzed. A total of 5554 patients were eligible for analysis. The median follow-up of the study was 6 years. Of the 5554 patients investigated, 1128 (20.3%) showed HER2 overexpression and 656 (58.2%) of them received adjuvant trastuzumab. The 10-year overall survival (OS) in the study cohort according to HR, HER2 status, and trastuzumab treatment was as follows: 78.4% for HR-/HER2-, 85.0% for HR+/HER2-, 70.4% HR-/HER2+/TRA-, 71.4% for HR+/HER2+/TRA-, 80.9% for HR-/HER2+/TRA+, and 89.2% for HR+/HER2+/TRA+. Trastuzumab treatment improved OS in the HR- patients only in the first 3 years, whereas in the HR+ group the effect of trastuzumab was still apparent 5 years after diagnosis. Notably, the relative improvement in a patient outcome was higher for HR+ patients. Nevertheless, matching for age, histological type, tumor stage, tumor grade, and performance status between patients with HR- and HR+ tumors demonstrated that the survival effect of trastuzumab was not affected by HR status; P=0.890. Trastuzumab treatment improves patients' survival regardless of HR status and should be offered to all HER2+ patients.

Adjuvant radiotherapy for vulvar cancer with close or positive surgical margins.

BACKGROUND: The survival effect of adjuvant radiotherapy (RT) for vulvar cancer has been poorly investigated. PATIENTS AND METHODS: We performed a multicentre retrospective register study of 257 patients with primary squamous vulvar cancer. The survival effect of adjuvant RT was investigated in two groups of patients, dependent on surgical margins. The outcome measure was overall survival. All statistical tests were two-sided. RESULTS: Of the 257 patients investigated, 192 had negative resection margins, while positive and/or close surgical margins were observed in 65 cases. Margin status was associated with unfavourable overall survival. The five-year overall survival was 66.1 and 49.2% in patients with negative and positive/close resection margins, respectively. Adjuvant RT directed to the vulva was associated with improved survival in patients with positive/close resection margins but not in patients with negative surgical margins. The 5-year overall survival of patients with positive/close surgical margins without RT was 29%, whereas with RT it increased to 67.6%. Notably, patients with positive/close surgical margins who received RT of the vulva had a 5-year survival rate similar to the patients with negative margins (67.6%). Multivariate analysis adjusted for age, stage of disease, tumour grade and lymph node metastases showed that adjuvant RT significantly reduced the mortality risk in patients with positive/close resection margins (HR 0.36, CI 0.14­0.94, p = 0.038). In the group of patients with negative resection margins, the involvement of lymph nodes was the strongest unfavourable prognostic factor. CONCLUSIONS: Adjuvant RT should be used for patients with positive/close surgical margins to improve their outcome.

Survival advantage of lymphadenectomy in endometrial cancer.

BACKGROUND: The lymphadenectomy in the treatment of endometrial cancer is a topic of ongoing debate. The direct comparison between no lymphadenectomy, pelvic lymphadenectomy, and pelvic/para-aortic lymphadenectomy regarding overall survival of patients with endometrial cancer is missing. METHODS: We performed a multicenter, retrospective, registry-based study of 1502 patients with endometrial cancer treated with no lymphadenectomy (n = 697), systemic pelvic lymphadenectomy (n = 543) and systemic pelvic/para-aortic lymphadenectomy (n = 262). The patients were divided into three groups of recurrence risk: low, intermediate, and high. The outcome measure was overall survival. RESULTS: Median follow-up was 78 months. Lymphadenectomy did not improve overall survival of patients with low risk of recurrence. The survival effect of systemic lymphadenectomy was significant in patients with intermediate and high risk of recurrence. Multivariate analysis showed that both pelvic (HR 0.63, CI 0.38-0.82, p = 0.001) and combination of pelvic/para-aortic lymphadenectomy (HR 0.50, CI 0.43-0.81, p < 0.0001) significantly reduced the mortality risk in patients with intermediate risk compared to the patients who underwent no lymphadenectomy. In patients with high risk, only combined pelvic/para-aortic lymphadenectomy (HR 0.62, CI 0.48-0.82, p = 0.005) was associated with decreased mortality rate compared with no lymphadenectomy. Among patients with intermediate and high risk of recurrence who did not receive any adjuvant therapy, pelvic/para-aortic lymphadenectomy significantly reduced the mortality risk (HR 0.52, CI 0.37-0.73, p < 0.0001) in comparison with no lymphadenectomy. This management was superior to pelvic lymphadenectomy alone. In patients with low risk of recurrence, lymphadenectomy had no effect on overall survival. CONCLUSIONS: Pelvic/para-aortic lymphadenectomy should be performed in all patients with endometrial cancer at intermediate and high risk of recurrence.

