Changing frameworks in treatment sequencing of triple-negative and HER2-positive, early-stage breast cancers

Pusztai, Lajos; Foldi, Julia; Dhawan, Arjun; DiGiovanna, Michael P.; Mamounas, Eleftherios P.

doi:10.1016/s1470-2045(19)30158-5

Cited by 68 publications

(54 citation statements)

References 45 publications

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“…Especially for high‐risk patients, such as those in the current study (>96% node‐positive and >40% with at least 4 positive nodes), there is an unmet need despite anti‐HER2 treatment, as indicated by the 10‐year disease‐free survival rates in the HERA trial of 74.5% for patients with 1 to 3 positive nodes and 54.5% for patients with 4 or more positive nodes who received 1 year of adjuvant trastuzumab . Since the demonstration that further adjuvant trastuzumab emtansine improves the prognosis of patients not achieving pathologic complete remission with neoadjuvant chemotherapy, treating patients with locally advanced HER2‐positive disease preoperatively has been recommended . However, real‐world data show that neoadjuvant therapy is vastly underused both in developed countries and in developing countries, and this underscores the value of optimizing adjuvant strategies …”

Section: Discussionmentioning

confidence: 74%

“…22 Since the demonstration that further adjuvant trastuzumab emtansine improves the prognosis of patients not achieving pathologic complete remission with neoadjuvant chemotherapy, 23 treating patients with locally advanced HER2-positive disease preoperatively has been recommended. 23,24 However, real-world data show that neoadjuvant therapy is vastly underused both in developed countries and in developing countries, and this underscores the value of optimizing adjuvant strategies. [25][26][27][28][29] Even though this prespecified analysis is the only report from a phase 3 randomized trial of DD adjuvant chemotherapy in combination with trastuzumab, it must be acknowledged that it suffers from several limitations.…”

Section: Discussionmentioning

confidence: 99%

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Efficacy and safety of tailored and dose‐dense adjuvant chemotherapy and trastuzumab for resected HER2‐positive breast cancer: Results from the phase 3 PANTHER trial

Papakonstantinou

Matikas

Bengtsson³

et al. 2019

Cancer

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Background Dose‐dense (DD) adjuvant chemotherapy improves outcomes in early breast cancer (BC). However, there are no phase 3 randomized data to inform on its combination with trastuzumab for patients with human epidermal growth factor receptor 2 (HER2)–positive disease. Methods This was a protocol‐predefined secondary analysis of the randomized phase 3 Pan‐European Tailored Chemotherapy (PANTHER) trial. Women 65 years old or younger with node‐positive or high‐risk, node‐negative BC were randomized 1:1 to either tailored (according to hematologic nadirs) and DD epirubicin and cyclophosphamide followed by docetaxel or standard 5‐fluorouracil, epirubicin, and cyclophosphamide plus docetaxel every 3 weeks. Patients with HER2‐positive disease received 1 year of adjuvant trastuzumab. The primary endpoint was BC relapse–free survival. In addition, HER2‐positive patients and an equal number of HER2‐negative patients matched for age, treatment group, and institution who were enrolled at Swedish sites were asked to participate in a predefined study of cardiac safety and underwent echocardiography or multigated acquisition scanning and electrocardiography at the baseline and at 4 and 6 years of follow‐up. Results There were 342 HER2‐positive patients; 335 received at least 1 dose of trastuzumab, and 29 patients discontinued trastuzumab prematurely. Relapse‐free survival was not statistically significantly in favor of the tailored and DD group (hazard ratio, 0.68; 95% confidence interval, 0.37‐1.27; P = .231). Cardiac outcomes after 4 and 6 years of follow‐up did not differ significantly between HER2‐positive and HER2‐negative patients or between the 2 treatment groups. Conclusions The combination of DD chemotherapy and trastuzumab decreased the relative risk for relapse by 32% in comparison with standard treatment, a statistically nonsignificant difference. Its efficacy and safety merit further evaluation as part of both escalation and de‐escalation strategies.

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of tailored and dose‐dense adjuvant chemotherapy and trastuzumab for resected HER2‐positive breast cancer: Results from the phase 3 PANTHER trial

Papakonstantinou

Matikas

Bengtsson³

et al. 2019

Cancer

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“…In addition, real-world data from the currently ongoing registries in the advanced setting should also be considered an important source of data to explore this unmet medical need. [26][27][28][29] With the current availability of several effective targeted agents as (neo)adjuvant and post-neoadjuvant treatment for patients with HER2-positive breast cancer, [30][31][32][33][34] defining the optimal performance of first-line anti-HER2 therapies in those relapsing after prior exposure in the early setting is becoming a clinically relevant research area. The present analysis has some limitations that should be acknowledged.…”

