Eyre TA, Cwynarski K, d'Amore F
… +13 more, de Leval L, Dreyling M, Eichenauer DA, Ferreri AJM, Giné E, Kersten MJ, Ladetto M, Specht L, Thieblemont C, Walewski J, Zucca E, Jerkeman M, ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org
Graeser M, Gluz O, Zu Eulenburg C
… +24 more, Kuemmel S, von Schumann R, Christgen M, Wuerstlein R, Pelz E, Kreipe HH, Schmid P, Thill M, Braun M, Potenberg J, Schumacher C, Tio J, Schumacher J, Wujak L, Hartkopf AD, Just M, Schem C, Luedtke-Heckenkamp K, Hilpert F, Kentsch A, Kates RE, Nitz U, Harbeck N, West German Study Group investigators
BACKGROUND: We analyzed outcomes and survival predictors in three West German Study Group (WSG) randomized de-escalation trials (ADAPT-HR-/HER2+, ADAPT-TP, TP-II) in human epidermal growth factor receptor 2 (HER2)-positi...BACKGROUND: We analyzed outcomes and survival predictors in three West German Study Group (WSG) randomized de-escalation trials (ADAPT-HR-/HER2+, ADAPT-TP, TP-II) in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (eBC) investigating short (12-week) neoadjuvant treatments with or without chemotherapy. PATIENTS AND METHODS: A total of 713 patients were analyzed; neoadjuvant chemotherapy (paclitaxel plus pertuzumab plus trastuzumab): n = 149, neoadjuvant chemotherapy-free (pertuzumab plus trastuzumab, trastuzumab-only)/antibody-drug conjugate (ADC, trastuzumab emtansine) treatment: n = 564. Patients with pathological complete response (pCR, ypT0/is ypN0) were allowed to omit further chemotherapy; chemotherapy was mandatory after non-pCR. The primary endpoint of each trial was pCR; survival was the secondary endpoint. Survival was analyzed using the Kaplan-Meier method and Cox regression. RESULTS: Median follow-up was 60.7 months. In total, 10 (7%) and 74 (13%) invasive disease-free survival (iDFS) events, 8 (5%) and 51 (9%) distant DFS (dDFS) events, and 6 (4%) and 34 (6%) deaths occurred in the neoadjuvant chemotherapy and chemotherapy-free/ADC groups, respectively; the respective 5-year survival rates were 96% [95% confidence interval (CI) 92% to 99%] and 88% (95% CI 85% to 91%) for iDFS (hazard ratio 0.56, 95% CI 0.29-1.08, P = 0.083) and 98% (95% CI 93% to 99%) and 97% (95% CI 95% to 98%) for overall survival (hazard ratio 0.88, 95% CI 0.36-2.11, P = 0.775). The 5-year iDFS rates in patients with pCR were 98% (95% CI 91% to 99%) after chemotherapy and 94% (95% CI 89% to 97%) after chemotherapy-free/ADC treatment (hazard ratio 0.76, 95% CI 0.27-2.12, P = 0.609). iDFS was comparable between patients with and without adjuvant chemotherapy after pCR to chemotherapy-free/ADC treatment (hazard ratio 1.25, 95% CI 0.39-4.00, P = 0.712). In multivariable analysis, node-negative status and pCR were favorably associated with iDFS in the chemotherapy-free/ADC group. CONCLUSIONS: This pooled analysis demonstrates that neoadjuvant de-escalation trials with further pCR-adapted treatment (de-)escalation are feasible and appear safe for HER2-positive eBC patients. Twelve-weekly neoadjuvant paclitaxel plus HER2 blockade is effective and well tolerated. Neoadjuvant chemotherapy-free/ADC treatments can be viable alternatives for stage I-II eBC. Excellent survival after pCR to neoadjuvant chemotherapy-free/ADC treatment lays the groundwork for further de-escalation strategies.
