Inavolisib-Based Therapy in PIK3CA-Mutated Advanced Breast Cancer.

BACKGROUND: Inavolisib is a highly potent and selective inhibitor of the alpha isoform of the p110 catalytic subunit of the phosphatidylinositol 3-kinase complex (encoded by PIK3CA) that also promotes the degradation of mutated p110α. Inavolisib plus palbociclib-fulvestrant has shown synergistic activity in preclinical models and promising antitumor activity in early-phase trials. METHODS: In a phase 3, double-blind, randomized trial, we compared first-line inavolisib (at an oral dose of 9 mg once daily) plus palbociclib-fulvestrant (inavolisib group) with placebo plus palbociclib-fulvestrant (placebo group) in patients with PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer who had had relapse during or within 12 months after the completion of adjuvant endocrine therapy. The primary end point was progression-free survival as assessed by the investigator. RESULTS: A total of 161 patients were assigned to the inavolisib group and 164 to the placebo group; the median follow-up was 21.3 months and 21.5 months, respectively. The median progression-free survival was 15.0 months (95% confidence interval [CI], 11.3 to 20.5) in the inavolisib group and 7.3 months (95% CI, 5.6 to 9.3) in the placebo group (hazard ratio for disease progression or death, 0.43; 95% CI, 0.32 to 0.59; P<0.001). An objective response occurred in 58.4% of the patients in the inavolisib group and in 25.0% of those in the placebo group. The incidence of grade 3 or 4 neutropenia was 80.2% in the inavolisib group and 78.4% in the placebo group; grade 3 or 4 hyperglycemia, 5.6% and 0%, respectively; grade 3 or 4 stomatitis or mucosal inflammation, 5.6% and 0%; and grade 3 or 4 diarrhea, 3.7% and 0%. No grade 3 or 4 rash was observed. Discontinuation of any trial agent because of adverse events occurred in 6.8% of the patients in the inavolisib group and in 0.6% of those in the placebo group. CONCLUSIONS: In patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer, inavolisib plus palbociclib-fulvestrant led to significantly longer progression-free survival than placebo plus palbociclib-fulvestrant, with a greater incidence of toxic effects. The percentage of patients who discontinued any trial agent because of adverse events was low. (Funded by F. Hoffmann-La Roche; INAVO120 ClinicalTrials.gov number, NCT04191499.).

Capivasertib in Hormone Receptor-Positive Advanced Breast Cancer.

BACKGROUND: AKT pathway activation is implicated in endocrine-therapy resistance. Data on the efficacy and safety of the AKT inhibitor capivasertib, as an addition to fulvestrant therapy, in patients with hormone receptor-positive advanced breast cancer are limited. METHODS: In a phase 3, randomized, double-blind trial, we enrolled eligible pre-, peri-, and postmenopausal women and men with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer who had had a relapse or disease progression during or after treatment with an aromatase inhibitor, with or without previous cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor therapy. Patients were randomly assigned in a 1:1 ratio to receive capivasertib plus fulvestrant or placebo plus fulvestrant. The dual primary end point was investigator-assessed progression-free survival assessed both in the overall population and among patients with AKT pathway-altered (PIK3CA, AKT1, or PTEN) tumors. Safety was assessed. RESULTS: Overall, 708 patients underwent randomization; 289 patients (40.8%) had AKT pathway alterations, and 489 (69.1%) had received a CDK4/6 inhibitor previously for advanced breast cancer. In the overall population, the median progression-free survival was 7.2 months in the capivasertib-fulvestrant group, as compared with 3.6 months in the placebo-fulvestrant group (hazard ratio for progression or death, 0.60; 95% confidence interval [CI], 0.51 to 0.71; P<0.001). In the AKT pathway-altered population, the median progression-free survival was 7.3 months in the capivasertib-fulvestrant group, as compared with 3.1 months in the placebo-fulvestrant group (hazard ratio, 0.50; 95% CI, 0.38 to 0.65; P<0.001). The most frequent adverse events of grade 3 or higher in patients receiving capivasertib-fulvestrant were rash (in 12.1% of patients, vs. in 0.3% of those receiving placebo-fulvestrant) and diarrhea (in 9.3% vs. 0.3%). Adverse events leading to discontinuation were reported in 13.0% of the patients receiving capivasertib and in 2.3% of those receiving placebo. CONCLUSIONS: Capivasertib-fulvestrant therapy resulted in significantly longer progression-free survival than treatment with fulvestrant alone among patients with hormone receptor-positive advanced breast cancer whose disease had progressed during or after previous aromatase inhibitor therapy with or without a CDK4/6 inhibitor. (Funded by AstraZeneca and the National Cancer Institute; CAPItello-291 ClinicalTrials.gov number, NCT04305496.).

Effect of baseline oestradiol serum concentration on the efficacy of anastrozole for preventing breast cancer in postmenopausal women at high risk: a case-control study of the IBIS-II prevention trial.

