Correlating the KELIM (CA125 elimination rate constant K) score and the chemo-response score as predictors of chemosensitivity in patients with advanced ovarian carcinoma.

BACKGROUND: The objective of this study is to assess the correlation between the pre-operative CA125 Elimination rate constant K(KELIM) score and the intraoperative chemo-response score (CRS) in patients with advanced high grade serous ovarian cancer(HGSC) treated with neoadjuvant chemotherapy(NACT). METHODS: This is a retrospective cohort study of patients with Stage III-IV HGSC treated with NACT from March 2010 to December 2019 at Princess Margaret Cancer Center, Toronto, Canada. KELIM scores were calculated based on the tool devised by You et al. available online. CRS was assessed using an established 3-tier scoring system. An association analysis was performed to determine if the KELIM score assessed during NACT can predict CRS score at the time of interval cytoreductive surgery(ICS). RESULTS: 172 patients were included in this analysis. Patients with CRS 1-2 had a lower median Platinum Free Interval(PFI) (9.24 vs 13.64 months, p = 0.005), lower median progression free survival(PFS) (14.99 vs 20.29 months, p = 0.003) and lower 5-year overall survival(OS) (63.8% vs 69.7%, p = 0.54) compared to patients with CRS3. Among patients with CRS 1-2(n = 115), 68.7% had KELIM <1, while 56.2% of patients with CRS3 had KELIM ≥1(56.2%), p = 0.0017, suggesting a correlation between the KELIM and CRS scores. Furthermore, patients with KELIM ≥1 and CRS3 had significantly higher PFS compared to other groups(median PFS 28.27 months vs 17.66 months for KELIM ≥1/CRS 1/2; 17.13 months for KELIM <1/CRS 3; and 14.53 months for KELIM <1/CRS 1-2, p = 0.003). CONCLUSION: The biochemical KELIM score correlated with the surgical pathologic CRS score and may predict pathological response to chemotherapy. This information can be utilized to tailor and personalize treatment in patients with advanced ovarian malignancy.

Toward a quantitative method for estimating tumour-stroma ratio in breast cancer using polarized light microscopy.

The tumour-stroma ratio (TSR) has been explored as a useful source of prognostic information in various cancers, including colorectal, breast, and gastric. Despite research showing potential prognostic utility, its uptake into the clinic has been limited, in part due to challenges associated with subjectivity, reproducibility, and quantification. We have recently proposed a simple, robust, and quantifiable high-contrast method of imaging intra- and peri-tumoural stroma based on polarized light microscopy. Here we report on its use to quantify TSR in human breast cancer using unstained slides from 40 patient samples of invasive ductal carcinoma (IDC). Polarimetric results based on a stromal abundance metric correlated well with pathology designations, showing a statistically significant difference between high- and low-stroma samples as scored by two clinical pathologists. The described polarized light imaging methodology shows promise for use as a quantitative, automatic, and standardizable tool for quantifying TSR, potentially addressing some of the challenges associated with its current estimation.

Retrospective observational study of HER2 immunohistochemistry in borderline breast cancer patients undergoing neoadjuvant therapy, with an emphasis on Group 2 (HER2/CEP17 ratio ≥2.0, HER2 copy number <4.0 signals/cell) cases.

BACKGROUND: The ASCO/CAP guidance on HER2 testing in breast cancer (BC) has recently changed. Group 2 tumours with immunohistochemistry score 2+ and HER2/CEP17 ratio ≥2.0 and HER2 copy number <4.0 signals/cell were re-classified as HER2 negative. This study aims to examine the response of Group 2 tumours to neoadjuvant chemotherapy (NACT). METHODS: 749 BC cases were identified from 11 institutions. The association between HER2 groups and pathological complete response (pCR) was assessed. RESULTS: 54% of immunohistochemistry HER2 positive (score 3+) BCs showed pCR, compared to 19% of immunohistochemistry 2+ FISH amplified cases. 27% of Group 2 treated with HER2 targeted therapy achieved pCR, compared to 19 and 11% in the combined Groups 1 + 3 and Groups 4 + 5, respectively. No difference in pCR rates was identified between Group 2 and Group 1 or combined Groups 1 + 3. However, Group 2 response rate was higher than Groups 4 + 5 (p = 0.017). CONCLUSION: No difference in pCR was detected in tumours with a HER2/CEP17 ratio ≥2.0 and a HER2 score 2+ by IHC when stratified by HER2 gene copy number. Our data suggest that ASCO/CAP HER2 Group 2 carcinomas should be evaluated further with respect to eligibility for HER2 targeted therapy.

First use of tofacitinib to treat an immune checkpoint inhibitor-induced arthritis.

Immune checkpoint inhibitors have revolutionised cancer treatment; however, immune-related adverse events do occur, with up to 7% developing inflammatory arthritis. Common rheumatoid arthritis therapies such as methotrexate, prednisolone and biologics have been used to treat this arthritis in small, uncontrolled case series with varying success. In this case of personalised medicine, we report the first use of tofacitinib, a small molecular inhibitor of the Janus kinase-signal transducer and activator of transcription pathway, to treat checkpoint inhibitor-related inflammatory arthritis. This resulted in a rapid clinical response and complete, sustained remission of the arthritis with associated marked reduction in synovial molecular and cellular immune response.

Predictors of pathological complete response to neoadjuvant treatment and changes to post-neoadjuvant HER2 status in HER2-positive invasive breast cancer.

