BJMO - 2019, issue 2, february 2019
Fadi Dalati
Prostate Cancer (PCa) is a major mortality cause with higher incidence in western countries and African population, and lower in Arab countries. Belgium’s population present different origins with 24.2% being immigrants and 46% descendants from outside European Union. The equal-open-access healthcare in Belgium provides an opportunity to study variations in PCa presentation among different ethnicities (Caucasians, Africans and Arabs).
We retrospectively reviewed 495 consecutive patients medical records (328 Caucasians, 78 Africans and 89 Arabs) who underwent Trans-Rectal-UltraSound(TRUS)-guided prostate biopsy in our institution between January 2013 and March 2017. The parameters analyzed were: age, ethnicity, PSA, digital rectal exam(DRE), Prostate Volume, Gleason score, number of prostate biopsy cores, percentage of cores invaded by cancer and TNM classification.
In our cohort, Africans presented PCa diagnosis at younger age (6 years less) compared to Caucasians and Arabs (p<0.001). Arabs have less PCa diagnosis (p<0.024). After multiple logistic regression Arabs present 45.3% less PCa diagnosis compared to Caucasians (OR 2.21,95%Confidence lntervals[CI] 1.32-3.72, p<0.003) and 39.7% less than Africans (OR 2.52,95%CI 1.25-5.07, p<0.01), even though its predominantly Gleason>7 and Gleason>7(4+3) (OR 2.83,95%CI 1.23-6.5, p<0.014 and OR 2.44,95%CI 1.03-5.76, p<0.043, respectively) and High Risk(HR) (OR 2.37,95%CI 1.07-5.25, p<0.033) when compared to Caucasians. Africans also present more Gleason>7(4+3) (OR 5.49,95%CI 2.25-13.36, p<0.001) and PCa≥HR (OR 4.59,95%CI 1.93- 10.9, p<0.001) compared to Caucasians.
In an equal-open-access healthcare system, although Arabs have less PCa prevalence, they usually present a predominantly Gleason≥7(4+3) and HR compared to Caucasians, with PCa features more similar to Africans. This may implicate limitations for treatment options as active surveillance.
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Christophe Van Berckelaer
The immune microenvironment seems to contributes to the aggressive and unique biological features associated with inflammatory breast cancer (IBC). In this study we assessed the spatial associations between immune cells in IBC.
Serial slides of 51 patients (= 104 tissue samples) were stained according to a validated protocol. We used five antibodies: PD-L1 (SP142 AB), CD79a (B cell lineage), CD8 (cytotoxic T cells), FOXP3 (Tregs) and CD163 (TAMs, Tumor-associated macrophages). Subsequently, slides were scanned, virtually aligned and evaluated using VISIOPHARM® software. To narrow down the number of stainings, Affymetrix gene expression data of the IBC patients were analyzed using the CIBERSORT module.
Using specific image analysis algorithms for every staining, we located each positive cell using XY coordinates. Spatial co-localization was examined using point pattern (effector indexm, El) and quadrant analysis (Morisita-Horn index, MHI), developed for ecological studies. The El is based on the number of cells within a circle of 30 μm surrounding a CD8+ cell and the MHI measures the dissimilarity in species between two quadrants.
Complete pathological response (pCR) after neo-adjuvant chemotherapy was achieved in 23.5% of our patients. A negative HR-status (P= 0.01) and a the presence of more CD8+ cells (P= 0.04) predicted pCR. Interestingly, a higher number of CD79a+(P= 0.005) or FOXP3+ cells (P= 0.02) in close distance of CD8+ T cells was associated with pCR (using both El and MHI), while solely the number of CD79α+ or FOXP3+ cells did not predict prognosis nor pCR.
PD-L1 positivity and the number of CD8+ cells were not associated with OS, but patients with more PD-L1+ cells (> 0.7 cells/30 μm) in close contact with the CD8+ cells had a worse survival outcome (5y OS: 50% vs 68%, P=0.03). TAMs near CD8+ cells also seem to inhibit a good cytotoxic immune response as the El for CD163+TAMs was also prognostic (P=0.02), while the absolute number of TAMs was not.
