The world’s largest and most important congress of clinical oncology took place in Chicago at the beginning of June. The latest data from current studies and innovations in cancer research were published and discussed at the annual meeting of the American Society of Clinical Oncology (ASCO). The theme of this year’s congress was: The Art and Science of Cancer Treatment: From Comfort to Cure.
The most effective multimodal approach for the treatment of resectable locally advanced esophageal adenocarcinoma (EAC) is controversial. A primary question is whether neoadjuvant chemoradiation therapy or perioperative chemotherapy is superior. In a multicenter, prospective, randomized study, neoadjuvant CROSS therapy (41.4 Gy plus carboplatin/paclitaxel) followed by surgery was therefore compared with perioperative FLOT therapy (5-FU/leucovorin/oxaliplatin/docetaxel) and surgery for the curative treatment of EAC [1]. Patients with cT1 cN+ cM0 or cT2-4a cNany cM0 resectable EAC were eligible. The primary endpoint was overall survival. 438 patients from 25 locations in Germany were randomly assigned to two treatment groups (221 FLOT; 217 CROSS). Neoadjuvant treatment was started in 403 patients (207 FLOT; 196 CROSS). The operation was performed on 371 patients (191 FLOT; 180 CROSS). R0 resection was achieved in 351 patients (180 FLOT; 171 CROSS). Mortality 90 days after surgery was 4.3% (3.2% FLOT; 5.6% CROSS). After a median follow-up period of 55 months, 218 patients had died (97 FLOT; 121 CROSS). The median OS was 66 months in the FLOT group and 37 months in the CROSS group. The 3-year OS rates were 57.4% for FLOT and 50.7% for CROSS. Among 359 patients with available tumor regression status, a pathological complete response was achieved in 35 in FLOT and in 24 in CROSS. Overall, perioperative FLOT improved survival in resectable EAC compared to neoadjuvant CROSS.
The influence of hormone receptor status in breast cancer
The expression of hormone receptors is a known positive prognostic and predictive factor in breast cancer (BC). In young patients with BRCA1 or BRCA2 germline variants(PVs), most tumors in BRCA2 carriersexpress hormone receptors, whereas most BC cases in BRCA1 carriersdo not express hormone receptors. However, there is limited evidence on the impact of hormone receptor status on clinical behavior and outcomes in young patients with BRCA PVs. An international, multicenter, hospital-based, retrospective cohort study included young patients (≤40 years) diagnosed with invasive BC between January 2000 and December 2020 who had germline PVs in BRCA genes. The analysis examined the influence of hormone receptor status on the clinical behavior and outcomes of BC. The type and pattern of recurrence and survival outcomes (disease-free survival [DFS], BC-specific survival [BCSS] and overall survival [OS]) were first analyzed by hormone receptor expression (positive vs. negative) and then by BC subtype (luminal A-like vs. luminal B-like vs. triple-negative vs. HER2-positive BC).
From 78 centers worldwide, 4709 BRCA carrierswere included in the analysis, of which 45.5% had hormone receptor-positive and 54.5% hormone receptor-negative BC. Patients with hormone receptor-positive BC were more likely to have BRCA2-PVs, while they were less likely to have grade 3 tumors and nodal involvement. The median follow-up time was 7.88 years. The rate of distant recurrence was higher in patients with hormone receptor-positive BC (13.1% vs. 9.6%,) while the rate of second primary BC was lower compared to patients with hormone receptor-negative disease (9.1% vs. 14.7%). The 8-year DFS was 65.8% in patients with hormone receptor-positive BC and 63.4% in those with hormone receptor-negative BC. No differences were found with regard to OS or BCSS. Of the 4363 patients eligible for subtype analysis, 612 had luminal A-like, 1038 had luminal B-like, 2373 had triple-negative and 340 had HER2-positive BC. Patients with luminal A-like BC had the worst long-term prognosis in terms of DFS compared to all other subgroups (8-year DFS: 60.8% for luminal A-like vs. 63.5% for triple-negative vs. 65.5% for HER2-positive and 69.7% for luminal B-like subtype). Accordingly, hormone receptor status does not appear to be a positive prognostic factor in young BRCAPV carriers with early BC. However, the differences in the pattern of recurrence and second primary BC between hormone receptor-positive and hormone receptor-negative diseases should be taken into account when counseling patients on treatment, follow-up strategies and indications for risk-reducing surgery.