BACKGROUND: An increased risk of breast cancer is associated with high serum concentrations of oestradiol and testosterone in postmenopausal women, but little is known about how these hormones affect response to endocrine therapy for breast cancer prevention or treatment. We aimed to assess the effects of serum oestradiol and testosterone concentrations on the efficacy of the aromatase inhibitor anastrozole for the prevention of breast cancer in postmenopausal women at high risk. METHODS: In this case-control study we used data from the IBIS-II prevention trial, a randomised, controlled, double-blind trial in postmenopausal women aged 40-70 years at high risk of breast cancer, conducted in 153 breast cancer treatment centres across 18 countries. In the trial, women were randomly assigned (1:1) to receive anastrozole (1 mg/day, orally) or placebo daily for 5 years. In this pre-planned case-control study, the primary analysis was the effect of the baseline oestradiol to sex hormone binding globulin (SHBG) ratio (oestradiol-SHBG ratio) on the development of all breast cancers, including ductal carcinoma in situ (the primary endpoint in the trial). Cases were participants in whom breast cancer was reported after trial entry and until the cutoff on Oct 22, 2019, and who had valid blood samples and no use of hormone replacement therapy within 3 months of trial entry or during the trial. For each case, two controls without breast cancer were selected at random, matched on treatment group, age (within 2 years), and follow-up time (at least that of the matching case). For each treatment group, we applied a multinominal logistic regression likelihood-ratio trend test to assess what change in the proportion of cases was associated with a one-quartile change in hormone ratio. Controls were used only to determine quartile cutoffs. Profile likelihood 95% CIs were used to indicate the precision of estimates. A secondary analysis also investigated the effect of the baseline testosterone-SHBG ratio on breast cancer development. We also assessed relative benefit of anastrozole versus placebo (calculated as 1 - the ratio of breast cancer cases in the anastrozole group to cases in the placebo group). The trial was registered with ISRCTN (number ISRCTN31488319) and completed recruitment on Jan 31, 2012, but long-term follow-up is ongoing. FINDINGS: 3864 women were recruited into the trial between Feb 2, 2003, and Jan 31, 2012, and randomly assigned to receive anastrozole (n=1920) or placebo (n=1944). Median follow-up time was 131 months (IQR 106-156), during which 85 (4·4%) cases of breast cancer in the anastrozole group and 165 (8·5%) in the placebo group were identified. No data on gender, race, or ethnicity were collected. After exclusions, the case-control study included 212 participants from the anastrozole group (72 cases, 140 controls) and 416 from the placebo group (142 cases, 274 controls). A trend of increasing breast cancer risk with increasing oestradiol-SHBG ratio was found in the placebo group (trend per quartile 1·25 [95% CI 1·08 to 1·45], p=0·0033), but not in the anastrozole group (1·06 [0·86 to 1·30], p=0·60). A weaker effect was seen for the testosterone-SHBG ratio in the placebo group (trend 1·21 [1·05 to 1·41], p=0·011), but again not in the anastrozole group (trend 1·18 [0·96 to 1·46], p=0·11). A relative benefit of anastrozole was seen in quartile 2 (0·55 [95% CI 0·13 to 0·78]), quartile 3 (0·54 [0·22 to 0·74], and quartile 4 (0·56 [0·23 to 0·76]) of oestradiol-SHBG ratio, but not in quartile 1 (0·18 [-0·60 to 0·59]). INTERPRETATION: These results suggest that serum hormones should be measured more routinely and integrated into risk management decisions. Measuring serum hormone concentrations is inexpensive and might help clinicians differentiate which women will benefit most from an aromatase inhibitor. FUNDING: Cancer Research UK, National Health and Medical Research Council (Australia), Breast Cancer Research Foundation, and DaCosta Fund.

Capivasertib and fulvestrant for patients with hormone receptor-positive, HER2-negative advanced breast cancer (CAPItello-291): patient-reported outcomes from a phase 3, randomised, double-blind, placebo-controlled trial.