BACKGROUND: Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate treatment for multiple solid tumors, carries risk of interstitial lung disease/pneumonitis (ILD). Management guidelines generally mandate interruptin...BACKGROUND: Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate treatment for multiple solid tumors, carries risk of interstitial lung disease/pneumonitis (ILD). Management guidelines generally mandate interrupting T-DXd treatment for grade 1 ILD, with possible retreatment following resolution of imaging findings. This pooled analysis examined T-DXd retreatment duration and ILD recurrence following recovery from grade 1 ILD. PATIENTS AND METHODS: Data were pooled from nine clinical trials of patients with various human epidermal growth factor receptor 2 (HER2)-positive, HER2-low, or HER2 (ERBB2)-mutant solid tumors treated with T-DXd (5.4-8.0 mg/kg). ILD events were reported and graded by investigators and confirmed as drug related by an independent ILD adjudication committee. Patients who recovered from a first investigator-assessed grade 1 and adjudication committee-confirmed drug-related ILD event (ILD1) could receive T-DXd retreatment. Patients were evaluated until disease progression or data cut-off. RESULTS: Among 2145 pooled patients, 9% (193/2145) had grade 1 ILD1, of which 23.3% (45/193) were retreated with T-DXd. Median retreatment duration was 85 days (range 1-848 days); 17.8% (8/45) of patients received T-DXd retreatment for ≥1 year. ILD recurrence (ILD2) occurred in 33.3% (15/45) of retreated patients; median time to ILD2 from T-DXd retreatment was 64 days (range, 22-391 days) and were low-grade events (grade 1, n = 6; grade 2, n = 9; no grade ≥3 or fatal events). Reasons for T-DXd retreatment discontinuation were disease progression [33.3% (15/45)]; ILD recurrence [20% (9/45)]; non-ILD adverse events [17.8% (8/45)]; and physician's decision [4.4% (2/45)]. At the analysis cut-off, 24.4% (11/45) of retreated patients were still receiving treatment, and most patients with ILD2 [60% (9/15)] had recovered with/without sequelae. CONCLUSIONS: This first large-scale pooled analysis demonstrates the safety of T-DXd retreatment after recovery from grade 1 ILD. ILD recurred in one-third of patients; all recurrence events were grade 1/2 and manageable using existing treatment guidelines. T-DXd retreatment following resolution of grade 1 drug-related ILD has potential to maximize therapeutic benefit.
Cancer of unknown primary site (CUP) is a syndrome of many different metastatic cancers arising from clinically occult primary tumors. There has been no established staging system applicable since it has not been possibl...Cancer of unknown primary site (CUP) is a syndrome of many different metastatic cancers arising from clinically occult primary tumors. There has been no established staging system applicable since it has not been possible to identify an anatomical primary tumor. In recent years, the globally accepted American Joint Committee on Cancer TNM (tumor-node-metastasis) staging manuals briefly addressed a few rare CUP subsets with highly suspected primary tumors (breast, oropharynx, nasopharynx, melanoma) that could be designated as primary category T0 (no evidence of primary tumor). Similar logic may now be applied to many other patients and TNM staging is an evolving narrative. Diagnostic pathology, particularly immunohistochemical staining and molecular testing, interpreted in the context of clinical features are now capable of diagnosing presumptive occult primaries with reasonable certainty in many other patients creating an avenue for a T0 category as a specific cancer type. This new diagnostic paradigm of lifting the veil of the unknown for some patients and separating them from the historical nondescript CUP diagnosis allows for TNM staging, precision site-specific therapy (SST), prognostication, evaluating treatment results and continuing investigation. Once the tumor type is unmasked and staged, additional molecular characterization and SST are indicated. Many CUP subsets now meet these criteria and considerable clinical trial data have revealed that their outcomes from SST appear superior to empiric chemotherapy and similar to their counterparts with overt primary tumors, although additional prospective comparative studies are warranted. Eventually most of the cancers responsible for the enigmatic CUP syndrome will be identified, making CUP an irrelevant clinical entity.
BACKGROUND: Invasive lobular carcinoma (ILC) is the second most common type of breast cancer and is increasingly recognized as a separate entity from invasive breast cancer of no-special type. Here, we present the curren...BACKGROUND: Invasive lobular carcinoma (ILC) is the second most common type of breast cancer and is increasingly recognized as a separate entity from invasive breast cancer of no-special type. Here, we present the current standings and challenges of clinical ILC research and discuss possible solutions to address these challenges. DESIGN: European and United States experts on ILC have summarized the recent developments, ongoing endeavors and remaining challenges concerning the histopathological diagnosis, imaging and treatment of ILC. RESULTS: Recent endeavors have led to guidelines for a more uniform and standardized pathological diagnosis of ILC. Future efforts are needed to refine the histological and biological subclassification and determine the indications for use of artificial intelligence for pathological diagnosis. Since standard-of-care imaging tools are suboptimal for ILC screening and local and systemic staging, new modalities such as contrast-enhanced mammography, novel positron emission tomography tracers and diffusion-weighted magnetic resonance imaging are under investigation. An alternative to the currently used RECIST v1.1 criteria is needed for clinical trial response assessment, as it is not uniformly applicable for patients with metastatic ILC. The use of liquid biopsies for detecting disease progression needs dedicated research. Regarding treatment, the efficacy of novel breast cancer therapies needs to be examined specifically for ILC, and evaluation of drugs targeting ILC-specific or enriched targets is warranted. CONCLUSIONS: While great progress has been made in ILC research, many challenges remain and require further investigation in the clinic to optimize treatment and outcomes for those diagnosed with this common tumor type.
