Sir Peter MacCallum Department of Oncology - Research Publications
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ItemEffect of palbociclib plus endocrine therapy on time to chemotherapy across subgroups of patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: Post hoc analyses from PALOMA-2 and PALOMA-3(CHURCHILL LIVINGSTONE, 2022-12)BACKGROUND: Previous analyses from the PALOMA-2 and PALOMA-3 studies showed that palbociclib (PAL) plus endocrine therapy (ET) prolongs time to first subsequent chemotherapy (TTC) versus placebo (PBO) plus ET in the overall population of patients with hormone receptor‒positive/human epidermal growth factor receptor 2‒negative (HR+/HER2-) advanced breast cancer (ABC). Here, we evaluated TTC in relevant patient subgroups. METHODS: These post hoc analyses evaluated TTC by subgroup using data from 2 randomized, phase 3 studies of women with HR+/HER2- ABC. In PALOMA-2, postmenopausal patients previously untreated for ABC were randomized 2:1 to receive PAL (125 mg/day, 3/1-week schedule) plus letrozole (LET; 2.5 mg/day; n = 444) or PBO plus LET (n = 222). In PALOMA-3, premenopausal or postmenopausal patients whose disease had progressed after prior ET were randomized 2:1 to receive PAL (125 mg/day, 3/1-week schedule) plus fulvestrant (FUL; 500 mg; n = 347) or PBO plus FUL (n = 174). RESULTS: First subsequent chemotherapy was received by 35.5% and 56.2% in PALOMA-2 and PALOMA-3 after progression on palbociclib plus ET or placebo plus ET. Across all subgroups analyzed, the median progression-free survival (PFS) was longer in the PAL plus ET arm than the PBO plus ET arm. TTC was longer with PAL plus ET versus PBO plus ET across the same patient subgroups in both studies. CONCLUSIONS: Across all subgroups, PAL plus ET versus PBO plus ET had longer median PFS and resulted in prolonged TTC in both the PALOMA-2 and PALOMA-3 studies. Pfizer Inc (NCT01740427, NCT01942135).
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ItemNo Preview AvailableAlpelisib Monotherapy for PI3K-Altered Pretreated Advanced Breast Cancer A Phase II Study(AMER ASSOC CANCER RESEARCH, 2022-09)UNLABELLED: There is limited knowledge on the benefit of the α-subunit-specific PI3K inhibitor alpelisib in later lines of therapy for advanced estrogen receptor-positive (ER+) HER2- and triple-negative breast cancer (TNBC). We conducted a phase II multicohort study of alpelisib monotherapy in patients with advanced PI3K pathway mutant ER+HER2- and TNBC. In the intention-to-treat ER+ cohort, the overall response rate was 30% and the clinical benefit rate was 36%. A decline in PI3K pathway mutant circulating tumor DNA (ctDNA) levels from baseline to week 8 while on therapy was significantly associated with a partial response, clinical benefit, and improved progression-free-survival [HR 0.24; 95% confidence interval (CI), 0.083-0.67, P = 0.0065]. Detection of ESR1 mutations at baseline in plasma was also associated with clinical benefit and improved progression-free survival (HR 0.22; 95% CI, 0.078-0.60, P = 0.003). SIGNIFICANCE: Alpelisib monotherapy displayed efficacy in heavily pretreated ER+ breast cancer with PIK3CA mutations. PIK3CA mutation dynamics in plasma during treatment and ESR1 mutations detected in plasma at baseline were candidate biomarkers predictive of benefit from alpelisib, highlighting the utility of ctDNA assays in this setting. This article is highlighted in the In This Issue feature, p. 2007.