BACKGROUND: CAPItello-291 is an ongoing phase 3 trial in which capivasertib-fulvestrant significantly improved progression-free survival versus placebo-fulvestrant in patients with hormone receptor-positive, HER2-negative advanced breast cancer who had relapse or disease progression during or after aromatase inhibitor treatment, in both the overall population and in patients with PIK3CA, AKT1, or PTEN-altered tumours. This study further explored patient-reported health-related quality of life (HRQOL), functioning, symptoms, and symptom tolerability in CAPItello-291. METHODS: This phase 3, randomised, double-blind, placebo-controlled trial, which was conducted across 193 hospitals and cancer centres in 19 countries, enrolled women with any menopausal status or men, aged ≥18 years (≥20 years in Japan), with hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer who had relapse or disease progression during or after treatment with an aromatase inhibitor, with or without previous cyclin-dependent kinase (CDK) 4 or 6 inhibitor therapy. Patients had an Eastern Cooperative Oncology Group/WHO performance score of 0 or 1 and could have received up to two previous lines of endocrine therapy and up to one previous line of chemotherapy for advanced disease. Patients were randomly assigned (1:1) using block randomisation (stratified according to the presence or absence of liver metastases, previous use of a CDK4/6 inhibitor [yes vs no], and geographical region) to receive oral capivasertib 400 mg (twice daily for 4 days, followed by 3 days off) plus intramuscular fulvestrant 500 mg (every 14 days for the first three injections, then every 28 days) or placebo with matching fulvestrant dosing. The dual primary endpoint of the trial was investigator-assessed progression-free survival assessed both in the overall population and among patients with PIK3CA, AKT1, or PTEN-altered tumours. The EORTC Quality of Life Questionnaire 30-item core module (QLQ-C30) and breast module (QLQ-BR23), Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), and Patient Global Impression of Treatment Tolerability (PGI-TT) questionnaires were used to assess patient-reported outcomes. Evaluation of EORTC QLQ-C30 and EORTC QLQ-BR23 were secondary endpoints and evaluation of PRO-CTCAE and PGI-TT were pre-defined exploratory endpoints, and these endpoints are the subject of analysis in this Article. Data were collected at baseline and prespecified timepoints. Patient-reported outcomes were analysed in all randomly assigned patients with an evaluable baseline assessment and at least one evaluable post-baseline assessment. Change from baseline was assessed using mixed model with repeated measures for EORTC QLQ-C30 and summarised for QLQ-BR23. Time to deterioration was described using the Kaplan-Meier method. PGI-TT and PRO-CTCAE responses were summarised at each treatment cycle. Patient-reported outcomes were not prospectively powered for statistical comparison. The trial is registered with ClinicalTrials.gov, NCT04305496. FINDINGS: Between June 2, 2020, and Oct 13, 2021, 901 patients were enrolled, of whom 708 patients were randomly assigned to receive capivasertib-fulvestrant (n=355) or placebo-fulvestrant (n=353). The median age of the patients was 59 years (IQR 51-67) in the capivasertib-fulvestrant group and 58 years (IQR 49-66) in the placebo-fulvestrant group. At data cutoff (Aug 15, 2022), the median duration of follow-up for progression-free survival in censored patients was 13·0 months (IQR 9·1-16·7) for capivasertib-fulvestrant and 12·7 months (IQR 2·0-16·4) for placebo-fulvestrant in the overall population. EORTC QLQ-C30 global health status/quality of life (GHS/QOL) scores were maintained from baseline and were similar between treatment groups throughout the study period (difference in mean change from baseline of -2·5 [95% CI -4·5 to -0·6] with capivasertib-fulvestrant vs -5·6 [-7·9 to -3·4] with placebo-fulvestrant; treatment difference 3·1 [95% CI 0·2 to 6·0]). Median time to deterioration in EORTC QLQ-C30 GHS/QOL was 24·9 months (95% CI 13·8 to not reached) in the capivasertib-fulvestrant group and 12·0 months (10·2 to 15·7) in the placebo-fulvestrant group (hazard ratio [HR] 0·70, 95% CI 0·53 to 0·92). Time to deterioration HRs for all EORTC QLQ-C30 and QLQ-BR23 subscale scores showed little difference between the treatment groups, except for diarrhoea, which was worse in the capivasertib-fulvestrant group than in the placebo-fulvestrant group (HR 2·75, 95% CI 2·01-3·81). In PRO-CTCAE symptom assessment, the proportion of patients reporting loose and watery stools "frequently" or "almost constantly" was 29% higher at cycle 1, day 15 in the capivasertib-fulvestrant group than in the placebo-fulvestrant group, decreasing at subsequent cycles. Other PRO-CTCAE-reported symptoms (rash, mouth or throat sores, itchy skin, and numbness or tingling in hands or feet) were absent or mild in most patients in both groups throughout treatment. According to the PGI-TT, most patients in both groups reported "not at all" or "a little bit" of bother from treatment side-effects. INTERPRETATION: Patient-reported outcomes from CAPItello-291 demonstrated that capivasertib-fulvestrant delayed time to deterioration of GHS/QOL and maintained other dimensions of HRQOL (except symptoms of diarrhoea) similarly to fulvestrant. With the clinical efficacy and manageable safety profile, these exploratory results further support the positive benefit-risk profile of capivasertib-fulvestrant in this population. FUNDING: AstraZeneca.

Clinical characterization, prognostic, and predictive values of HER2-low in patients with early breast cancer in the PALLAS trial (ABCSG-42/AFT-05/BIG-14-13/PrE0109).

BACKGROUND: Bidirectional crosstalk between HER2 and estrogen receptor (ER) pathways may influence outcomes and the efficacy of endocrine therapy (ET). Low HER2 expression levels (HER2-low) have emerged as a predictive biomarker in patients with breast cancer (BC). METHODS: PALLAS is an open, international, phase 3 study evaluating the addition of palbociclib for 2 years to adjuvant ET in patients with stage II-III ER-positive/HER2-negative BC. To assess the impact of HER2 expression on patient outcomes in the phase III PALLAS trial, we analyzed (1) the association between rate of HER2-low with demographic and clinicopathological parameters, (2) the prognostic value of HER2-low status on invasive disease-free survival (iDFS), distant relapse-free survival (DRFS), and overall survival (OS) and (3) HER2 expression's value as a predictive biomarker of response to palbociclib. HER2-low was defined as HER2 immunohistochemistry (IHC) 1 + or IHC 2 + with negative in situ hybridization (ISH). All pathologic evaluation was performed locally. Prognostic and predictive power of HER2 were assessed with Cox models. RESULTS: From the original PALLAS intention-to-treat population (N = 5753), 5304 patients (92.2%) were included in this analysis. Among these, 2254 patients (42.5%) were classified as having HER2 IHC 0 (HER2-0), and 3050 (57.5%) as having HER2-low disease (1838 with IHC 1 + and 1212 with IHC 2 +). Median follow-up was 59.8 months. HER2-low prevalence varied significantly across 21 participating countries (range 16.7% to 75.6%; p < 0.001) and was more frequent in patients enrolled in North America (63.1%) than in Europe (53.4%) or other regions (53.4%) (p < 0.001). HER2 status was not significantly associated with iDFS in a multivariable Cox model (hazard ratio 0.93, 95% confidence interval 0.81 - 1.06). No significant interaction was observed between treatment arm and HER2 status for iDFS (p = 0.43). Similar results were obtained for DRFS and OS. CONCLUSIONS: In this large, prospective, global patient cohort, no differences were observed in clinical parameters, prognosis, or differential benefit from palbociclib between HER2-0 and HER2-low tumors. Significant geographic variability was observed in the prevalence of HER2-low status, suggesting a high degree of variation in pathologic assessment of HER2 expression without impact on outcomes.

On-treatment biopsies to predict response to neoadjuvant chemotherapy for breast cancer.

