Search

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

Background: The PI3Kα subunit specific inhibitor alpelisib in combination with fulvestrant is approved in advanced breast cancer harbouring PIK3CA mutations, but predictive biomarkers are lacking. We performed a phase II single arm study of alpelisib monotherapy in previously treated advanced hormone receptor-positive HER2-negative (HR+HER2-) and triple negative breast cancer (TNBC) cohorts. Methods: Eligible patients with genomic aberrations in the PI3K pathway determined via tumour sequencing or ctDNA were given alpelisib 350mg oral daily as monotherapy. The primary endpoint was RECIST objective response rate (ORR) by central review. Secondary endpoints were clinical benefit rate (CBR), defined as complete or partial response or stable disease for ≥24 weeks, and progression free survival (PFS). Positron emission tomography (FDG-PET) was performed at baseline and 8 weeks. Efficacy was analysed according to baseline tumour alterations and serial ctDNA assays. Analyses were conducted separately for the HR+HER2- and TNBC cohorts. Stated p values are nominal without multiplicity adjustment. Results: 43 patients were recruited in total (33 in ER+HER2-, 10 in TNBC). Median follow-up was 44.6 months. In the TNBC cohort ORR and CBR were 0%, hence the cohort was stopped early. Data will be presented here for the HR+HER2- cohort. Of 33 ER+HER2- patients recruited, 28 (85%) were evaluable and 26 (79%) were evaluable for ORR after central review. PI3K pathway aberrations at study entry were mutations in PIK3CA (26/28; 93%) and PTEN (2/28; 7%). The median age was 60 (41 - 77yrs) and 27/28 of patients were female. 85.7% of cases had visceral disease, and 57% had >3 metastatic sites. 100% of patients had received prior endocrine therapy and 78.6% prior chemotherapy, with a median of 3 prior lines (range 1 - 9). All patients were endocrine refractory. The ORR was 38% and CBR 43%. Median PFS was 4.6 months (95% CI, 3.7 - 7.3) and median OS 16.0 months (95% CI, 8.5 - 34.4). In patients with PET scans at baseline and 8 weeks, 67% (17/25) achieved a partial metabolic response but this was not associated with clinical benefit. In patients with partial response by RECIST, serial ctDNA levels at week 8 declined from baseline (p = 0.008) compared to patients with stable or progressive disease (p = 0.17), with similar results seen for patients with clinical benefit. Decline in ctDNA at week 8 was also associated with improved PFS (HR 0.24 [95% CI 0.08-0.67], p = 0.0065; 5.6 v 3.6 months). Multiple PIK3CA mutations were detected in plasma in 31% (8/26) of patients but had no impact on ORR/CBR. 39% (11/28) of patients had mutations in ESR1 detected in plasma at baseline, and this was associated with clinical benefit (p = 0.019) and improved PFS (HR=0.22 [95% CI 0.078-0.60], P=0.0032, 8.21 v 4.53 months). ctDNA assays detected 11 cases with ESR1 mutations compared to tumour sequencing which detected 5 cases only. No other baseline alterations were significantly associated with outcomes, although no patients (0/4) with PTEN alterations achieved clinical benefit. End of treatment ctDNA analysis identified multiple new alterations including MAP3K1 in 39% (11/28), TP53 in 32% (9/28) and PTEN in 25% (7/28). Adverse events included 20.9% grade ≥3 hyperglycaemia and 25.6% ≥grade 3 rash consistent with reported data. Permanent discontinuation of alpelisib for toxicity occurred in 15.2% (5/33) of patients. Conclusions: Alpelisib monotherapy in pre-treated ER+HER2- disease showed evidence of clinical efficacy. Decline in the levels of PIK3CA mutations detected with ctDNA on therapy are significantly associated with clinical benefit, as are the presence of ESR1 mutations at baseline. ctDNA improves the yield of ESR1 mutation detection and warrants further study as a biomarker of alpelisib monotherapy benefit in endocrine-refractory populations. Citation Format: Peter Savas, Louisa Lisa Lo, Stephen James Luen, Elizabeth Fay Blackley, Courtney Templeton van Geelen, Yi-An Ko, Kate Moodie, Jason William Callahan, Chen-Fang Weng, Andjelija Zivanovic Bujak, Miriam Manning Yeung, Sarah Ftouni, Prudence Anne Francis, Sarah-Jane Dawson, Sherene Loi. Alpelisib monotherapy for PI3K-altered, pre-treated advanced breast cancer: A phase II study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-14.