In a validation cohort of 51 patients we showed that not only the presence, but also the spatial localization of immune cells predicts prognosis and response to therapy in IBC.
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Mireille Diane Langouo Fontsa
Tumor-infiltrating lymphocytes (TIL) have been associated with good clinical outcomes in HER2-positive (HER2+) and triple-negative (TN) breast cancer (BC) patients. Recently, we demonstrated that in 60% of BC, TIL are organized in tertiary lymphoid structures (TLS) located in the stroma. We further identified a CXCL13-producing CD4+T follicular helper (Tfh) cell subpopulation that is associated with positive clinical outcomes in BC.
We aimed to investigate how CD4+Tfh cells, expressing the CXCL13 receptor CXCR5, contribute to immune response in BC TLS.
Prospectively collected fresh primary BC tissues were dissociated without enzymes to separate tumor supernatants and TIL and used for Immunoglobulin (lg)/cytokines quantification and flow cytometric analysis/sorting. Matching formalin-fixed paraffin-embedded (FFPE) were used for spatial analysis.
In our BC cohort, around 15%CD4+TIL, 13% CD8+TIL and >95% B cell TIL express CXCR5 while confocal microscopy reveals that they colocalized in BC TLS. in some BC, Tfh TIL (as activated tonsillar Tfh) express ICOS and PD-1 suggesting they are activated. RNA analysis on Tfh TIL detected high expression of IL-21, INFg, and CXCL13. In an in vitro assay where Tfh TIL were activated with splenic B cells revealed that only ICOS+PD-1+Tfh TIL from TN/HER2+ BC are capable of inducing Ig secretion by B cells. mRNA analysis of sorted ICOS+PD-1+Tfh TIL confirms an activated, functional nature for the former with high levels of IL-21, INFg, and CXCL13. Moreover, we found that CXCR5+CD8 TIL expressing ICOS and PD-1 expressed high level of CCL4, FASL, granzyme B and IFNy. Multiplex IHC analyses confirm the presence of activated CD8+ TIL in close contact with functional Tfh and B TIL. A high correlation between the presence of functional Tfh with activated CD8 TIL and with Ig secreted in the NANT from TN/HER2+ BC was observed.
We describe two distinct subpopulations of Tfh TIL. The CXCR5 TfhX13 producing CXCL13 that may recruit the CXCR5+Tfh TIL in TLS. Functional Tfh TIL probesto guide humoral and cytotoxic antitumor immunity in TLS. These data shed light on anti-tumor immune responses taking place in the TLS, whose functional activities may have important treatment implications, particularly for immunotherapy in BC.
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Elisabeth De Meue
There is a need for response indicators that reliably reflect survival and occur early in patients with metastatic castration-resistant prostate cancer (mCRPC).
Recently, we demonstrated in real-life mCRPC patients that the measurement of circulating tumor cell (CTC) dynamics at 10-12 weeks during treatment with androgen-receptor signaling inhibitors provides independent prognostication over >50% PSA declines (De Laere, Prostate, 2018). Additionally, we demonstrated that absence of CTCs at 10-12 weeks, regardless if CTCs were detected at baseline, was associated with superior overall survival (OS).
Heller et al. demonstrated the high prognostic value of reaching undetectable CTC levels at week 13 after a nonzero baseline measurement (i.e. CTC0) in patients with mCRPC (Heller, J Clin Oncol, 2018) in a retrospective analysis of five prospective randomized phase III trials.
With the recent findings on the CTC0 endpoint, we revisited our data and performed a similar analysis.
We retrospectively analyzed data of a multicenter, prospective and non-interventional study in which blood samples for CTC enumeration were collected from patients with mCRPC starting treatment with abiraterone acetate or enzalutamide at baseline and at 10-12 weeks.