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ItemNo Preview AvailableIntratumoral CD8+T cells with a tissue-resident memory phenotype mediate local immunity and immune checkpoint responses in breast cancer(CELL PRESS, 2023-03-13)CD8+ tumor-infiltrating lymphocytes with a tissue-resident memory T (TRM) cell phenotype are associated with favorable prognosis in patients with triple-negative breast cancer (TNBC). However, the relative contribution of CD8+ TRM cells to anti-tumor immunity and immune checkpoint blockade efficacy in breast cancer remains unknown. Here, we show that intratumoral CD8+ T cells in murine mammary tumors transcriptionally resemble those from TNBC patients. Phenotypic and transcriptional studies established two intratumoral sub-populations: one more enriched in markers of terminal exhaustion (TEX-like) and the other with a bona fide resident phenotype (TRM-like). Treatment with anti-PD-1 and anti-CTLA-4 therapy resulted in expansion of these intratumoral populations, with the TRM-like subset displaying significantly enhanced cytotoxic capacity. TRM-like CD8+ T cells could also provide local immune protection against tumor rechallenge and a TRM gene signature extracted from tumor-free tissue was significantly associated with improved clinical outcomes in TNBC patients treated with checkpoint inhibitors.
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ItemNo Preview AvailableGenomic characterisation of hormone receptor-positive breast cancer arising in very young women(ELSEVIER, 2023-04)BACKGROUND: Very young premenopausal women diagnosed with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+HER2-) early breast cancer (EBC) have higher rates of recurrence and death for reasons that remain largely unexplained. PATIENTS AND METHODS: Genomic sequencing was applied to HR+HER2- tumours from patients enrolled in the Suppression of Ovarian Function Trial (SOFT) to determine genomic drivers that are enriched in young premenopausal women. Genomic alterations were characterised using next-generation sequencing from a subset of 1276 patients (deep targeted sequencing, n = 1258; whole-exome sequencing in a young-age, case-control subsample, n = 82). We defined copy number (CN) subgroups and assessed for features suggestive of homologous recombination deficiency (HRD). Genomic alteration frequencies were compared between young premenopausal women (<40 years) and older premenopausal women (≥40 years), and assessed for associations with distant recurrence-free interval (DRFI) and overall survival (OS). RESULTS: Younger women (<40 years, n = 359) compared with older women (≥40 years, n = 917) had significantly higher frequencies of mutations in GATA3 (19% versus 16%) and CN amplifications (CNAs) (47% versus 26%), but significantly lower frequencies of mutations in PIK3CA (32% versus 47%), CDH1 (3% versus 9%), and MAP3K1 (7% versus 12%). Additionally, they had significantly higher frequencies of features suggestive of HRD (27% versus 21%) and a higher proportion of PIK3CA mutations with concurrent CNAs (23% versus 11%). Genomic features suggestive of HRD, PIK3CA mutations with CNAs, and CNAs were associated with significantly worse DRFI and OS compared with those without these features. These poor prognostic features were enriched in younger patients: present in 72% of patients aged <35 years, 54% aged 35-39 years, and 40% aged ≥40 years. Poor prognostic features [n = 584 (46%)] versus none [n = 692 (54%)] had an 8-year DRFI of 84% versus 94% and OS of 88% versus 96%. Younger women (<40 years) had the poorest outcomes: 8-year DRFI 74% versus 85% and OS 80% versus 93%, respectively. CONCLUSION: These results provide insights into genomic alterations that are enriched in young women with HR+HER2- EBC, provide rationale for genomic subgrouping, and highlight priority molecular targets for future clinical trials.