BACKGROUND: Patients with pathologic complete response (pCR) to neoadjuvant chemotherapy for invasive breast cancer (BC) have better outcomes, potentially warranting less extensive surgical and systemic treatments. Early prediction of treatment response could aid in adapting therapies. METHODS: On-treatment biopsies from 297 patients with invasive BC in three randomized, prospective neoadjuvant trials were assessed (GeparQuattro, GeparQuinto, GeparSixto). BC quantity, tumor-infiltrating lymphocytes (TILs), and the proliferation marker Ki-67 were compared to pre-treatment samples. The study investigated the correlation between residual cancer, changes in Ki-67 and TILs, and their impact on pathologic complete response (pCR) and disease-free survival (DFS). RESULTS: Among the 297 samples, 138 (46%) were hormone receptor-positive (HR+)/human epidermal growth factor 2-negative (HER2-), 87 (29%) were triple-negative (TNBC), and 72 (24%) were HER2+. Invasive tumor cells were found in 70% of on-treatment biopsies, with varying rates across subtypes (HR+/HER2-: 84%, TNBC: 62%, HER2+: 51%; p < 0.001). Patients with residual tumor on-treatment had an 8% pCR rate post-treatment (HR+/HER2-: 3%, TNBC: 19%, HER2+: 11%), while those without any invasive tumor had a 50% pCR rate (HR+/HER2-: 27%; TNBC: 48%, HER2+: 66%). Sensitivity for predicting residual disease was 0.81, with positive and negative predictive values of 0.92 and 0.50, respectively. Increasing TILs from baseline to on-treatment biopsy (if residual tumor was present) were linked to higher pCR likelihood in the overall cohort (OR 1.034, 95% CI 1.013-1.056 per % increase; p = 0.001) and with a longer DFS in TNBC (HR 0.980, 95% CI 0.963-0.997 per % increase; p = 0.026). Persisting or increased Ki-67 was associated with with lower pCR probability in the overall cohort (OR 0.957, 95% CI 0.928-0.986; p = 0.004) and shorter DFS in TNBC (HR 1.023, 95% CI 1.001-1.047; p = 0.04). CONCLUSION: On-treatment biopsies can predict patients unlikely to achieve pCR post-therapy. This could facilitate therapy adjustments for TNBC or HER2 + BC. They also might offer insights into therapy resistance mechanisms. Future research should explore whether standardized or expanded sampling enhances the accuracy of on-treatment biopsy procedures. Trial registration GeparQuattro (EudraCT 2005-001546-17), GeparQuinto (EudraCT 2006-005834-19) and GeparSixto (EudraCT 2011-000553-23).

Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer.

BACKGROUND: Patients with metastatic triple-negative breast cancer have a poor prognosis. Sacituzumab govitecan is an antibody-drug conjugate composed of an antibody targeting the human trophoblast cell-surface antigen 2 (Trop-2), which is expressed in the majority of breast cancers, coupled to SN-38 (topoisomerase I inhibitor) through a proprietary hydrolyzable linker. METHODS: In this randomized, phase 3 trial, we evaluated sacituzumab govitecan as compared with single-agent chemotherapy of the physician's choice (eribulin, vinorelbine, capecitabine, or gemcitabine) in patients with relapsed or refractory metastatic triple-negative breast cancer. The primary end point was progression-free survival (as determined by blinded independent central review) among patients without brain metastases. RESULTS: A total of 468 patients without brain metastases were randomly assigned to receive sacituzumab govitecan (235 patients) or chemotherapy (233 patients). The median age was 54 years; all the patients had previous use of taxanes. The median progression-free survival was 5.6 months (95% confidence interval [CI], 4.3 to 6.3; 166 events) with sacituzumab govitecan and 1.7 months (95% CI, 1.5 to 2.6; 150 events) with chemotherapy (hazard ratio for disease progression or death, 0.41; 95% CI, 0.32 to 0.52; P<0.001). The median overall survival was 12.1 months (95% CI, 10.7 to 14.0) with sacituzumab govitecan and 6.7 months (95% CI, 5.8 to 7.7) with chemotherapy (hazard ratio for death, 0.48; 95% CI, 0.38 to 0.59; P<0.001). The percentage of patients with an objective response was 35% with sacituzumab govitecan and 5% with chemotherapy. The incidences of key treatment-related adverse events of grade 3 or higher were neutropenia (51% with sacituzumab govitecan and 33% with chemotherapy), leukopenia (10% and 5%), diarrhea (10% and <1%), anemia (8% and 5%), and febrile neutropenia (6% and 2%). There were three deaths owing to adverse events in each group; no deaths were considered to be related to sacituzumab govitecan treatment. CONCLUSIONS: Progression-free and overall survival were significantly longer with sacituzumab govitecan than with single-agent chemotherapy among patients with metastatic triple-negative breast cancer. Myelosuppression and diarrhea were more frequent with sacituzumab govitecan. (Funded by Immunomedics; ASCENT ClinicalTrials.gov number, NCT02574455; EudraCT number, 2017-003019-21.).

Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer.