The response of human epidermal growth factor receptor2 (HER2)- positive breast cancer (BC) patients to anti-HER2 targeted therapy is significant. However, the response is not uniform and a proportion of HER2-positive patients do not respond. This study aims to identify predictors of response in the neoadjuvant treatment and to assess the discordance rate of HER2 status between pre- and post-treatment specimens in HER2-positive BC patients. The study group comprised 500 BC patients treated with neoadjuvant chemotherapy (NACT) and/or neoadjuvant anti-HER2 therapy and surgery who had tumours that were 3+ or 2+ with HER2 immunohistochemistry (IHC). HER2 IHC 2+ tumours were classified into five groups by fluorescence in situ hybridisation (FISH) according to the 2018 ASCO/CAP guidelines of which Groups 1, 2 and 3 were considered HER2 amplified. Pathological complete response (pCR) was more frequent in HER2 IHC 3+ tumours than in HER2 IHC 2+/HER2 amplified tumours, when either in receipt of NACT alone (38% versus 13%; p = 0.22) or neoadjuvant anti-HER2 therapy (52% versus 20%; p < 0.001). Multivariate logistic regression analysis showed that HER2 IHC 3+ and histological grade 3 were independent predictors of pCR following neoadjuvant anti-HER2 therapy. In the HER2 IHC 2+/HER2 amplified tumours or ASCO/CAP FISH Group 1 alone, ER-negativity was an independent predictor of pCR following NACT and/or neoadjuvant anti-HER2 therapy. In the current study, 22% of HER2-positive tumours became HER2-negative by IHC and FISH following neoadjuvant treatment, the majority (74%) HER2 IHC 2+/HER2 amplified tumours. Repeat HER2 testing after neoadjuvant treatment should therefore be considered.

Evaluation of an enhanced pathological examination protocol for sentinel lymph nodes from patients with breast carcinoma.

Clinical trials have shown that many patients with breast cancer with limited sentinel lymph node (SLN) metastatic disease can safely avoid axillary lymph node dissection. Ultra-staging of initially negative SLNs may not confer additional clinical benefit. Despite this, protocols of 'enhanced pathological examination' (EPE) are still widely used. We evaluated the impact of our EPE protocol. If initial SLN H&Es are negative, we cut three additional H&E levels at 500 µm intervals with two spare sections at each level, to allow for immunohistochemistry if necessary. Occult micrometastases or isolated tumour cells were identified, using this protocol, in 3.4%, resulting in change of N stage in 3%. 1% of patients had further axillary surgery based on these findings. Our SLN-EPE protocol provided additional information in a small number of cases and changed axillary management in a minority. It represented a significant workload for scientists and pathologists, and had time and cost implications. We concluded that emphasising careful gross examination along with judicious use of additional levels and immunohistochemistry may be more beneficial than our current protocol.

Assessing the impact of the 2018 American Society of Clinical Oncology/College of American Pathologists recommendations on human epidermal growth factor receptor 2 testing by fluorescence in situ hybridization in breast carcinoma.

The American Society of Clinical Oncology/College of American Pathologists recently updated their recommendations on human epidermal growth factor receptor 2 (HER2) testing by fluorescence in situ hybridization (FISH) in invasive breast cancer, with a focus on the clarification of less common test patterns of ISH. We assessed the impact of the updated ASCO/CAP guidelines on 1044 FISH tested tumors by comparing categorization according to the 2007, 2013, and 2018 ISH classification criteria. The 2013 guidelines increased the number of positive cases (17.4% vs 10.7%) identifying 70 (6.7%) additional patients who met the eligibility criteria for consideration for HER2-targeted therapy compared with the 2007 guidelines. There was a reduction in equivocal tumors (7.7%) with tumors classified as equivocal by the 2007 guidelines (n = 136) redistributed into positive (74, 54.4%) and negative (49, 36.0%) groups. The 2018 guidelines reclassified 10.8% of tumors in our series with a reduction in the number of positive tumors (7.1%). While the proportion of positive tumors (10.2%) was similar to that in 2007 (10.7%), the composition of this group was significantly altered. HER2 equivocal cases, a group which under the 2013 guidelines caused diagnostic and treatment difficulties, were largely eliminated. Our findings suggest that the 2018 update represents a potentially significant change in therapeutic options for a substantial proportion of patients with 2.9% of FISH-positive tumors according to the 2007 and 2013 guidelines now categorized as HER2 negative and, thus, ineligible for HER2-targeted therapy.

Composite Blastoid Variant of Mantle Cell Lymphoma and Classical Hodgkin Lymphoma.

Composite lymphoma (CL) describes the rare occurrence of 2 or more distinct types of lymphoma in a single anatomical location. We present the case of a 78-year-old man presenting with a 3-month history of weakness, malaise, and increasing dyspnea. A lymph node excised from the posterior triangle of the neck revealed the coexistence of 2 morphologically and phenotypically distinct lymphoid neoplasms consistent with a blastoid variant of mantle cell lymphoma (MCL) occurring in composite with classical Hodgkin lymphoma (cHL), mixed cellularity subtype. A t(11;14)(q13;q32) translocation was demonstrated by fluorescence in situ hybridization in the MCL and Hodgkin Reed-Sternberg cells of the cHL. Multiplex polymerase chain reaction detected clonal Immunoglobulin heavy chain (VFR1-J, VFR2-J, and VFR3-J), clonal immunoglobulin light chain kappa (V-J and V/JC intron-kde) and clonal immunoglobulin light chain lambda (V-J) gene rearrangements in the MCL. This report represents the first case of a blastoid variant of MCL occurring in composite with cHL.