ABSTRACTS

Topics in gastrointestinal NEN (neuroendocrine neoplasms)

In 2010, the classification of gastrointestinal neuro-endocrine tumours was changed from a classification based on the grade of differentiation to a classification based on the ki 67 index. Both methods provide prognostic information, but the ki 67 staining is a more reproducible method. Grade of differentiation was mentioned less often in pathology reports after 2010.

However, well-differentiated tumours with a higher ki 67 index exist, especially in the pancreas. Poorly differentiated carcinomata and well differentiated neuroendocrine tumours in the pancreas have a clearly different genetic background, the former harbouring abnormalities in DAXX/ATRX or MEN1, the latter in TP53, SMAD4 or RB1. Therefore, the WHO 2017 classification has introduced a new classification for neuroendocrine neoplasms of the pancreas with well-differentiated NET G1 (ki 67 index < 3), G2 (ki 67 index < 20) and G3 (ki 67 index above 20) as opposed to poorly differentiated NEC, small or large cell (also with ki 67 index above 20).

The WHO update for gastrointestinal tumours, including NET outside of the pancreas, has not been published yet. Probably the same changes will be introduced.

Poorly differentiated neuroendocrine carcinomata respond to specific therapies. One large Scandinavian trial has nicely shown different response rates on combination therapy with platinum-etoposide in subgroups of G3 NEN.

In the well differentiated NEN, treatment choices include octreotide analogues, everolimus, peptide receptor radionucleide therapy, debulking surgery and locally ablative therapies (selective internal radiation therapy or cold embolization), temodal-capecitabine, streptozotocin-based chemotherapy and sunitinib. All these therapies have proven to be effective in somewhat different populations and there is no evidence on optimal sequence of treatments.

The prognosis of patients with functioning tumours is often determined by the syndrome. Patients with carcinoid syndrome can develop pellagra or right heart failure. Telotristat etiprate blocks the binding of tryptophan to TPH, reducing the production of serotonin. This leads to a signifcant decrease in diarrhea in patients with carcinoid syndrome and possibly has a positive impact on the evolution of carcinoid heart disease.

Tissue Agnostic Oncology

Tissue agnostic oncology represents a new way of thinking about how cancers are treated, which is in contrast with how treatments have been developed in the past. A tissue agnostic treatment is a drug treatment that is used to treat any cancer, regardless of the site or origin but based on a specific molecular alteration that is targeted by the drug.

The checkpoint inhibitor pembrolizumab was the first drug to be FDA approved with a tumor-agnostic indication in tumors with microsatellite instability (MSI-high) or mismatch repair deficiency. More recently, the FDA also approved larotectrinib to treat all cancers with a gene alteration known as the neurotrophic receptor tyrosine kinase (NTRK) gene fusion.

Tissue-agnostic treatments are often studied in basket trials which can be very challenging due to the infrequency of some alterations. Moreover, there are many examples that targeting genetic alterations is not always as efficient throughout all tumor types. We therefore need a better understanding on the driving molecular alterations across tumor types in order to make a step forward in precision medicine for cancer treatment.

Lessons learned after two decades of international academic clinical research in breast cancer (BC)

The Breast International Group (BIG), founded in 1999, is today the largest academic network in the world dedicated to conducting research designed to accelerate and refine the use of anticancer treatments and diagnostic tools for the benefit of women and men with breast cancer (BC).

BIG’s collaborative research model provides academic leadership in industry-sponsored randomized clinical trials. Some of these trials have successfully led to the rapid registration of new anticancer drugs with a significant impact on breast cancer mortality, such as the HERA trial.

BIG also supports clinical trials sponsored by its academic member groups and facilitates collaboration between international researchers and the US cooperative groups: the SOFT and TEXT trials evaluating adjuvant endocrine therapies for 5,738 premenopausal women are an example of such a collaboration.

Despite its success, BIG and its affiliated cooperative groups must battle constantly to remain vigorously involved in clinical trial design and conduct and in translational research. Without academic leadership in the research process, critical issues important for patient care will remain unaddressed. Moreover, healthcare costs will continue to rise substantially as a consequence of the worrisome “add on” approach in registration trials.

This talk will try to formulate important messages for the next generation of oncology leaders.

Clinical outcome and prognostic factors in oligometastatic breast cancer

Background

Metastatic breast cancer is generally regarded as incurable. A subset of these patients presents with oligometastasic. We wanted to describe patient, disease and treatment characteristics of this subgroup and identify their long-term outcome and prognostic factors.