Focus on treatment resistance of glioblastomas
Despite decades of clinical trials, glioblastoma (GBM) is still a rapidly fatal disease. Much of the treatment resistance in GBM is attributed to intratumoral heterogeneity, where subclones develop rapidly and treatment-resistant cell populations emerge. Understanding heterogeneity at the time of diagnosis and its relationship to the origins of recurrence is critical to selecting therapies that are effective across the tumor. However, only a few genomic studies go beyond the analysis of individual tumor samples per patient. Now, using a spatially oriented whole tumor sampling approach, 43 biopsies were taken from 3 GBMs at diagnosis and recurrence [3]. Pyclone and ClonEvol were applied to whole-exome sequencing to reconstruct clonal evolution, FACETs identified copy number variations, and HATCHet estimated tumor purity. Candidate driver mutations were evaluated in the context of the Catalogue of Somatic Mutations In Cancer.
A single founding clone and several subclones were identified for each diagnostic recurrence pair. Tumor-wide clonal alterations representing the initial clonal expansion of these GBMs included canonical alterations (Chr 7 gain, Chr 10 loss, CDKN2A deletion, EGFR amplification) as well as a number of large-scale copy number variations (Chr 19, 20 gain), driver mutations (PTEN, KDR, CDH11, CNTNAP2) and fusions (LIMCH1::UCHL1, KANK::DOCK8). A second subset of alterations (Chr 8 gain, ATRX mutation) appeared to be cross-tumor at diagnosis but was not identified at recurrence. Cancer-causing factors were also present subclonally, including CDKN2A deletion, MDM2 amplification and mutations in NF1 and GRM3. The evolutionary trees consisted of 5 generations of clones in patient 323 (P323), 3 in P454 and 4 in P534. The divergence of recurrent tumors from the corresponding primary tumors occurred in the second generation in P454 and P534 and in the third generation in P323. As a result, an average of 37% of the potential drivers of oncogenesis and clonal expansion in the entire cohort occurred after divergence. In addition, each recurrent tumor contained at least one tumor-wide driver change that was subclonal or undetected at diagnosis.
Taking samples from the entire tumor of three GBM patients at both diagnosis and recurrence revealed a diversity of genomic drivers and deeper and more complex genetic roots of individual GBM than previous single-biopsy studies. Tumor recurrences consistently arose from a single subclone that split off early in the development of the primary tumor and contained clonal drivers that were either not detected in the primary tumor or were subclonal – suggesting a role for these drivers in persistence and expansion. In the era of personalized medicine, the study highlights the clinical potential of tumor-wide sampling in identifying therapeutic targets that could avoid heterogeneity-related therapeutic failures.
Increased secondary risk with solid tumors?
Pathogenic variants in germline genes that predispose to cancer (e.g. BRCA1/2, PALB2) lead to an increased risk of solid tumors, but not of de novomyeloid malignancies. Many of these genes are associated with DNA repair mechanisms. It is not known whether exposure to genotoxic therapy increases the risk of secondary hematologic malignancies. An analysis showed the incidence of hematological malignancy after the diagnosis of a solid tumor in patients with a pathogenic germline variant of PALB2 [4]. Of the 176 medical records examined, 102 (57%) had a history of malignancy, of which 68 (66%) received genotoxic chemotherapy. The median follow-up time after chemotherapy was 59 months. The most common malignancies and chemotherapies were breast cancer (75%) and doxorubicin, cyclophosphamide and paclitaxel (31%). The results of the patients were compared depending on whether they had received chemotherapy or not. There were no differences between the two groups in terms of race, age at cancer diagnosis, surgery rate, treatment with hormone therapy or secondary malignancy. Irradiation rates were higher in those who received genotoxic therapy than in those who did not (65% versus 41%), but there was no difference in Gray treatment or post-irradiation follow-up. The mortality rate in the group with genotoxic therapy was 15% compared to 9% in the group without genotoxic therapy. Two subjects developed a hematologic malignancy (one case each of CLL and CML); both had previously received chemotherapy and radiation. The results show that cancer survivors with a pathogenic germline variant of PALB2 and subsequent exposure to genotoxic therapy appear to have a low risk of secondary hematologic malignancy. Although two subjects in the chemotherapy group developed leukemia, it is unlikely that these were related to treatment exposure given the cases observed.
