Breast Cancer Treatment: A Review Waks, Adrienne G; Winer, Eric P
JAMA : the journal of the American Medical Association,
01/2019, Volume:
321, Issue:
3
Journal Article
Peer reviewed
IMPORTANCE: Breast cancer will be diagnosed in 12% of women in the United States over the course of their lifetimes and more than 250 000 new cases of breast cancer were diagnosed in the United ...States in 2017. This review focuses on current approaches and evolving strategies for local and systemic therapy of breast cancer. OBSERVATIONS: Breast cancer is categorized into 3 major subtypes based on the presence or absence of molecular markers for estrogen or progesterone receptors and human epidermal growth factor 2 (ERBB2; formerly HER2): hormone receptor positive/ERBB2 negative (70% of patients), ERBB2 positive (15%-20%), and triple-negative (tumors lacking all 3 standard molecular markers; 15%). More than 90% of breast cancers are not metastatic at the time of diagnosis. For people presenting without metastatic disease, therapeutic goals are tumor eradication and preventing recurrence. Triple-negative breast cancer is more likely to recur than the other 2 subtypes, with 85% 5-year breast cancer–specific survival for stage I triple-negative tumors vs 94% to 99% for hormone receptor positive and ERBB2 positive. Systemic therapy for nonmetastatic breast cancer is determined by subtype: patients with hormone receptor–positive tumors receive endocrine therapy, and a minority receive chemotherapy as well; patients with ERBB2-positive tumors receive ERBB2-targeted antibody or small-molecule inhibitor therapy combined with chemotherapy; and patients with triple-negative tumors receive chemotherapy alone. Local therapy for all patients with nonmetastatic breast cancer consists of surgical resection, with consideration of postoperative radiation if lumpectomy is performed. Increasingly, some systemic therapy is delivered before surgery. Tailoring postoperative treatment based on preoperative treatment response is under investigation. Metastatic breast cancer is treated according to subtype, with goals of prolonging life and palliating symptoms. Median overall survival for metastatic triple-negative breast cancer is approximately 1 year vs approximately 5 years for the other 2 subtypes. CONCLUSIONS AND RELEVANCE: Breast cancer consists of 3 major tumor subtypes categorized according to estrogen or progesterone receptor expression and ERBB2 gene amplification. The 3 subtypes have distinct risk profiles and treatment strategies. Optimal therapy for each patient depends on tumor subtype, anatomic cancer stage, and patient preferences.
Pembrolizumab showed durable antitumour activity and manageable safety in metastatic triple-negative breast cancer in the single-arm KEYNOTE-012 and KEYNOTE-086 trials. In this study, we compared ...pembrolizumab with chemotherapy for second-line or third-line treatment of patients with metastatic triple-negative breast cancer.
KEYNOTE-119 was a randomised, open-label, phase 3 trial done at 150 medical centres (academic medical centres, community cancer centres, and community hospitals) in 31 countries. Patients aged 18 years or older, with centrally confirmed metastatic triple-negative breast cancer, Eastern Cooperative Oncology Group performance status of 0 or 1, who had received one or two previous systemic treatments for metastatic disease, had progression on their most recent therapy, and had previous treatment with an anthracycline or taxane were eligible. Patients were randomly assigned (1:1) using a block method (block size of four) and an interactive voice-response system with integrated web-response to receive intravenous pembrolizumab 200 mg once every 3 weeks for 35 cycles (pembrolizumab group), or to single-drug chemotherapy per investigator's choice of capecitabine, eribulin, gemcitabine, or vinorelbine (60% enrolment cap for each; chemotherapy group). Randomisation was stratified by PD-L1 tumour status (positive combined positive score (CPS) ≥1 vs negative CPS <1) and history of previous neoadjuvant or adjuvant treatment versus de-novo metastatic disease at initial diagnosis. Primary endpoints were overall survival in participants with a PD-L1 combined positive score (CPS) of 10 or more, those with a CPS of 1 or more, and all participants; superiority of pembrolizumab versus chemotherapy was tested in all participants only if shown in those with a CPS of one or more. The primary endpoint was analysed in the intention-to-treat population; safety was analysed in the all-subjects-as-treated population. This Article describes the final analysis of the trial, which is now completed. This trial is registered with ClinicalTrials.gov, number NCT02555657.