Jones C, Dutey-Magni P, Murphy LR
… +18 more, Murray ML, Brown JE, McCloskey E, Brown M, Amos CL, Gilbert DC, Jones RJ, Cross W, Matheson D, Millman R, Parmar MKB, Attard G, Sydes MR, Brown LC, James ND, Clarke NW, Sachdeva A, STAMPEDE Trial Investigators
BACKGROUND: Androgen deprivation therapy (ADT), the mainstay systemic treatment for high risk non-metastatic (M0) and metastatic (M1) prostate cancer is associated with bone loss and increased fracture risk. The STAMPEDE...BACKGROUND: Androgen deprivation therapy (ADT), the mainstay systemic treatment for high risk non-metastatic (M0) and metastatic (M1) prostate cancer is associated with bone loss and increased fracture risk. The STAMPEDE trial tested the addition of zoledronic acid (ZA) ± docetaxel (with prednisolone) to ADT. Both regimens may impact bone health. However, long-term fracture incidence remains uncertain. PATIENTS AND METHODS: Health systems data were obtained for patients recruited from England and randomised to standard-of-care (SOC) ADT compared with SOC plus ZA or docetaxel or both docetaxel and ZA. ICD10 diagnosis and OPCS procedure codes from inpatient hospital admissions were used to identify fracture-related hospitalisations. Flexible parametric competing risks models were used to estimate 5- and 10-year cumulative incidence and sub-distribution hazard ratios (SDHR). RESULTS: 2140 of 2705 (79%) patients recruited from trial sites in England were eligible for this secondary analysis. Linked data were available for 2042/2140 (96%) pts (734 M0, 1308 M1). 5-year cumulative incidence of fracture for M0 and M1 patients treated with SOC only was 11% [95% confidence interval (CI), 8% to 15%] and 23% (95% CI, 19% to 28%), respectively. 10-year cumulative incidence in M0 patients was 26% (95% CI, 20% to 33%). Allocation to ZA significantly reduced the risk of fracture in M1 patients (SDHR 0.73, 95% CI 0.55-0.97; P = 0.015) but not M0 patients (SDHR 0.88, 95% CI 0.59-1.32; P = 0.549). Docetaxel had no clear effect on the risk of fracture in M0 (P = 0.570) or M1 (P = 0.264) patients. CONCLUSIONS: High cumulative incidence of fracture was observed in both M0 and M1 prostate cancer patients receiving ADT. The addition of ZA to ADT ± docetaxel significantly reduced long-term fracture risk in M1 participants but had no clear effect in M0 disease. These data support the use of bone protective agents to reduce fracture risk in men with M1 prostate cancer undergoing ADT.