Exposure to Melan-A/MART-126-35 tumor epitope specific CD8(+)T cells reveals immune escape by affecting the ubiquitin-proteasome system (UPS).

Efficient processing of target antigens by the ubiquitin-proteasome-system (UPS) is essential for treatment of cancers by T cell therapies. However, immune escape due to altered expression of IFN-γ-inducible components of the antigen presentation machinery and consequent inefficient processing of HLA-dependent tumor epitopes can be one important reason for failure of such therapies. Here, we show that short-term co-culture of Melan-A/MART-1 tumor antigen-expressing melanoma cells with Melan-A/MART-126-35-specific cytotoxic T lymphocytes (CTL) led to resistance against CTL-induced lysis because of impaired Melan-A/MART-126-35 epitope processing. Interestingly, deregulation of p97/VCP expression, which is an IFN-γ-independent component of the UPS and part of the ER-dependent protein degradation pathway (ERAD), was found to be essentially involved in the observed immune escape. In support, our data demonstrate that re-expression of p97/VCP in Melan-A/MART-126-35 CTL-resistant melanoma cells completely restored immune recognition by Melan-A/MART-126-35 CTL. In conclusion, our experiments show that impaired expression of IFN-γ-independent components of the UPS can exert rapid immune evasion of tumor cells and suggest that tumor antigens processed by distinct UPS degradation pathways should be simultaneously targeted in T cell therapies to restrict the likelihood of immune evasion due to impaired antigen processing.

Moderate HER2 expression as a prognostic factor in hormone receptor positive breast cancer.

Overexpression and/or amplification of human epidermal growth factor receptor 2 (HER2) is associated with poor prognosis in breast cancer and predicts response to anti-HER2 therapy in breast cancer. The prognostic relevance of moderate expression of HER2 is unclear. Data of 9872 patients with primary nonmetastatic breast cancer from the cancer registries of Magdeburg and Halle, Germany, were analyzed retrospectively. A total of 5907 patients with complete data sets including follow-up were eligible for analysis. HER2 status was determined as recommended by international guidelines. Of 5907 patients investigated, 5023 (68.4%) had HER2 0 and 1+ expression and 884 (12.0%) had HER2 (2+)/HER2- expression. Patients with hormone receptor positive (HR+) and HER2 (2+) tumors had a shorter median disease-free survival (DFS; P<0.0001) and breast cancer specific survival (BCSS; P=0.019) than HR+ patients with HER2 (0/1+) tumors. Among patients with HR- breast cancer there was no significant difference between HER2 (2+) and HER2 (0/1+) tumors. In multivariate analysis after adjustment for other prognostic factors, HER2 (2+) status remained an unfavorable prognostic factor for DFS (hazard ratio (HR)=1.217, 95% CI=1.052-1.408; P=0.008) but not for BCSS (HR=1.045, 95% CI=0.926-1.178; P=0.474). The HER2 (2+) status is an unfavorable prognostic factor for survival of patients with HR+ breast cancer. The impact of anti-HER2 therapy in this group of patients should be evaluated.

Chondrocyte mechanotransduction: effects of compression on deformation of intracellular organelles and relevance to cellular biosynthesis.

OBJECTIVE: The effects of mechanical deformation of intact cartilage tissue on chondrocyte biosynthesis in situ have been well documented, but the mechanotransduction pathways that regulate such phenomena have not been elucidated completely. The goal of this study was to examine the effects of tissue deformation on the morphology of a range of intracellular organelles which play a major role in cell biosynthesis and metabolism. DESIGN: Using chemical fixation, high pressure freezing, and electron microscopy, we imaged chondrocytes within mechanically compressed cartilage explants at high magnification and quantitatively and qualitatively assessed changes in organelle volume and shape caused by graded levels of loading. RESULTS: Compression of the tissue caused a concomitant reduction in the volume of the extracellular matrix (ECM), chondrocyte, nucleus, rough endoplasmic reticulum, and mitochondria. Interestingly, however, the Golgi apparatus was able to resist loss of intraorganelle water and retain a portion of its volume relative to the remainder of the cell. These combined results suggest that a balance between intracellular mechanical and osmotic gradients govern the changes in shape and volume of the organelles as the tissue is compressed. CONCLUSIONS: Our results lead to the interpretive hypothesis that organelle volume changes appear to be driven mainly by osmotic interactions while shape changes are mediated by structural factors, such as cytoskeletal interactions that may be linked to extracellular matrix deformations. The observed volume and shape changes of the chondrocyte organelles and the differential behavior between organelles during tissue compression provide evidence for an important mechanotransduction pathway linking translational and post-translational events (e.g., elongation and sulfation of glycosaminoglycans (GAGs) in the Golgi) to cell deformation.