In our cohort, 63/102 (62%) patients with at least 10-12 weeks survival were CTC-positive at baseline and qualified for CTC0 response evaluation. In this group, 40/63 (63.5%) patients were chemotherapy-naive.
At 10-12 weeks, 28/63 (44%) of patients demonstrated a CTC0 response with a superior OS compared to CTC-positive patients (not reached versus 12.6 months, p<0.0001). In multivariable Cox regression analysis, not reaching a CTC0 response (HR 10.3, 95% CI 2.2-47.9, p<0.0001) was independently associated with shorter OS, whereas not reaching a ≥50% PSA decline was not.
The present analysis, although immature in OS events, demonstrates independent and confirmatory evidence of the potential clinical utility of CTC0 as measure of benefit in routine clinical practice. Interestingly, the evaluability rate in our study (62%) is lower than that in the study of Heller et al. (75%), probably because of the higher rate of chemotherapy-naive patients in our study. As the disease burden increases towards end-stage disease, the evaluability rates for CTC-driven response measure will increase accordingly.
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Bert Van Den Heuvel
To explore the clinical impact of FU-FDG-PET/CT in patients with LA-HNSCC treated with CRT or ST.
Real-life scan reports of LA-HNSCC patients having FU-FDG-PET/CT performed 6-18 months after ST/CRT were retrospectively analyzed. Equivocal reports were scored as positive. Excluded were patients with histological proof of recurrence before FU-FDG-PET/CT. The reference standard was the occurrence of a second primary (SP) or a recurrence within 12 months after FU-FDG-PET/CT. Primary endpoints included sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) on a patient level.
Between 7/10/2005 and 28/10/2016, 73 patients were identified: median age 61 (range 35-80), male: n=55. Primary tumor site: oropharynx: n=35; larynx: n=17; hypopharynx: n=11; oral cavity: n=4; paranasal sinus: n=4; unknown: n=5. Tumor stage (UICC 7): II (T2N0): n=1; III: n=9; IV: n=63. T1: n=8; T2: n=20; T3: n=16; T4: n=24; NO: n=10; N1: n=7; N2: n=53; N3: n=3. Patients were treated by CRT (n=29), IC + CRT (n=43), IC + RT (n=1). Median time between end of treatment and FU-FDG-PET/CT was 12 months (range 6-17). Median follow-up after FU-FDG-PET/CT was 48 months (range 2-130). Sensitivity, specificity, PPV and NPV were 83% (95% CI 52-98), 87% (95% CI 76-94), 56% (95% CI 31-78) and 96% (95% CI 87-100), respectively. Local recurrences, SPs and distant metastases were detected in 5, 1, 4 patients, respectively. 18 patients (25%) recurred after a false positive (n=8), false negative (n=2) or true negative (n=53) FU-FDG-PET-CT. One FU-FDG-PET/CT-detected local recurrence and one SP were treated with curative intent. All false-positive patients underwent biopsy (n=5) or surgery (n=3). Metastases were irradiated stereotactically in 2 patients. Median overall survival was 49 (95% CI 29 – 68) and 98 (95% CI 86-111) months in FU-FDG-PET/CT-positive and -negative patients, respectively (p = 0,000196).
FU-FDG-PET/CT in real-life has a high NPV, but low PPV. Prognostic value is significant but false-positive FU-FDG-PET/CTs induce invasive procedures in a significant fraction of patients.
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T. Wessels MD
Solitary fibrous tumor (SFT), a rare variant of soft tissue sarcoma (STS), is characterized by the presence of a NAB2-STAT6 fusion. Given the orphan character of SFT we performed a retrospective analysis.
We retrospectively reviewed all patients (pts) with SFT treated in our institution between 12/1990 – 09/2017.