BACKGROUND: In PSMAfore, [Lu]Lu-PSMA-617 (Lu-PSMA-617) prolonged radiographic progression-free survival (rPFS) in taxane-naive patients with metastatic castration-resistant prostate cancer (mCRPC), with a favourable safe...BACKGROUND: In PSMAfore, [Lu]Lu-PSMA-617 (Lu-PSMA-617) prolonged radiographic progression-free survival (rPFS) in taxane-naive patients with metastatic castration-resistant prostate cancer (mCRPC), with a favourable safety profile, versus a change in androgen receptor pathway inhibitor (ARPI). We report the final overall survival (OS) analysis and updated safety data. PATIENTS AND METHODS: PSMAfore (NCT04689828) was an open-label, international, phase III trial. Patients with prostate-specific membrane antigen (PSMA)-positive mCRPC who had experienced disease progression once on a previous ARPI and were candidates for ARPI change were randomized 1 : 1 to Lu-PSMA-617 or ARPI change to abiraterone or enzalutamide. Crossover from ARPI change to Lu-PSMA-617 was allowed after centrally confirmed radiographic progression. Endpoints included rPFS (primary), OS (key secondary), and safety (secondary). RESULTS: Patients were randomized to Lu-PSMA-617 or ARPI change (n = 234 each): 141/234 participants (60.3%) randomized to ARPI change crossed over (75.4% of those with centrally confirmed radiographic progression). The median OS was 24.48 months [95% confidence interval (CI) 19.55-28.94 months] with Lu-PSMA-617 versus 23.13 months (95% CI 19.61-25.53 months) with ARPI change [hazard ratio (HR) 0.91, 95% CI 0.72-1.14, P = 0.20] based on the intention-to-treat (ITT) principle; the crossover-adjusted OS HR by inverse probability of censoring weighting modelling was 0.59 (95% CI 0.38-0.91). For Lu-PSMA-617 versus ARPI change, exposure-adjusted incidences of grade ≥3 and serious treatment-emergent adverse events were 60.8 versus 85.1 and 32.5 versus 49.9 per 100 patient-treatment years, respectively. Dry mouth occurred in 135/227 participants (59.5%; 2/227 grade ≥3) and anaemia in 62/227 (27.3%; 14/227 grade ≥3) in the Lu-PSMA-617 arm. CONCLUSIONS: OS analyses did not show a statistically significant difference between the Lu-PSMA-617 and ARPI arms based on the ITT principle; results were likely confounded by the high rate of crossover. The safety profile of Lu-PSMA-617 was favourable with no new safety signals identified.
Zumsteg ZS, Luu M, Fortpied C
… +14 more, Jang JK, Chen MM, Mallen-St Clair J, Walgama E, Le QT, Machtay M, Tribius S, Forastiere A, Wong S, Ozsahin EM, Gregoire V, Vermorken JB, Ho AS, Yom SS
BACKGROUND: Post-operative chemoradiation (CRT) is generally recommended for head and neck cancer patients with extranodal extension (ENE) and/or positive margins, but not for patients without these features, based on a...BACKGROUND: Post-operative chemoradiation (CRT) is generally recommended for head and neck cancer patients with extranodal extension (ENE) and/or positive margins, but not for patients without these features, based on a post hoc analysis of Radiation Therapy Oncology Group (RTOG) 9501 and European Organisation for Research and Treatment of Cancer (EORTC) 22931. However, this analysis lacked tests of interaction necessary to identify a predictive biomarker. In addition, updated data are now available. PATIENTS AND METHODS: This study assessed 744 patients enrolled on RTOG 9501 and EORTC 22931, randomized trials that compared CRT with radiation (RT) following surgery. Overall survival (OS) was analyzed with Cox regression. Cancer-specific mortality (CSM), other-cause mortality (OCM), and recurrence outcomes were analyzed with competing risks methodology. Tests of interaction assessed for differential benefits of CRT in various subgroups. RESULTS: Median follow-up was 6.9 years. Among all patients, CRT improved OS [hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.68-0.97, P = 0.026]. Although CRT improved OS in the subgroup with ENE and/or positive margins (HR 0.71, 95% CI 0.57-0.89, P = 0.003) and not in those without these features (HR 0.94, 95% CI 0.68-1.30, P = 0.7), tests of interaction showed no evidence of a differential effect of CRT in these subgroups (P-interaction = 0.17). There was also no evidence of interaction when analyzing other outcomes, or when assessing ENE and margin status individually. While CRT significantly reduced CSM (HR 0.68, 95% CI 0.55-0.83, P < 0.001), it also significantly increased OCM (HR 1.51, 95% CI 1.07-2.12, P = 0.018). Post-operative CRT improved locoregional recurrence (HR 0.64, 95% CI 0.48-0.85, P = 0.002), but not distant metastasis (HR 0.83, 95% CI 0.64-1.08, P = 0.17). CONCLUSIONS: Concurrent chemotherapy improved OS in head and neck cancer patients undergoing post-operative radiotherapy in the combined populations of EORTC 22931 and RTOG 9501. ENE and/or positive margins are not predictive biomarkers, and patients without these features may still benefit from CRT. CRT improved CSM, but this was partly offset by higher OCM. Refining the population most likely to benefit from post-operative CRT, taking into consideration both oncologic and patient-related factors, needs further exploration.