Patients with metastatic triple-negative breast cancer were treated with standard chemotherapy or the anti–Trop-2 antibody–drug conjugate sacituzumab govitecan. Patients receiving the drug conjugate ...had significantly longer progression-free and overall survival as well as more frequent myelotoxic effects and diarrhea.
Background
The oncologic safety of sentinel lymph node biopsy (SLNB) alone for clinically node-positive (cN1–2) patients who convert to pathologic node-negativity (ypN0) after neoadjuvant ...chemotherapy (NAC) is not well established.
Methods
This study retrospectively identified 244 consecutive patients with a diagnosis of cT1–3cN0–2 breast cancer who underwent NAC followed by SLNB at the authors’ institution between 2013 and 2018. The patients were categorized as clinically node-negative (cN0) or cN1–2 before the onset of NAC, and the Kaplan–Meier method was used to compare locoregional and distant recurrence rates after SLNB alone for ypN0 patients.
Results
Among 244 patients who underwent NAC followed by surgery with SLNB for axillary staging, 112 (45.9%) were cN0 at presentation, whereas 132 (54.5%) had biopsy-proven cN1–2 disease and converted to cN0 after treatment. Of the patients presenting with cN0 disease, 102 (91.1%) were ypN0 on SLNB pathology compared with 60 cN1/2 patients (45.5%;
p
< 0.001). Regional nodal irradiation was administered to 5% of the cN0/ypN0 patients compared with 70.7% of the cN1–2/ypN0 patients (
p
< 0.001). Overall, 211 patients were treated with SLNB alone and had a median follow-up period of 36 months (interquartile range IQR, 24–53 months). For 101 cN0/ypN0 patients who underwent SLNB alone, the 5-year local and regional recurrence rates were respectively 5.7% (95% confidence interval CI, 2.4–13.8) and 1% (95% CI 0.1–7.0). For 58 cN1–2/ypN0 patients who underwent SLNB alone, the 5-year local and regional recurrence rates were respectively 4.1% (95% CI 1.0–15.5) and 0%, with no axillary recurrences noted.
Conclusion
For ypN0 patients, SLNB alone after NAC is associated with low and acceptable short-term axillary recurrence rates. Additional follow-up data from prospective clinical trials are needed to confirm long-term oncologic safety and define optimal local therapy recommendations.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
DNA mismatch repair defects (MMRd) and tumor hypermutation are rare and under-characterized in metastatic prostate cancer (mPC). Furthermore, because hypermutated MMRd prostate cancers can respond to ...immune checkpoint inhibitors, there is an urgent need for practical detection tools.
We analyzed plasma cell-free DNA-targeted sequencing data from 433 patients with mPC with circulating tumor DNA (ctDNA) purity ≥2%. Samples with somatic hypermutation were subjected to 185 × whole-exome sequencing and capture of mismatch repair gene introns. Archival tissue was analyzed with targeted sequencing and IHC.
Sixteen patients (3.7%) had somatic hypermutation with MMRd etiology, evidenced by deleterious alterations in
, or
, microsatellite instability, and characteristic trinucleotide signatures. ctDNA was concordant with mismatch repair protein IHC and DNA sequencing of tumor tissue. Tumor suppressors such as
, and
were inactivated by mutation rather than copy-number loss. Hotspot mutations in oncogenes such as
, and
were common, and the androgen receptor (
)-ligand binding domain was mutated in 9 of 16 patients. We observed high intrapatient clonal diversity, evidenced by subclonal driver mutations and shifts in mutation allele frequency over time. Patients with hypermutation and MMRd etiology in ctDNA had a poor response to AR inhibition and inferior survival compared with a control cohort.
Hypermutated MMRd mPC is associated with oncogene activation and subclonal diversity, which may contribute to a clinically aggressive disposition in selected patients. In patients with detectable ctDNA, cell-free DNA sequencing is a practical tool to prioritize this subtype for immunotherapy.
.
Background
Radium-223, an alpha-emitting therapeutic radiopharmaceutical, prolongs overall survival (OS) in patients with symptomatic bone-predominant metastatic castration-resistant prostate cancer ...(mCRPC). PSMA PET/CT is a molecular imaging tool for whole-body imaging of prostate cancer and may inform on the mechanisms of radium-223 activity and treatment resistance in mCRPC patients.
Methods
In an open-label, single-arm, prospective trial, we enrolled patients with bone-predominant mCRPC to undergo baseline PSMA PET/CT, 6 cycles of radium-223, and post-therapy PSMA PET/CT. We assessed the relationship between multiple parameters of interval change on PSMA PET/CT on aPROMISE PSMA automated analysis and a human reader, and laboratory measurements.