We identified 94 SFT pts (incl. hemangiopericytoma) with a med. follow-up for 4.7 yrs. Common anatomic sites were chest (33%), abdomen (21.3%), brain (12.8%) and extremities (9.6%). The symptomatology at diagnosis was variable. Only 6.4% presented with synchronous metastasis. Hypoglycemia (Doege-Potter syndrome) was seen in 2.1% of cases. A resection of the primary SFT was done in 86 pts (91.5%), their disease-free survival was 35.5 mo and 43% stayed SFT-free during follow-up. Local recurrence occurred in 26.7% of cases, associated with a med. overall survival (OS) of 45.1 mo. Metachronous metastasis was seen in 30.2% of pts, occurring after a med. follow-up of 36 mo. Med. OS after diagnosis of metastasis was 19.0 mo. Systemic therapy was given to 92.9% of pts with inoperable/metastatic disease. The most common 1st line therapy was doxorubicin single agent (57.7% of pts), achieving responses in 13.3% of pts. 2nd linetherapies included ifosfamide and pazopanib (31.3% of pts each), 3rd line treatment was very heterogeneous. Conclusion: SFT is an orphan malignancy with a variable clinical course, low incidence of distant spread at first diagnosis but considerable risk of local failure and metachronous metastasis. Surgery is the only curative option at diagnosis, time of relapse and in case of resectable metastasis. Palliative systemic therapy is considered in pts with inoperable/metastatic disease but achieves low response rates. The natural course and survival outcomes of SFT cases treated with palliative intent tends to be better than in non-selected STS pts.
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Luc Dirix
In the phase 3 study ARIEL3, rucaparib (600 mg BID) maintenance treatment following response to platinum-based chemotherapy significantly improved progression-free survival (PFS) vs placebo in all patient populations regardless of biomarker status (Coleman. Lancet. 2017;390:1949-61). This post hoc exploratory analysis investigated the effect of the number of prior chemotherapy regimens on investigator-assessed PFS, the primary endpoint in ARIEL3.
All patients received ≥2 prior platinum-based regimens per the protocol. Investigator-assessed PFS was evaluated in subgroups of patients who received 2 or ≥3 prior chemotherapy regimens and is reported by predefined cohort: BRCA mutant; BRCA mutant + BRCA wild type/high loss of heterozygosity (LOH); and intent-to-treat (ITT) population.
The visit cutoff dates for efficacy and safety were 15 April 2017 (date of unblinding for primary efficacy analyses) and 15 August 2017 (date of dataset in the US prescribing information).
In the BRCA-mutant cohort, median PFS in the 2 prior chemotherapies subgroup (rucaparib, n=73; placebo, n=40) was 21.9 vs 5.4 months (hazard ratio [HR], 0.24; 95% confidence interval [CI], 0.14-0.40; P<0.0001) and in the ≥3 prior chemotherapies subgroup (rucaparib, n=57; placebo, n=26) was 13.7 vs 5.4 months (HR, 0.21; 95% CI, 0.11-0.40; P<0.0001).
In the BRCA mutant + BRCA wild-type/high LOH cohort, median PFS in the 2 prior chemotherapies subgroup (rucaparib, n=136; placebo, n=75) was 14.1 vs 5.5 months (HR, 0.34; 95% CI, 0.23-0.49; P<0.0001) and in the ≥3 prior chemotherapies subgroup (rucaparib, n=100; placebo, n=43) was 11.1 vs 5.4 months (HR, 0.27; 95% CI, 0.16-0.44; P<0.0001).
In the ITT population, median PFS in the 2 prior chemotherapies subgroup (rucaparib, n=231; placebo, n=124) was 10.4 vs 5.4 months (HR, 0.42; 95% CI, 0.32-0.55; P<0.0001) and in the ≥3 prior chemotherapies subgroup (rucaparib, n=144; placebo, n=65) was 11.1 vs 5.3 months (HR, 0.28; 95% CI, 0.19-0.41; P<0.0001).
Rucaparib’s safety profile was consistent between the 2 and ≥3 prior chemotherapies subgroups as assessed by the rate of grade ≥3 (59% and 59%) treatment-emergent adverse events.
Rucaparib maintenance treatment improved PFS vs placebo in all predefined cohorts regardless of the number of prior chemotherapy regimens received.
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