ABSTRACTS

Practice changing topics in breast cancer

The most important new paradigm in the field of systemic breast cancer treatment is the concept of treatment intensifcation with trastuzumab emtansine in case of poor response to neoadjuvant chemotherapy in HER2+ disease. In the phase 3 KATHERINE study, 1,486 patients who did not achieve pathological complete response after standard neoadjuvant chemotherapy in combination with trastuzumab +/- pertuzumab were randomly assigned to 14 cycles of trastuzumab or 14 cycles of trastuzumab emtansine. The patients treated with the latter treatment had a 50% reduction in the risk of invasive breast cancer recurrence or death, with a probability of being free of invasive cancer at 3 years of 88.3% in the trastuzumab emtansine arm and 77.0% in the trastuzumab arm. Neoadjuvant treatment is now de facto the standard of care for HER2+ disease, except for patients who are candidates for the Tolaney regimen. In hormone receptor positive metastatic disease, further studies have positioned the CDK4/6 inhibitors palbociclib, ribociclib and abemaciclib as the treatment of choice in first or second line. After PALOMA-3 showed a trend towards an improved OS of the same magnitude as the improvement shown for PFS, concerns about accelerated post-treatment progression are receding.

In the same disease setting, the SOLAR-1 study showed a PFS benefit of adding alpelisib (a PI3K inhibitor) to fulvestrant in patients with tumors harboring a PIK3CA mutation (median PFS of 11.0 vs 5.7 months). The identification of PIK3CA mutations on the tumor and/or cfDNA will soon become a standard in this context. Finally, the IMPASSION130 study, a phase 3 study in which 451 first line metastatic triple negative breast cancer patients were randomly assigned to nab-paclitaxel + atezolizumab or nab-paclitaxel + placebo, showed a modest PFS benefit in the ITT population, with a median PFS of 7.2 months in the immunotherapy arm and 5.5 months in the placebo arm. Although the statistical plan did not allow for the analysis of this endpoint, it was reported that in the subgroup of patients whose tumor was PD-L1 positive, the median OS in the atezolizumab arm reached 25.0 months, vs 15.5 months in the placebo arm (no p-value).

Practice changing topics in Sarcoma

“Soft tissue sarcomas represent 75% of all sarcomas and constitute a group of more than 50 different histological subtypes, with an even greater number of molecular subtypes.

Localized STSs are generally treated by surgery followed, or preceded, by radiotherapy and according to criteria linked with the risk of local recurrence.

Metastatic STSs are principally treated by systemic treatments such as chemotherapy and targeted drugs. The most important drugs used are doxorubicin, ifosfamide, dacarbazine, gemcitabine/docetaxel, eribulin and trabectedin; but also, pazopanib.

The place of localized treatments (surgery, radiotherapy, radiofrequency, …) in this setting is reserved for oligometastatic disease.

A multidisciplinary approach is mandatory, with centralization of all cases in reference centers, as early as at the time of the clinical diagnosis of a suspected sarcoma. This “centralized” approach, for this rare and complex 7

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.