Section: Discussionmentioning

confidence: 99%

Prognostic role of distant disease-free interval from completion of adjuvant trastuzumab in HER2-positive early breast cancer: analysis from the ALTTO (BIG 2-06) trial

et al. 2020

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BackgroundIn HER2-positive breast cancer, time elapsed between completion of (neo)adjuvant trastuzumab and diagnosis of metastatic disease (‘trastuzumab-free interval’, TFI) is crucial to choose the optimal first-line treatment. Nevertheless, there is no clear evidence to support its possible prognostic role.MethodsIn the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) trial, patients with HER2-positive early breast cancer were randomised to 1 year of either trastuzumab alone, lapatinib alone, their sequence or their combination. This exploratory analysis included only patients in the trastuzumab alone or trastuzumab plus lapatinib arms who developed a distant disease-free survival (DDFS) event. Overall survival (OS) was defined as time between date of DDFS event and death; age at diagnosis, tumour size and hormone receptor status were the variables included in the multivariate models.ResultsOut of 8381 patients included in ALTTO, 404 patients in the trastuzumab alone and trastuzumab plus lapatinib arms developed a DDFS event, of which 201 occurred <12 months (group A) and 203 >12 months (group B) after completion of adjuvant trastuzumab. No significant difference in location of first DDFS event was observed (p=0.073); a numerically higher number of patients in group A than in group B developed brain metastasis (26% vs 15%). Choice of first-line therapy differed between the two groups (p=0.022): in group A, more patients received lapatinib (25% vs 11%) and less pertuzumab (8% vs 17%). Median OS was 29.3 and 18.4 months in groups B and A, respectively (adjusted HR 0.69; 95% CI 0.54–0.89; p=0.004). The longer OS for patients in group B was observed across the analysed subgroups without interaction according to hormone receptor status (p=0.814) nor type of administered adjuvant anti-HER2 treatment (p=0.233).ConclusionsTFI has prognostic value in patients with HER2-positive early breast cancer treated with adjuvant trastuzumab-based therapy. TFI is a valid tool to better individualise clinical recommendations and to design future first-line treatment trials for metastatic patients.

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“…They lack clinically significant expression of first-line systemic drug therapy targets (estrogen receptor, human epidermal growth factor receptor-2 [HER2]), are typically high-grade, are metabolically active, and often exhibit basal-like and/or mesenchymal phenotypes (Perou et al, 2000;Prat et al, 2010). Cytotoxic chemotherapy is a mainstay of clinical management, but 40-80% of patients still experience distant relapse and premature death, often involving visceral and brain metastases (Fulford et al, 2007;Pusztai et al, 2019). TNBC exhibits considerable molecular and clinical heterogeneity, unsurprising given theirs is a diagnosis of exclusion.…”

Section: Introductionmentioning

confidence: 99%

Tradeoff between metabolic i-proteasome addiction and immune evasion in triple-negative breast cancer

et al. 2020

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In vitro studies have suggested proteasome inhibitors could be effective in triple-negative breast cancer (TNBC). We found that bortezomib and carfilzomib induce proteotoxic stress and apoptosis via the unfolded protein response (UPR) in TNBC cell lines, with sensitivity correlated with expression of immuno-(PSMB8/9/10) but not constitutive-(PSMB5/6/7) proteasome subunits. Equally, the transcriptomes of i-proteasome–high human TNBCs are enriched with UPR gene sets, and the genomic copy number landscape reflects positive selection pressure favoring i-proteasome activity, but in the setting of adjuvant treatment, this is actually associated with favorable prognosis. Tumor expression of PSMB8 protein (β5i) is associated with levels of MHC-I, interferon-γ–inducible proteasome activator PA28β, and the densities of stromal antigen-presenting cells and lymphocytes (TILs). Crucially, TILs were protective among TNBCs that maintain high β5i but did not stratify survival amongst β5i-low TNBCs. Moreover, β5i expression was lower in brain metastases than in patient-matched primary breast tumors (n = 34; P = 0.007), suggesting that suppression contributes to immune evasion and metastatic progression. Hence, inhibiting proteasome activity could be counterproductive in the adjuvant treatment setting because it potentiates anti-TNBC immunity.

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Changing frameworks in treatment sequencing of triple-negative and HER2-positive, early-stage breast cancers

Cited by 68 publications

References 45 publications

Efficacy and safety of tailored and dose‐dense adjuvant chemotherapy and trastuzumab for resected HER2‐positive breast cancer: Results from the phase 3 PANTHER trial

Efficacy and safety of tailored and dose‐dense adjuvant chemotherapy and trastuzumab for resected HER2‐positive breast cancer: Results from the phase 3 PANTHER trial

Prognostic role of distant disease-free interval from completion of adjuvant trastuzumab in HER2-positive early breast cancer: analysis from the ALTTO (BIG 2-06) trial

Tradeoff between metabolic i-proteasome addiction and immune evasion in triple-negative breast cancer

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