Methods

We retrospectively selected patients diagnosed with synchronous metastatic breast cancer in our institution over the past 15 years who underwent resection of the primary tumour. Exclusion criteria were non-radical breast surgery, number of metastatic lesions >5 and number of organs involved >3. Kaplan-Meier method was used for progression-free survival (PFS) and overall survival (OS) analysis. Univariate and multivariate analysis were performed with Cox proportional hazards model. A p-value <0.05 was considered statistically significant.

Results

Sixty-five patients were included in the study. After a median follow-up of 77 months, PFS-rate was 46% and OS-rate was 63%. In univariate analysis, PFSwas significantly longerfor patients who underwent additional local treatment for metastases (n = 40/65; treatment modalities including radiotherapy, surgery and/or radiofrequency ablation) (hazard ratio (HR) 0.32, p = 0.001), endocrine receptor positive breast cancer (HR 0.44, p = 0.047) and invasive ductal carcinoma compared to other histological subtypes (HR 0.32, p = 0.016). A trend towards better PFS was additionally seen in premenopausal patients, HER2-positive tumours and patients selected for local therapy for metastases after neoadjuvant chemotherapy or endocrine treatment. Only local treatment for metastases correlated significantly with better OS (HR 0.25, p = 0.002). After correction for endocrine receptor positivity in multivariate analysis, local treatment for metastases remained a significant predictor of PFS (HR 0.33, p = 0,002) and OS (HR 0.26, p = 0.002).

Conclusion

Our data suggest that a significant proportion of highly selected oligometastatic breast cancer patients experience long term remission. In the oligometastatic population who underwent surgery of the primary tumour with curative intent, local therapy for metastases is an independent predictor of better PFS and OS. Ongoing and future efforts will better delineate the optimal patient population where significant benefit of this approach can be achieved, while avoiding morbidity of multimodality treatment in patients who will not encounter long-term disease control.

Fertility preservation does not delay the initiation of chemotherapy in breast cancer patients treated with adjuvant or neo-adjuvant chemotherapy

Purpose

The aim of this study was to verify whether fertility preservation (FP) in adult women diagnosed with breast cancer (BC) has an impact on the time frame between diagnosis and initiation of chemotherapy in an adjuvant or neo-adjuvant setting.

Methods

A retrospective cohort study encompassing patients diagnosed with breast cancer between January 2012 and December 2017, who underwent FP before chemotherapy, and matched control patients, who were not referred to a fertility centre for FP counselling, was performed in two study population groups, more specifically BC patients undergoing neo-adjuvant chemotherapy (NAC) and BC patients undergoing adjuvant chemotherapy. Case patients were selected from the patient database of the Centre for Reproductive Medicine (CRG) at Universitair Ziekenhuis Brussel (UZ Brussel). Fertility preservation consisted of oocyte cryopreservation after ovarian stimulation, ovarian tissue cryopreservation or in vitro maturation of immature oocytes retrieved transvaginally or obtained during an ovarian tissue cryopreservation procedure. The FP procedure was patient-tailored and some patients underwent a combination of procedures. Control patients were selected from the patient database of the Breast Cancer Clinic at UZ Brussel. Cases and controls were matched for tumour characteristics and type of oncological treatment. Time intervals between oncological diagnosis and initiation of chemotherapy were analysed.

Results

Fifty-nine BC patients who underwent FP, of which 29 received NAC and 30 received adjuvant chemotherapy, were selected and matched to control patients. The average time to chemotherapy in BC patients with NAC was 28.5 days (27.3 (range: 14.0-44.0) days in cases and 29.6 (range: 14.0-62.0) days in controls, p = 0.441) and in BC patients with adjuvant chemotherapy 58.9 days (57.2 (range: 36.0-106.0) days in cases and 60.7 (range: 31.0-105.0) days in controls, p = 0.145). The FP procedure took on average 7.1 ± 6.1 days in BC patients with NAC and 11.8 ± 6.9 days in BC patients with adjuvant chemotherapy.

Conclusion

The initiation of chemotherapy is not delayed when adult women diagnosed with breast cancer are referred to an oncofertility team to undergo fertility preservation.

Ethnic Paradigm in Prostate Cancer – does it really matter?

Background

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).

Methods

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.

Results

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.

Conclusions

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.

The spatial localization of immune cells predicts prognosis and response to therapy in inflammatory breast cancer

Background

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.

Methodology

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.

Results

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.

Conclusion

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.