From Nov 25, 2015, to April 11, 2017, 1098 participants were assessed for eligibility and 622 (57%) were randomly assigned to receive either pembrolizumab (312 50%) or chemotherapy (310 50%). Median study follow-up was 31·4 months (IQR 27·8–34·4) for the pembrolizumab group and 31·5 months (27·8–34·6) for the chemotherapy group. Median overall survival in patients with a PD-L1 CPS of 10 or more was 12·7 months (95% CI 9·9–16·3) for the pembrolizumab group and 11·6 months (8·3–13·7) for the chemotherapy group (hazard ratio HR 0·78 95% CI 0·57–1·06; log-rank p=0·057). In participants with a CPS of 1 or more, median overall survival was 10·7 months (9·3–12·5) for the pembrolizumab group and 10·2 months (7·9–12·6) for the chemotherapy group (HR 0·86 95% CI 0·69–1·06; log-rank p=0·073). In the overall population, median overall survival was 9·9 months (95% CI 8·3–11·4) for the pembrolizumab group and 10·8 months (9·1–12·6) for the chemotherapy group (HR 0·97 95% CI 0·82–1·15). The most common grade 3–4 treatment-related adverse events were anaemia (three 1% patients in the pembrolizumab group vs ten 3% in the chemotherapy group), decreased white blood cells (one <1% vs 14 5%), decreased neutrophil count (one <1% vs 29 10%), and neutropenia (0 vs 39 13%). 61 (20%) patients in the pembrolizumab group and 58 (20%) patients in the chemotherapy group had serious adverse events. Three (<1%) of 601 participants had treatment-related adverse events that led to death (one <1% in the pembrolizumab group due to circulatory collapse; two 1% in the chemotherapy group, one <1% due to pancytopenia and sepsis and one <1% haemothorax).
Pembrolizumab did not significantly improve overall survival in patients with previously treated metastatic triple-negative breast cancer versus chemotherapy. These findings might inform future research of pembrolizumab monotherapy for selected subpopulations of patients, specifically those with PD-L1-enriched tumours, and inform a combinatorial approach for the treatment of patients with metastatic triple-negative breast cancer.
Merck Sharp & Dohme.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Triple-negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. BET bromodomain inhibitors, which have shown efficacy in several ...models of cancer, have not been evaluated in TNBC. These inhibitors displace BET bromodomain proteins such as BRD4 from chromatin by competing with their acetyl-lysine recognition modules, leading to inhibition of oncogenic transcriptional programs. Here we report the preferential sensitivity of TNBCs to BET bromodomain inhibition in vitro and in vivo, establishing a rationale for clinical investigation and further motivation to understand mechanisms of resistance. In paired cell lines selected for acquired resistance to BET inhibition from previously sensitive TNBCs, we failed to identify gatekeeper mutations, new driver events or drug pump activation. BET-resistant TNBC cells remain dependent on wild-type BRD4, which supports transcription and cell proliferation in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify strong association with MED1 and hyper-phosphorylation of BRD4 attributable to decreased activity of PP2A, identified here as a principal BRD4 serine phosphatase. Together, these studies provide a rationale for BET inhibition in TNBC and present mechanism-based combination strategies to anticipate clinical drug resistance.
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IJS, KISLJ, NUK, SBMB, UL, UM, UPUK
Abstract
Background
Understanding the impact of the tumor immune microenvironment and BRCA1/2-related DNA repair deficiencies on the clinical activity of immune checkpoint inhibitors may help ...optimize both patient and treatment selection in metastatic triple-negative breast cancer. In this substudy from the phase 3 IMpassion130 trial, immune biomarkers and BRCA1/2 alterations were evaluated for association with clinical benefit with atezolizumab and nab-paclitaxel (A+nP) vs placebo and nP in unresectable (P+nP) locally advanced or metastatic triple-negative breast cancer.
Methods
Patients were randomly assigned 1:1 to nab-paclitaxel 100 mg/m2 (days 1, 8, and 15 of a 28-day cycle) and atezolizumab 840 mg every 2 weeks or placebo until progression or toxicity. Progression-free survival and overall survival were evaluated based on programmed death-ligand 1 (PD-L1) expression on immune cells (IC) and tumor cells, intratumoral CD8, stromal tumor-infiltrating lymphocytes, and BRCA1/2 mutations.