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ItemAn open label, randomized phase 2 trial assessing the impact of food on the tolerability of abemaciclib in patients with advanced breast cancer(SPRINGER, 2022-08-01)PURPOSE: Abemaciclib, a CDK4 & 6 inhibitor, is indicated for advanced breast cancer treatment. Diarrhea is a frequently associated adverse event of abemaciclib. The study objective was to investigate if food intake impacts local gastrointestinal toxicity. METHODS: This Phase 2 study (I3Y-MC-JPCP, NCT03703466) randomized 72 patients 1:1:1 to receive abemaciclib 200 mg monotherapy twice daily (1) with a meal, (2) in a modified fasting state or (3) without regard to food. Primary endpoints included: incidence of investigator assessed severe (≥ Grade 3), prolonged (> 7 days) Grade 2 diarrhea, treatment discontinuation, dose modifications, and loperamide utilization during the first 3 cycles of treatment. Patient outcomes were captured via a daily electronic diary. Pharmacokinetics (PK) are reported. RESULTS: Incidence of investigator assessed severe diarrhea (Grade ≥ 3) was 1.4% (1 patient in Arm 1). Median duration of Grade 3 diarrhea was 1 day by both investigator assessment (1 patient in Arm 1) and patient-reported assessment (1 patient each in Arms 1 and 3). Median duration of investigator-assessed Grade 2 diarrhea was 2 days overall. No patient discontinued treatment due to diarrhea. Nine patients (12.7%) had a dose reduction, and 7 patients (9.9%) had a dose omission due to diarrhea. Ninety-four percent of patients used loperamide at least once. Abemaciclib PK was comparable across the 3 arms. CONCLUSION: The results suggest that diarrhea incidence associated with abemaciclib was unrelated to timing of food intake, was predominantly low grade, of short duration and well managed with loperamide and dose modifications.
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ItemPredictive Role of CD36 Expression in HER2-Positive Breast Cancer Patients Receiving Neoadjuvant Trastuzumab(OXFORD UNIV PRESS INC, 2022-07-05)BACKGROUND: Despite huge efforts to identify biomarkers associated with long-term clinical outcomes in patients with early-stage HER2-positive breast cancer (HER2+ BC) treated with (neo)adjuvant anti-HER2 therapy, no reliable predictors have been identified so far. Fatty acid uptake, a process mediated by the transmembrane transporter CD36, has recently emerged as a potential determinant of resistance to anti-HER2 treatments in preclinical HER2+ BC models. METHODS: Here, we investigated the association between baseline intratumor CD36 gene expression and event-free survival in 180 patients enrolled in the phase III trial Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization (NeoALTTO), which randomly assigned stage II-III HER2+ BC patients to receive neoadjuvant lapatinib, trastuzumab, or lapatinib-trastuzumab in combination with chemotherapy. To this aim, we selected NeoALTTO trial patients for whom pretreatment whole transcriptomic data were available. The main study results were validated in an independent cohort of patients enrolled in the neoadjuvant phase II trial NeoSphere. RESULTS: In 180 NeoALTTO patients, high intratumor CD36 expression was independently associated with worse event-free survival in patients treated with trastuzumab-based therapy (hazard ratio [HR] = 1.72, 95% confidence interval [CI] = 1.20 to 2.46), but not with lapatinib-based (HR = 1.02, 95% CI = 0.68 to 1.53) or trastuzumab-lapatinib-based (HR = 1.08, 95% CI = 0.60 to 1.94) therapy. Among 331 NeoSphere patients evaluated, high CD36 expression was independently associated with worse patient disease-free survival in both the whole study cohort (HR = 1.197, 95% CI = 1.002 to 1.428) and patients receiving trastuzumab-based neoadjuvant therapy (HR = 1.282, 95% CI = 1.049 to 1.568). CONCLUSIONS: High CD36 expression predicts worse clinical outcomes in early-stage HER2+ BC treated with trastuzumab-based neoadjuvant therapy.