Results
Fourteen patients were enrolled and 9 patients completed both protocol-defined PSMA PET/CT. Of the 9 evaluable patients, 1 (11%) had a complete response and 8 (89%) had PSMA PET progressive disease. All patients showed decreases in PSMA uptake in some disease sites evident on the baseline scan. The change in overall burden of disease on PSMA PET was more strongly correlated with changes in PSA (
ρ
= 0.95) than ALP (
ρ
= 0.62). Progression in bone was a common finding on post-treatment PSMA PET/CT.
Conclusion
PSMA PET was able to assess response in individual lesions during radium-223 therapy in mCRPC patients. PSMA PET responses in previously established disease sites were universal, but most patients also showed overall PSMA PET progression during 6 cycles of radium-223. Given high correlation with changes in PSA, PSMA PET may be of limited value in follow-up during or after radium-223 in bone-predominant mCRPC.
Graphical abstract
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Response to neoadjuvant chemotherapy (NAC) in triple negative breast cancer (TNBC) is highly prognostic and determines whether adjuvant chemotherapy is needed if residual tumor is found at surgery. ...To evaluate the predictive and prognostic values of circulating tumor DNA (ctDNA) in this setting, we analyzed tumor and serial bloods from 26 TNBC patients collected prior, during, and after NAC. Individual digital droplet PCR assays were developed for 121 variants (average 5/patient) identified from tumor sequencing, enabling ctDNA detection in 96% of patients at baseline. Mutant allele frequency at baseline was associated with clinical characteristics. Levels drastically fell after one cycle of NAC, especially in patients whose tumors would go on to have a pathological complete response (pCR), but then rose significantly before surgery in patients with significant residual tumor at surgery (p = 0.0001). The detection of ctDNA early during treatment and also late at the end of NAC before surgery was strongly predictive of residual tumor at surgery, but its absence was less predictive of pCR, especially when only TP53 variants are considered. ctDNA detection at the end of neoadjuvant chemotherapy indicated significantly worse relapse-free survival (HR = 0.29 (95% CI 0.08-0.98), p = 0.046), and overall survival (HR = 0.27 95% CI 0.075-0.96), p = 0.043). Hence, individualized multi-variant ctDNA testing during and after NAC prior to surgery has prognostic and predictive value in early TNBC patients.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The advent of anti-HER2 targeted therapies has dramatically improved the outcome of HER2-positive breast cancer; however, resistance to treatment in the metastatic setting remains a challenge, ...highlighting the need for novel therapies. The arrival of new treatment options and clinical trials examining the efficacy of novel agents may improve outcomes in the metastatic setting, including in patients with brain metastases. In the first-line setting, we can potentially cure a selected number of patients treated with pertuzumab + trastuzumab + taxane. In the second-line setting, clinical trials show that trastuzumab deruxtecan (T-DXd) is a highly effective option, resulting in a shift from trastuzumab emtansine (T-DM1) as the previous standard of care. Moreover, we now have data for patients with brain metastases to show that tucatinib + trastuzumab + capecitabine can improve survival in this higher-risk group and be an effective regimen for all patients in the third-line setting. Finally, we have a number of effective anti-HER2 therapies that can be used in subsequent lines of therapy to improve patient outcomes. This review paper discusses the current treatment options and presents a practical treatment sequencing algorithm in the context of the Canadian landscape.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK, VSZLJ
Although adjuvant trastuzumab improves survival in patients with HER2-positive early breast cancer, there is growing concern about the long-term effect of trastuzumab-induced cardiotoxicity (TIC). We ...retrospectively assessed the incidence of TIC and heart failure (HF) to identify possible risk and protective factors.
Retrospective study.
Institute for Cancer Research and Treatment, Medical Oncology Department.
Consecutive patients who started adjuvant trastuzumab between 2007 and 2010.
Measures TIC was defined as an absolute left ventricular ejection fraction (LVEF) decrease ≥ 15 points from baseline or a LVEF<50%. Logistic regression was used to estimate OR and their 95% CI in order to evaluate the risk of TIC, considering potential cardiac risk factors (hypertension, hypercholesterolaemia, diabetes mellitus, smoke, cardiac ischaemia and previous chest radiotherapy) and protective factors (β-blockers, ACE inhibitors and/or angiotensin receptor blockers).
Among 179 patients, 78 cases of TIC (44%, 95% CI 37% to 51%) and four cases of HF (2%, 95% CI 0% to 4%) were reported. 14 patients stopped trastuzumab as a result of TIC. None of the cardiac risk factors or concomitant cardiovascular medications altered the risk of TIC. A previous cumulative dose >240 mg/m(2) of doxorubicin or >500 mg/m(2) of epirubicin increased the risk of TIC compared with lower doses (OR 3.07; 95% CI 1.29 to 7.27, p=0.0011).
TIC is a frequent, albeit generally mild, adverse event in clinical practice. Further studies are warranted to better define the risk of and protective factors for TIC.