Metastases in the meninges in melanoma
Patients with advanced-stage melanoma may develop leptomeningeal disease (LMD), a rare form of metastasis in the meninges. Unfortunately, there are currently no rational treatment options for melanoma-associated LMD (M-LMD), and the prognosis is grim; survival time is measured in weeks. A major obstacle to the development of effective therapies for this disease is the lack of model systems, such as patient-derived models with circulating tumor cells in the cerebrospinal fluid (PD-CSF-CTC), to identify and evaluate new therapeutics. Added to this is the difficulty of collecting and analyzing M-LMD samples in the clinic and at autopsy. To overcome these hurdles, CSF and tissue (in clinic and at autopsy) was collected and CSF CTCs from M-LMD patients were successfully propagated in vitro and in xenograft mouse models. These valuable resources enabled proteomic and transcriptomic analyses of CSF and PD-CSF-CTCs. By comparing M-LMD-omics data with those of normal brain and extracranial diseases, unique LMD-specific biological signaling pathways were found. A study has now identified clinical agents that target these biological signaling pathways and could be effective against PD-CSF-CTCs in vitro and in vivo [6].
Of the 1436 FDA-approved small molecules, 57 inhibited 95% proliferation and 20 had 100% killing efficacy in PD-CSF-CTCs and murine melanoma cell lines. The substances with the highest sensitivity include ponatinib, sorafenib, ceritinib and homoharringtonine (HHT). In a randomized preclinical M-LMD study in mice, HHT was selected because it is a cephalotaxin ester compound that can penetrate the brain. The results show that HHT was well tolerated in vivo when administered systemically or IT via a murine ommaya. M-LMD mice that received 14.5ng HHT (g.d. IT) showed significantly prolonged median survival.
Congress: American Society of Clinical Oncology (ASCO) 2024
Literature:
- Hoeppner J, et al: Prospective randomized multicenter phase III trial comparing perioperative chemotherapy (FLOT protocol) to neoadjuvant chemoradiation (CROSS protocol) in patients with adenocarcinoma of the esophagus (ESOPEC trial). J Clin Oncol 42, 2024 (suppl 17; abstr LBA1).
- Arecco L, et al: Impact of hormone receptor status and tumor subtypes on clinical behavior and outcomes of breast cancer in young BRCA carriers. J Clin Oncol 42, 2024 (suppl 16; abstr 504).
- Lerman BJ, et al: Longitudinal tumor-wide sampling of glioblastoma reveals diverse genomic drivers of the earliest clonal expansion at diagnosis and recurrence. J Clin Oncol 42, 2024 (suppl 16; abstr 2009).
- Ellaithy H, et al: Risk of secondary leukemias in patients with germline PALB2 pathogenic variants after chemotherapy exposure. J Clin Oncol 42, 2024 (suppl 16; abstr 10598).
- Law V, et al: Identification of pharmaceutics with selective activity against melanoma-associated leptomeningeal disease using patient-derived circulating tumor cells. J Clin Oncol 42, 2024 (suppl 16; abstr 2032).
InFo ONKOLOGIE & HÄMATOLOGIE 2024; 12(3): 20-21 (published on 3.7.24, ahead of print)