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ItemComparative biomarker analysis of PALOMA-2/3 trials for palbociclib(NATURE PORTFOLIO, 2022-08-16)While cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, including palbociclib, combined with endocrine therapy (ET), are becoming the standard-of-care for hormone receptor-positive/human epidermal growth factor receptor 2‒negative metastatic breast cancer, further mechanistic insights are needed to maximize benefit from the treatment regimen. Herein, we conducted a systematic comparative analysis of gene expression/progression-free survival relationship from two phase 3 trials (PALOMA-2 [first-line] and PALOMA-3 [≥second-line]). In the ET-only arm, there was no inter-therapy line correlation. However, adding palbociclib resulted in concordant biomarkers independent of initial ET responsiveness, with shared sensitivity genes enriched in estrogen response and resistance genes over-represented by mTORC1 signaling and G2/M checkpoint. Biomarker patterns from the combination arm resembled patterns observed in ET in advanced treatment-naive patients, especially patients likely to be endocrine-responsive. Our findings suggest palbociclib may recondition endocrine-resistant tumors to ET, and may guide optimal therapeutic sequencing by partnering CDK4/6 inhibitors with different ETs. Pfizer (NCT01740427; NCT01942135).
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ItemCombining Radiotherapy and Immunotherapy in Metastatic Breast Cancer: Current Status and Future Directions(MDPI, 2022-04)The role of radiotherapy and immunotherapy with immune checkpoint inhibitors (ICI) is of emerging interest in many solid tumours, including breast cancer. There is increasing evidence that the host's immune system plays an important role in influencing the response to treatment and prognosis in breast cancer. Several pre-clinical studies and clinical trials have reported on the 'abscopal effect-regression of distant untreated tumour sites, mediated by an immunological response following ionizing radiation to a targeted tumour site. Stereotactic Ablative Body Radiotherapy (SABR) is a non-invasive technique used to augment various immune responses with an ablative tumoricidal dose when compared to conventional radiotherapy. SABR is characterized by typically 1-5 precision radiotherapy treatments that simultaneously deliver a high dose, whilst sparing normal tissues. Following SABR, there is evidence of systemic immune activation in patients with increased PD1 expression on CD8+ and CD4+ T cells. Studies continue to focus on metastatic triple-negative disease, a highly immunogenic subtype of breast cancer with poor prognosis. In this review, we discuss the immunological effect of SABR, alone and in combination with immunotherapy, and the importance of dose and fractionation. We also propose future strategies for treating oligometastatic disease, where this approach may be most useful for producing durable responses.
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ItemNo Preview AvailableCopy Number Aberration Analysis to Predict Response to Neoadjuvant Anti-HER2 Therapy: Results from the NeoALTTO Phase III Clinical Trial(AMER ASSOC CANCER RESEARCH, 2021-10-15)PURPOSE: The heterogeneity of response to anti-HER2 agents represents a major challenge in patients with HER2-positive breast cancer. To better understand the sensitivity and resistance to trastuzumab and lapatinib, we investigated the role of copy number aberrations (CNA) in predicting pathologic complete response (pCR) and survival outcomes in the NeoALTTO trial. EXPERIMENTAL DESIGN: The neoadjuvant phase III NeoALTTO trial enrolled 455 patients with HER2-positive early-stage breast cancer. DNA samples from 269 patients were assessed for genome-wide copy number profiling. Recurrent CNAs were found with GISTIC2.0. RESULTS: CNA estimates were obtained for 184 patients included in NeoALTTO. Among those, matched transcriptome and whole-exome data were available for 154 and 181 patients, respectively. A significant association between gene copy number and pCR was demonstrated for ERBB2 amplification. Nevertheless, ERBB2 amplification ceased to be predictive once ERBB2 expression level was considered. GISTIC2.0 analysis revealed 159 recurrent CNA regions. Lower copy number levels of the 6q23-24 locus predicted absence of pCR in the whole cohort and in the estrogen receptor-positive subgroup. 6q23-24 deletion was significantly more frequent in TP53 wild-type (WT) compared with TP53-mutated, resulting in copy number levels significantly associated with lack of pCR only in the TP53 WT subgroup. Interestingly, a gene-ontology analysis highlighted several immune processes correlated to 6q23-24 copy number. CONCLUSIONS: Our analysis identified ERBB2 copy number as well as 6q23-24 CNAs as predictors of response to anti-HER2-based treatment. ERBB2 expression outperformed ERBB2 amplification. The complexity of the 6q23-24 region warrants further investigation.