Purpose
Radium-223 has been demonstrated in clinical trials to improve survival in castration-resistant prostate cancer (CRPC) patients with bone metastases. However, its performance in routine use ...remains to be fully characterized. This study aims to describe patient outcomes in the real world as well as identify factors associated with completion of the 6-dose regimen and alkaline phosphatase (ALP) response.
Methods
Thirty-six patients who received at least one dose of radium-223 at the Jewish General Hospital in Montréal, Canada, were analysed in a retrospective manner. Using logistic regression, the primary analysis aimed to identify factors associated with treatment completion, and the secondary analysis aimed to identify factors associated with ALP response.
Results
Twenty-one out of 36 patients received all 6 doses of radium-223. Fifteen patients had an ALP response, defined as a 30% decrease in ALP from baseline values. On primary analysis, baseline ALP > 120 U/L and prostate-specific antigen (PSA) > 50 μg/L were significantly associated with lower therapy completion rates (OR = 0.10,
p
= 0.004; OR = 0.18,
p
= 0.022 respectively). On adjustment for confounders, only ALP remained significant (OR = 0.14,
p
= 0.021). Clinical disease progression was the most common reason for treatment non-completion, and it was also associated with elevated baseline ALP (OR = 6.00,
p
= 0.044). On secondary analysis, previous chemotherapy for CRPC was a negative predictor of ALP response (OR = 0.15,
p
= 0.034).
Conclusion
Elevated baseline ALP and PSA were associated with a lower rate of radium-223 regimen completion; receiving chemotherapy for CRPC prior to radium-223 was associated with a lower rate of ALP response.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
There is an increasing demand for real-world data pertaining to the usage of cancer treatments, especially in settings where no standard treatment is specifically recommended. This study presents the ...first real-world analysis of third-line treatment patterns in HER2-positive metastatic breast cancer (mBC) patients in Canada. The purpose was to assess evolution of clinical practice and identify unmet needs in post-second-line therapy. Retrospective data from medical records of 66 patients who received third-line treatment before 31st October 2018, and data from 56 patients who received third-line treatment after this date, extracted from the Personalize My Treatment (PMT) cancer patient registry, were analyzed. In the first cohort, the study revealed heterogeneity in the third-line setting, with trastuzumab, lapatinib, and T-DM1 being the main treatment options. Even though data were collected before the wide availability of tucatinib, neratinib and trastuzumab deruxtecan in Canada, the PMT cohort revealed the emergence of new therapeutic combinations and a shift from lapatinib usage to T-DM1 choice was observed. These findings underscore the evolving nature of third-line treatment strategies in Canada, a facet that is intrinsically tied to the availability of new drugs. The absence of a consensus on post-second-line treatment highlights the pressing need for more efficient therapeutic alternatives beyond the currently available options. This study not only offers valuable insights into the present landscape of third-line treatment in Canada but validates the significance and effectiveness of the PMT registry as a tool for generating pan-Canadian real-world evidence in oncology and its capacity to provide information on evolution of therapeutic practices.
ObjectivesImmune checkpoint inhibitors (ICIs) are indicated for metastatic urothelial cancer (mUC), but predictive and prognostic factors are lacking. We investigated clinical variables associated ...with ICI outcomes.MethodsWe performed a multicentre retrospective cohort study of 135 patients who received ICI for mUC, 2016–2021, at three Canadian centres. Clinical characteristics, body mass index (BMI), metastatic sites, neutrophil-to-lymphocyte ratio (NLR), response and survival were abstracted from chart review.ResultsWe identified 135 patients and 62% had received ICI as a second-line or later treatment for mUC. A BMI ≥25 was significantly correlated to a higher overall response rate (ORR) (45.4% vs 16.3%, p value=0.020). Patients with BMI ≥30 experienced longer median overall survival (OS) of 24.8 vs 14.4 for 25≤BMI<30 and 8.5 months for BMI <25 (p value=0.012). The ORR was lower in the presence of bone metastases (16% vs 41%, p value=0.006) and liver metastases (16% vs 39%, p value=0.013). Metastatic lymph nodes were correlated with higher ORR (40% vs 20%, p value=0.032). The median OS for bone metastases was 7.3 versus 18 months (p value <0.001). Patients with liver metastases had a median OS of 8.6 versus 15 months (p value=0.006). No difference for lymph nodes metastases (13.5 vs 12.7 months, p value=0.175) was found. NLR ≥4 had worse OS (8.2 vs 17.7 months, p value=0.0001). In multivariate analysis, BMI ≥30, bone metastases, NLR ≥4, performance status ≥2 and line of ICI ≥2 were independent factors for OS.ConclusionsOur data identified BMI and bone metastases as novel clinical biomarkers that were independently associated with ICI outcomes in mUC. External and prospective validation are warranted.
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