Results
PD-L1 IC+ in either primary or metastatic tumor tissue was linked to progression-free survival and overall survival benefit with A+nP. PD-L1 IC+ low (26.9%; 243 of 902 patients) and high (13.9%; 125 of 902 patients) populations had improved outcomes that were comparable. Intratumoral CD8 and stromal tumor-infiltrating lymphocytes positivity (sTIL+) were associated with PD-L1 IC+ status; improved outcomes were observed with A+nP vs P+nP only in CD8+ and sTIL+ patients who were also PD-L1 IC+. BRCA1/2 mutations (occurring in 14.5% 89 of 612 patients) were not associated with PD-L1 IC status, and PD-L1 IC+ patients benefited from A+nP regardless of BRCA1/2 mutation status.
Conclusions
Although A+nP was more efficacious in patients with richer tumor immune microenvironment, clinical benefit was only observed in patients whose tumors were PD-L1 IC+.
Trastuzumab emtansine (T-DM1) is a novel HER2-directed antibody-drug conjugate. T-DM1 consists of the potent antimicrotubule agent DM1, linked via a noncleavable linker to the HER2-specific ...monoclonal antibody trastuzumab. Preclinical studies demonstrate that T-DM1 has dual mechanisms of action: selective delivery of DM1 to the HER2-positive (HER2(+)) tumor cell combined with trastuzumab's activation of antibody-dependent cell-mediated cytotoxicity and inhibition of HER2-mediated signal transduction. In phase II studies, T-DM1 was active in patients with trastuzumab- and lapatinib-refractory metastatic breast cancer and led to improved progression-free survival compared with the combination of trastuzumab and docetaxel in the first-line setting. In a recent phase III trial in patients with metastatic breast cancer who previously received trastuzumab and a taxane, T-DM1 resulted in improved progression-free and overall survival compared with capecitabine and lapatinib. T-DM1 is associated with a favorable toxicity profile; reversible thrombocytopenia and hepatic transaminase elevations are the only grade ≥3 adverse event present in 5% or more of patients. Alopecia, peripheral neuropathy, and neutropenia are distinctly uncommon. On the basis of its improved efficacy and toxicity compared with capecitabine/lapatinib, T-DM1 should be considered the standard for patients with HER2(+) metastatic breast cancer who have previously progressed on trastuzumab and a taxane. Results from additional randomized studies in metastatic breast cancer are pending, and trials in the (neo)adjuvant setting are being initiated.
Secondary acute myeloid leukemia (sAML) is a complex diagnosis that includes AML caused by either an antecedent hematologic disease (AML-AHD) or from previous treatment with chemotherapy or ...radiation. This disease carries a poor prognosis and is historically chemorefractory; additionally, often patients are ineligible for standard chemotherapy because of advanced age and other comorbidities. The advances of molecular diagnostics and reclassification of World Health Organization criteria have aided in the categorization of this disease. This article describes the etiology and pathophysiology of sAML, and delves into past successful treatments as well as promising new treatments.
At 8 years of follow-up, premenopausal women with breast cancer had higher rates of disease-free and overall survival with the addition of ovarian suppression to antiestrogen therapy and a higher ...rate of hormonal side effects than with tamoxifen alone.
Immunotherapy in combination with chemotherapy has shown promising efficacy across many different tumour types. We report the prespecified second interim overall survival analysis of the phase 3 ...IMpassion130 study assessing the efficacy and safety of atezolizumab plus nab-paclitaxel in patients with unresectable, locally advanced or metastatic triple-negative breast cancer.
In this randomised, placebo-controlled, double-blind, phase 3 trial, done in 246 academic centres and community oncology practices in 41 countries, patients aged 18 years or older, with previously untreated, histologically documented, locally advanced or metastatic triple-negative breast cancer, and Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) using a permuted block method (block size of four) and an interactive voice–web response system. Randomisation was stratified by previous taxane use, liver metastases, and PD-L1 expression on tumour-infiltrating immune cells. Patients received atezolizumab 840 mg or matching placebo intravenously on day 1 and day 15 of every 28-day cycle and nab-paclitaxel 100 mg/m2 of body surface area intravenously on days 1, 8, and 15 until progression or unacceptable toxicity. Investigators, patients, and the funder were masked to treatment assignment. Coprimary endpoints were investigator-assessed progression-free survival per Response Evaluation Criteria in Solid Tumors version 1.1 and overall survival, assessed in the intention-to-treat population and in patients with PD-L1 immune cell-positive tumours (tumours with ≥1% PD-L1 expression). The final progression-free survival results were previously reported at the first interim overall survival analysis. The prespecified statistical testing hierarchy meant that overall survival in the subgroup of PD-L1 immune cell-positive patients could only be formally tested if overall survival was significantly different between the treatment groups in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02425891.