BACKGROUND: Poly(adenosine diphosphate-ribose) polymerase inhibitors target cancers with defects in homologous recombination repair by synthetic lethality. New therapies are needed to reduce recurrence in patients with BRCA1 or BRCA2 germline mutation-associated early breast cancer. METHODS: We conducted a phase 3, double-blind, randomized trial involving patients with human epidermal growth factor receptor 2 (HER2)-negative early breast cancer with BRCA1 or BRCA2 germline pathogenic or likely pathogenic variants and high-risk clinicopathological factors who had received local treatment and neoadjuvant or adjuvant chemotherapy. Patients were randomly assigned (in a 1:1 ratio) to 1 year of oral olaparib or placebo. The primary end point was invasive disease-free survival. RESULTS: A total of 1836 patients underwent randomization. At a prespecified event-driven interim analysis with a median follow-up of 2.5 years, the 3-year invasive disease-free survival was 85.9% in the olaparib group and 77.1% in the placebo group (difference, 8.8 percentage points; 95% confidence interval [CI], 4.5 to 13.0; hazard ratio for invasive disease or death, 0.58; 99.5% CI, 0.41 to 0.82; P<0.001). The 3-year distant disease-free survival was 87.5% in the olaparib group and 80.4% in the placebo group (difference, 7.1 percentage points; 95% CI, 3.0 to 11.1; hazard ratio for distant disease or death, 0.57; 99.5% CI, 0.39 to 0.83; P<0.001). Olaparib was associated with fewer deaths than placebo (59 and 86, respectively) (hazard ratio, 0.68; 99% CI, 0.44 to 1.05; P = 0.02); however, the between-group difference was not significant at an interim-analysis boundary of a P value of less than 0.01. Safety data were consistent with known side effects of olaparib, with no excess serious adverse events or adverse events of special interest. CONCLUSIONS: Among patients with high-risk, HER2-negative early breast cancer and germline BRCA1 or BRCA2 pathogenic or likely pathogenic variants, adjuvant olaparib after completion of local treatment and neoadjuvant or adjuvant chemotherapy was associated with significantly longer survival free of invasive or distant disease than was placebo. Olaparib had limited effects on global patient-reported quality of life. (Funded by the National Cancer Institute and AstraZeneca; OlympiA ClinicalTrials.gov number, NCT02032823.).

Impact of Imaging-Guided Localization on Performance of Tailored Axillary Surgery in Patients with Clinically Node-Positive Breast Cancer: Prospective Cohort Study Within TAXIS (OPBC-03, SAKK 23/16, IBCSG 57-18, ABCSG-53, GBG 101).

BACKGROUND: Tailored axillary surgery (TAS) is a novel surgical concept for clinical node-positive breast cancer. It consists of the removal of the sentinel lymph nodes (LNs), as well as palpably suspicious nodes. The TAS technique can be utilized in both the upfront and neoadjuvant chemotherapy (NACT) setting. This study assessed whether/how imaging-guided localization (IGL) influenced TAS. PATIENTS AND METHODS: This was a prospective observational cohort study preplanned in the randomized phase-III OPBC-03/TAXIS trial. IGL was performed at the surgeon's discretion for targeted removal of LNs during TAS. Immediate back-up axillary lymph node dissection (ALND) followed TAS according to TAXIS randomization. RESULTS: Five-hundred patients were included from 44 breast centers in six countries, 151 (30.2%) of whom underwent NACT. IGL was performed in 84.4% of all patients, with significant variation by country (77.6-100%, p < 0.001). No difference in the median number of removed (5 vs. 4, p = 0.3) and positive (2 vs. 2, p = 0.6) LNs by use of IGL was noted. The number of LNs removed during TAS with IGL remained stable over time (p = 0.8), but decreased significantly without IGL, from six (IQR 4-6) in 2019 to four (IQR 3-4) in 2022 (p = 0.015). An ALND was performed in 249 patients, removing another 12 (IQR 9-17) LNs, in which a median number of 1 (IQR 0-4) was positive. There was no significant difference in residual nodal disease after TAS with or without IGL (68.0% vs. 57.6%, p = 0.2). CONCLUSIONS: IGL did not significantly change either the performance of TAS or the volume of residual nodal tumor burden. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03513614.

Radiotherapy statements of the 18th St. Gallen International Breast Cancer Consensus Conference-a German expert perspective.

PURPOSE: To summarize the radiotherapy-relevant statements of the 18th St. Gallen Breast Cancer Consensus Conference and interpret the findings in light of German guideline recommendations. METHODS: Statements and voting results from the 18th St. Gallen International Breast Cancer Consensus Conference were collected and analyzed according to their relevance for the radiation oncology community. The voting results were discussed in two hybrid meetings among the authors of this manuscript on March 18 and 19, 2023, in light of the German S3 guideline and the 2023 version of the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) guidelines. RESULTS AND CONCLUSION: There was a high level of agreement between the radiotherapy-related statements of the 18th St. Gallen International Breast Cancer Consensus Conference and the German S3 and AGO guidelines. Discrepancies include the impact of number of lymph node metastases for the indication for postmastectomy radiotherapy.

Summary of quality of life in the ASCENT phase 3 clinical trial for people with metastatic triple-negative breast cancer.

WHAT IS THIS SUMMARY ABOUT?: A medicine called sacituzumab govitecan (brand name TRODELVY®) has been proven to be an effective treatment for metastatic triple-negative breast cancer (mTNBC for short). Metastatic breast cancer is cancer that has spread to other parts of the body. In mTNBC, the breast cancer cells do not have 3 common proteins on the cell surface, called receptors. mTNBC is more difficult to treat and more likely to come back than other types of breast cancer. The ASCENT study showed that participants with mTNBC treated with sacituzumab govitecan had a higher likelihood of living longer and delayed progression (worsening) of their cancer than those treated with standard chemotherapy. Here, we summarize the quality of life of participants with mTNBC in the ASCENT study. We compared quality of life between 236 participants treated with sacituzumab govitecan and 183 participants treated with standard chemotherapy. All participants previously received 2 or more chemotherapies that no longer controlled their cancer. WHAT ARE THE KEY TAKEAWAYS?: This analysis showed that participants treated with sacituzumab govitecan had better overall quality of life than participants treated with standard chemotherapy. They also had better "physical functioning", which is the ability to walk and do physical activities. Participants treated with sacituzumab govitecan maintained their overall quality of life for a longer time than those treated with standard chemotherapy. Participants treated with sacituzumab govitecan had less pain and were less tired than those treated with standard chemotherapy. On the other hand, participants treated with sacituzumab govitecan had worse diarrhea (loose or watery stools) and were more likely to have nausea/vomiting (feel sick or throw up) than participants treated with standard chemotherapy. WHAT WERE THE MAIN CONCLUSIONS REPORTED BY THE RESEARCHERS?: Participants treated with sacituzumab govitecan had a higher likelihood of living longer and delayed progression (worsening) of their cancer. Participants also had a better overall quality of life, which was maintained (did not get worse) for a longer time. However, they experienced worsening of diarrhea and/or nausea/vomiting.Clinical Trial Registration: NCT02574455 (ASCENT) (ClinicalTrials.gov).

A plain language summary of the CAPItello-291 study: Capivasertib in hormone receptor-positive advanced breast cancer.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of the article discussing the results of the CAPItello-291 study. In the study, participants had advanced breast cancer that could not be completely removed with surgery, and that was diagnosed as a type of breast cancer where tumor cells had hormone receptors (HR-positive) but did not have HER2 receptors (HER2-negative). All participants were also required to have previously received treatment with a type of therapy called an aromatase inhibitor (with or without a CDK4/6 inhibitor), but over time their cancer cells had still grown or spread. The CAPItello-291 study researchers wanted to find out if a treatment combination of the medications capivasertib plus fulvestrant worked better than placebo plus fulvestrant. Capivasertib is a drug that blocks the activity of a protein called AKT, which is found inside breast cancer cells. WHAT ARE THE KEY TAKEAWAYS?: The main finding was that participants who took capivasertib plus fulvestrant lived longer without their disease getting worse (progressing) compared with those treated with placebo plus fulvestrant. This is called progression-free survival. This result was seen across all participants (median progression-free survival of 7.2 months with capivasertib plus fulvestrant vs 3.6 months with placebo plus fulvestrant). It was also seen in participants whose tumors had detectable genetic alterations in genes called PIK3CA, AKT1, and/ or PTEN (median progression-free survival of 7.3 months with capivasertib plus fulvestrant vs 3.1 months with placebo plus fulvestrant). The most common side effects experienced by participants included diarrhea and different types of rash. These were as expected (given how capivasertib works). The CAPItello-291 study is still ongoing, and more results are expected to be released in the future. WHAT WERE THE MAIN CONCLUSIONS REPORTED BY THE RESEARCHERS?: Results from the CAPItello-291 study showed that capivasertib plus fulvestrant compared with placebo plus fulvestrant improved progression-free survival in participants with HR-positive/ HER2-negative advanced breast cancer whose cancer had grown or spread despite hormone therapy (with/without a CDK4/6 inhibitor).Clinical Trial Registration: NCT04305496 (CAPItello-291) (ClinicalTrials.gov).

The effect of denosumab on disseminated tumor cells (DTCs) of breast cancer patients with neoadjuvant treatment: a GeparX translational substudy.

BACKGROUND: Disseminated tumor cells (DTCs) in the bone marrow are observed in about 40% at primary diagnosis of breast cancer and predict poor survival. While anti-resorptive therapy with bisphosphonates was shown to eradicate minimal residue disease in the bone marrow, the effect of denosumab on DTCs, particularly in the neoadjuvant setting, is largely unknown. The recent GeparX clinical trial reported that denosumab, applied as an add-on treatment to nab-paclitaxel based neoadjuvant chemotherapy (NACT), did not improve the patient's pathologic complete response (pCR) rate. Herein, we analyzed the predictive value of DTCs for the response to NACT and interrogated whether neoadjuvant denosumab treatment may eradicate DTCs in the bone marrow. METHODS: A total of 167 patients from the GeparX trial were analyzed for DTCs at baseline by immunocytochemistry using the pan-cytokeratin antibody A45-B/B3. Initially DTC-positive patients were re-analyzed for DTCs after NACT ± denosumab. RESULTS: At baseline, DTCs were observed in 43/167 patients (25.7%) in the total cohort, however their presence did not predict response to nab-paclitaxel based NACT (pCR rates: 37.1% in DTC-negative vs. 32.6% DTC-positive; p = 0.713). Regarding breast cancer subtypes, the presence of DTCs at baseline was numerically associated with response to NACT in TNBC patients (pCR rates: 40.0% in DTC-positive vs. 66.7% in DTC-negative patients; p = 0.16). Overall, denosumab treatment did not significantly increase the given DTC-eradication rate of NACT (NACT: 69.6% DTC-eradication vs. NACT + denosumab: 77.8% DTC-eradication; p = 0.726). In TNBC patients with pCR, a numerical but statistically non-significant increase of DTC-eradication after NACT + denosumab was observed (NACT: 75% DTC-eradication vs. NACT + denosumab: 100% DTC-eradication; p = 1.00). CONCLUSION: This is the first study worldwide, demonstrating that neoadjuvant add-on denosumab over a short-term period of 24 months does not increase the DTC-eradication rate in breast cancer patients treated with NACT.

Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer.