Between June 23, 2015, and May 24, 2017, 902 patients were enrolled, of whom 451 were randomly assigned to receive atezolizumab plus nab-paclitaxel and 451 were assigned to receive placebo plus nab-paclitaxel (the intention-to-treat population). Six patients from each group did not receive treatment. At the second interim analysis (data cutoff Jan 2, 2019), median follow-up was 18·5 months (IQR 9·6–22·8) in the atezolizumab group and 17·5 months (8·4–22·4) in the placebo group. Median overall survival in the intention-to-treat patients was 21·0 months (95% CI 19·0–22·6) with atezolizumab and 18·7 months (16·9–20·3) with placebo (stratified hazard ratio HR 0·86, 95% CI 0·72–1·02, p=0·078). In the exploratory overall survival analysis in patients with PD-L1 immune cell-positive tumours, median overall survival was 25·0 months (95% CI 19·6–30·7) with atezolizumab versus 18·0 months (13·6–20·1) with placebo (stratified HR 0·71, 0·54–0·94). As of Sept 3, 2018 (the date up to which updated safety data were available), the most common grade 3–4 adverse events were neutropenia (38 8% of 453 patients in the atezolizumab group vs 36 8% of 437 patients in the placebo group), peripheral neuropathy (25 6% vs 12 3%), decreased neutrophil count (22 5% vs 16 4%), and fatigue (17 4% vs 15 3%). Treatment-related deaths occurred in two (<1%) patients in the atezolizumab group (autoimmune hepatitis related to atezolizumab n=1 and septic shock related to nab-paclitaxel n=1) and one (<1%) patient in the placebo group (hepatic failure). No new treatment-related deaths have been reported since the primary clinical data cutoff date (April 17, 2018).
Consistent with the first interim analysis, this second interim overall survival analysis of IMpassion130 indicates no significant difference in overall survival between the treatment groups in the intention-to-treat population but suggests a clinically meaningful overall survival benefit with atezolizumab plus nab-paclitaxel in patients with PD-L1 immune cell-positive disease. However, this positive result could not be formally tested due to the prespecified statistical testing hierarchy. For patients with PD-L1 immune cell-positive metastatic triple-negative breast cancer, atezolizumab plus nab-paclitaxel is an important therapeutic option in a disease with high unmet need.
F Hoffmann-La Roche and Genentech.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Positive interim analysis findings from four large adjuvant trials evaluating trastuzumab in patients with early-stage human epidermal growth factor receptor 2 (HER2) -positive breast cancer were ...first reported in 2005. One of these reports, the joint analysis of North Central Cancer Treatment Group NCCTG N9831 (Combination Chemotherapy With or Without Trastuzumab in Treating Women With HER2-Overexpressing Breast Cancer) and the National Surgical Adjuvant Breast and Bowel Project NSABP B-31 (Doxorubicin and Cyclophosphamide Plus Paclitaxel With or Without Trastuzumab in Treating Women With Node-Positive Breast Cancer That Overexpresses HER2), was updated in 2011. We now report the planned definitive overall survival (OS) results from this joint analysis along with updates on the disease-free survival (DFS) end point.
In all, 4,046 patients with HER2-positive operable breast cancer were enrolled to receive doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in both trials. The required number of events for the definitive statistical analysis for OS (710 events) was reached in September 2012. Updated analyses of overall DFS and related subgroups were also performed.
Median time on study was 8.4 years. Adding trastuzumab to chemotherapy led to a 37% relative improvement in OS (hazard ratio HR, 0.63; 95% CI, 0.54 to 0.73; P < .001) and an increase in 10-year OS rate from 75.2% to 84%. These results were accompanied by an improvement in DFS of 40% (HR, 0.60; 95% CI, 0.53 to 0.68; P < .001) and increase in 10-year DFS rate from 62.2% to 73.7%. All patient subgroups benefited from addition of this targeted anti-HER2 agent.
The addition of trastuzumab to paclitaxel after doxorubicin and cyclophosphamide in early-stage HER2-positive breast cancer results in a substantial and durable improvement in survival as a result of a sustained marked reduction in cancer recurrence.
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