BACKGROUND: Patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer who have disease progression after therapy with multiple HER2-targeted agents have limited treatment options. Tucatinib is an investigational, oral, highly selective inhibitor of the HER2 tyrosine kinase. METHODS: We randomly assigned patients with HER2-positive metastatic breast cancer previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine, who had or did not have brain metastases, to receive either tucatinib or placebo, in combination with trastuzumab and capecitabine. The primary end point was progression-free survival among the first 480 patients who underwent randomization. Secondary end points, assessed in the total population (612 patients), included overall survival, progression-free survival among patients with brain metastases, confirmed objective response rate, and safety. RESULTS: Progression-free survival at 1 year was 33.1% in the tucatinib-combination group and 12.3% in the placebo-combination group (hazard ratio for disease progression or death, 0.54; 95% confidence interval [CI], 0.42 to 0.71; P<0.001), and the median duration of progression-free survival was 7.8 months and 5.6 months, respectively. Overall survival at 2 years was 44.9% in the tucatinib-combination group and 26.6% in the placebo-combination group (hazard ratio for death, 0.66; 95% CI, 0.50 to 0.88; P = 0.005), and the median overall survival was 21.9 months and 17.4 months, respectively. Among the patients with brain metastases, progression-free survival at 1 year was 24.9% in the tucatinib-combination group and 0% in the placebo-combination group (hazard ratio, 0.48; 95% CI, 0.34 to 0.69; P<0.001), and the median progression-free survival was 7.6 months and 5.4 months, respectively. Common adverse events in the tucatinib group included diarrhea, palmar-plantar erythrodysesthesia syndrome, nausea, fatigue, and vomiting. Diarrhea and elevated aminotransferase levels of grade 3 or higher were more common in the tucatinib-combination group than in the placebo-combination group. CONCLUSIONS: In heavily pretreated patients with HER2-positive metastatic breast cancer, including those with brain metastases, adding tucatinib to trastuzumab and capecitabine resulted in better progression-free survival and overall survival outcomes than adding placebo; the risks of diarrhea and elevated aminotransferase levels were higher with tucatinib. (Funded by Seattle Genetics; HER2CLIMB ClinicalTrials.gov number, NCT02614794.).

Trends in use of neoadjuvant systemic therapy in patients with clinically node-positive breast cancer in Europe: prospective TAXIS study (OPBC-03, SAKK 23/16, IBCSG 57-18, ABCSG-53, GBG 101).

PURPOSE: The aim of this study was to evaluate clinical practice heterogeneity in use of neoadjuvant systemic therapy (NST) for patients with clinically node-positive breast cancer in Europe. METHODS: The study was preplanned in the international multicenter phase-III OPBC-03/TAXIS trial (ClinicalTrials.gov Identifier: NCT03513614) to include the first 500 randomized patients with confirmed nodal disease at the time of surgery. The TAXIS study's pragmatic design allowed both the neoadjuvant and adjuvant setting according to the preferences of the local investigators who were encouraged to register eligible patients consecutively. RESULTS: A total of 500 patients were included at 44 breast centers in six European countries from August 2018 to June 2022, 165 (33%) of whom underwent NST. Median age was 57 years (interquartile range [IQR], 48-69). Most patients were postmenopausal (68.4%) with grade 2 and 3 hormonal receptor-positive and human epidermal growth factor receptor 2-negative breast cancer with a median tumor size of 28 mm (IQR 20-40). The use of NST varied significantly across the countries (p < 0.001). Austria (55.2%) and Switzerland (35.8%) had the highest percentage of patients undergoing NST and Hungary (18.2%) the lowest. The administration of NST increased significantly over the years (OR 1.42; p < 0.001) and more than doubled from 20 to 46.7% between 2018 and 2022. CONCLUSION: Substantial heterogeneity in the use of NST with HR+/HER2-breast cancer exists in Europe. While stringent guidelines are available for its use in triple-negative and HER2+ breast cancer, there is a need for the development of and adherence to well-defined recommendations for HR+/HER2-breast cancer.

Characterization of Hormone Receptor and HER2 Status in Breast Cancer Using Mass Spectrometry Imaging.

Immunohistochemical evaluation of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 status stratify the different subtypes of breast cancer and define the treatment course. Triple-negative breast cancer (TNBC), which does not register receptor overexpression, is often associated with worse patient prognosis. Mass spectrometry imaging transcribes the molecular content of tissue specimens without requiring additional tags or preliminary analysis of the samples, being therefore an excellent methodology for an unbiased determination of tissue constituents, in particular tumor markers. In this study, the proteomic content of 1191 human breast cancer samples was characterized by mass spectrometry imaging and the epithelial regions were employed to train and test machine-learning models to characterize the individual receptor status and to classify TNBC. The classification models presented yielded high accuracies for estrogen and progesterone receptors and over 95% accuracy for classification of TNBC. Analysis of the molecular features revealed that vimentin overexpression is associated with TNBC, supported by immunohistochemistry validation, revealing a new potential target for diagnosis and treatment.

mdm2 gene amplification is associated with luminal breast cancer progression in humanized PDX mice and a worse outcome of estrogen receptor positive disease.

Estrogen receptor-positive breast cancer is a highly prevalent but heterogeneous disease among women. Advanced molecular stratification is required to enable individually most efficient treatments based on relevant prognostic and predictive biomarkers. First objective of our study was the hypothesis-driven discovery of biomarkers involved in tumor progression upon xenotransplantation of Luminal breast cancer into humanized mice. The second objective was the marker validation and correlation with the clinical outcome of Luminal breast cancer disease within the GeparTrio trial. An elevated mdm2 gene copy number was associated with enhanced tumor growth and lung metastasis in humanized tumor mice. The viability, proliferation and migration capacity of inherently mdm2 positive breast cancer cells in vitro were significantly reduced upon mdm2 knockdown or anti-mdm2 targeting. An mdm2 gain significantly correlated with a worse DFS and OS of Luminal breast cancer patients, albeit it was also associated with an enhanced preoperative pathological response rate. We provide evidence for an enhanced Luminal breast cancer stratification based on mdm2. Moreover, mdm2 can potentially be utilized as a therapeutic target in the Luminal subtype.

Breast cancer.

Breast cancer is still the most common cancer worldwide. But the way breast cancer is viewed has changed drastically since its molecular hallmarks were extensively characterised, now including immunohistochemical markers (eg, ER, PR, HER2 [ERBB2], and proliferation marker protein Ki-67 [MKI67]), genomic markers (eg, BRCA1, BRCA2, and PIK3CA), and immunomarkers (eg, tumour-infiltrating lymphocytes and PD-L1). New biomarker combinations are the basis for increasingly complex diagnostic algorithms. Neoadjuvant combination therapy, often including targeted agents, is a standard of care (especially in HER2-positive and triple-negative breast cancer), and the basis for de-escalation of surgery in the breast and axilla and for risk-adapted post-neoadjuvant strategies. Radiotherapy remains an important cornerstone of breast cancer therapy, but de-escalation schemes have become the standard of care. ER-positive tumours are treated with 5-10 years of endocrine therapy and chemotherapy, based on an individual risk assessment. For metastatic breast cancer, standard therapy options include targeted approaches such as CDK4 and CDK6 inhibitors, PI3K inhibitors, PARP inhibitors, and anti-PD-L1 immunotherapy, depending on tumour type and molecular profile. This range of treatment options reflects the complexity of breast cancer therapy today.

Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer.

BACKGROUND: PIK3CA mutations occur in approximately 40% of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. The PI3Kα-specific inhibitor alpelisib has shown antitumor activity in early studies. METHODS: In a randomized, phase 3 trial, we compared alpelisib (at a dose of 300 mg per day) plus fulvestrant (at a dose of 500 mg every 28 days and once on day 15) with placebo plus fulvestrant in patients with HR-positive, HER2-negative advanced breast cancer who had received endocrine therapy previously. Patients were enrolled into two cohorts on the basis of tumor-tissue PIK3CA mutation status. The primary end point was progression-free survival, as assessed by the investigator, in the cohort with PIK3CA-mutated cancer; progression-free survival was also analyzed in the cohort without PIK3CA-mutated cancer. Secondary end points included overall response and safety. RESULTS: A total of 572 patients underwent randomization, including 341 patients with confirmed tumor-tissue PIK3CA mutations. In the cohort of patients with PIK3CA-mutated cancer, progression-free survival at a median follow-up of 20 months was 11.0 months (95% confidence interval [CI], 7.5 to 14.5) in the alpelisib-fulvestrant group, as compared with 5.7 months (95% CI, 3.7 to 7.4) in the placebo-fulvestrant group (hazard ratio for progression or death, 0.65; 95% CI, 0.50 to 0.85; P<0.001); in the cohort without PIK3CA-mutated cancer, the hazard ratio was 0.85 (95% CI, 0.58 to 1.25; posterior probability of hazard ratio <1.00, 79.4%). Overall response among all the patients in the cohort without PIK3CA-mutated cancer was greater with alpelisib-fulvestrant than with placebo-fulvestrant (26.6% vs. 12.8%); among patients with measurable disease in this cohort, the percentages were 35.7% and 16.2%, respectively. In the overall population, the most frequent adverse events of grade 3 or 4 were hyperglycemia (36.6% in the alpelisib-fulvestrant group vs. 0.7% in the placebo-fulvestrant group) and rash (9.9% vs. 0.3%). Diarrhea of grade 3 occurred in 6.7% of patients in the alpelisib-fulvestrant group, as compared with 0.3% of those in the placebo-fulvestrant group; no diarrhea of grade 4 was reported. The percentages of patients who discontinued alpelisib and placebo owing to adverse events were 25.0% and 4.2%, respectively. CONCLUSIONS: Treatment with alpelisib-fulvestrant prolonged progression-free survival among patients with PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer who had received endocrine therapy previously. (Funded by Novartis Pharmaceuticals; SOLAR-1 ClinicalTrials.gov number, NCT02437318.).

Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer.

BACKGROUND: Patients who have residual invasive breast cancer after receiving neoadjuvant chemotherapy plus human epidermal growth factor receptor 2 (HER2)-targeted therapy have a worse prognosis than those who have no residual cancer. Trastuzumab emtansine (T-DM1), an antibody-drug conjugate of trastuzumab and the cytotoxic agent emtansine (DM1), a maytansine derivative and microtubule inhibitor, provides benefit in patients with metastatic breast cancer that was previously treated with chemotherapy plus HER2-targeted therapy. METHODS: We conducted a phase 3, open-label trial involving patients with HER2-positive early breast cancer who were found to have residual invasive disease in the breast or axilla at surgery after receiving neoadjuvant therapy containing a taxane (with or without anthracycline) and trastuzumab. Patients were randomly assigned to receive adjuvant T-DM1 or trastuzumab for 14 cycles. The primary end point was invasive disease-free survival (defined as freedom from ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause). RESULTS: At the interim analysis, among 1486 randomly assigned patients (743 in the T-DM1 group and 743 in the trastuzumab group), invasive disease or death had occurred in 91 patients in the T-DM1 group (12.2%) and 165 patients in the trastuzumab group (22.2%). The estimated percentage of patients who were free of invasive disease at 3 years was 88.3% in the T-DM1 group and 77.0% in the trastuzumab group. Invasive disease-free survival was significantly higher in the T-DM1 group than in the trastuzumab group (hazard ratio for invasive disease or death, 0.50; 95% confidence interval, 0.39 to 0.64; P<0.001). Distant recurrence as the first invasive-disease event occurred in 10.5% of patients in the T-DM1 group and 15.9% of those in the trastuzumab group. The safety data were consistent with the known safety profile of T-DM1, with more adverse events associated with T-DM1 than with trastuzumab alone. CONCLUSIONS: Among patients with HER2-positive early breast cancer who had residual invasive disease after completion of neoadjuvant therapy, the risk of recurrence of invasive breast cancer or death was 50% lower with adjuvant T-DM1 than with trastuzumab alone. (Funded by F. Hoffmann-La Roche/Genentech; KATHERINE ClinicalTrials.gov number, NCT01772472 .).