Supplementary Data from Alpelisib Monotherapy for PI3K-Altered, Pretreated Advanced Breast Cancer: A Phase II Study

Supplementary Figure from Alpelisib Monotherapy for PI3K-Altered, Pretreated Advanced Breast Cancer: A Phase II Study

Supplementary Methods

Supplementary Tables S1-5

Supplementary Table S8

Supplementary Table S7

Supplementary Table S6

Supplementary Figures

Supplementary Table S9

Objective To assess the sensitivity and specificity of clinical breast examination for detecting breast cancer in asymptomatic women with predisposing germline mutations enrolled in a cancer risk management program that includes radiologic screening. Design, setting Retrospective, longitudinal cohort study of women with BRCA1/2 mutations who attended the Breast and Ovarian Cancer Risk Management Clinic at the Peter MacCallum Cancer Centre, a tertiary referral centre in Melbourne, during 1 September 2001 - 31 December 2019. Participants Consecutive women with BRCA1/2 mutations who did not have personal histories of cancer and had not undergone bilateral risk-reducing mastectomy, and who had visited the clinic at least twice during the study period. Participants had generally undergone breast examination at 6- or 12-month intervals, and annual breast imaging (mammography; and magnetic resonance imaging [MRI] for women aged 50 years or younger). Main outcome measures Sensitivity (proportion of all biopsy-confirmed breast cancers detected by breast examination alone) and specificity of breast examination for detecting breast cancer. Results Of 414 eligible women (mean age, 35.5 years; SD, 11.2 years), 35 were diagnosed with breast cancer during 1761 woman-years of follow-up. Only two were diagnosed based on breast examination alone (ie, without radiologic evidence), neither of whom was undergoing MRI screening. The sensitivity of breast examination was 6% (95% CI, 1-19%), the specificity 97% (95% CI, 95-98%); the positive predictive value was 14% (95% CI, 2-43%), the negative predictive value 92% (95% CI, 89-94%). Conclusion Clinical breast examination did not increase the number of breast cancers detected in MRI-screened women with BRCA1/2 mutations. Removing breast examination from surveillance programs that include MRI may be reasonable for these women.

Venetoclax, a potent and selective BCL2 inhibitor, synergizes with endocrine therapy in preclinical models of ER-positive breast cancer. Using a phase Ib 3 + 3 dose-escalation and expansion study design, 33 patients with ER and BCL2-positive metastatic disease (mean prior regimens, 2; range, 0–8) were treated with daily tamoxifen (20 mg) and venetoclax (200–800 mg). Apart from uncomplicated “on-target” lymphopenia, no dose-limiting toxicities or high-grade adverse events were observed in the escalation phase (15 patients), and 800 mg was selected as the recommended phase II dose (RP2D). In the expansion phase (18 patients), few high-grade treatment-related adverse events were observed. For 24 patients treated at the RP2D, the confirmed radiologic response rate was 54% and the clinical benefit rate was 75%. Treatment responses were preempted by metabolic responses (FDG-PET) at 4 weeks and correlated with serial changes in circulating tumor DNA. Radiologic responses (40%) and clinical benefit (70%) were observed in 10 patients with plasma-detected ESR1 mutations. Significance: In the first clinical study to evaluate venetoclax in a solid tumor, we demonstrate that combining venetoclax with endocrine therapy has a tolerable safety profile and elicits notable activity in ER and BCL2-positive metastatic breast cancer. These findings support further investigation of combination therapy for patients with BCL2-positive tumors. See related commentary by Drago et al., p. 323. This article is highlighted in the In This Issue feature, p. 305

The treatment landscape for metastatic melanoma has increased dramatically in the past five years, with the pivotal discovery of activating BRAF mutations in half of all melanomas spurring the development for effective treatments that target mitogen-activated protein kinase (RAS/RAF/MEK/ERK) pathway. Vemurafenib, a selective mutant BRAF Val600 inhibitor, results in striking tumour responses and a survival advantage over conventional chemotherapy. We present here the case of a 38-year-old woman with metastatic BRAFV600E mutant melanoma and a severe tablet phobia, who was found to have been crushing and/or chewing her vemurafenib tablets. In this case, she attained a partial response and significant clinical benefit, albeit temporarily.

Osteosarcoma is the most common primary bone cancer affecting adolescent and young adults. The majority of osteosarcomas occur sporadically, although increasing age is associated with a higher risk of secondary osteosarcoma. Common causes of secondary osteosarcoma include pre-existing Paget's disease and prior irradiation. Bone infarct-associated sarcoma (IAS) is a rare subset of secondary sarcoma with few reports to date. We present the case of a 28-year-old male who presented with IAS potentially related to previous steroid exposure from treated Hodgkin disease in childhood. He is currently undergoing neoadjuvant chemotherapy with consideration of a limb-sparing surgery after two cycles.

Background: Demand for screening breast magnetic resonance imaging (MRI) for women with a hereditary predisposition to breast cancer has increased since the introduction of a medicare item number. To aid future service planning, we examined the practicalities of establishing and running a breast MRI screening programme for high risk women and to describe the early outcomes of our screening programme. Methods: We undertook a retrospective audit of prospectively collected data. Women

1055Background: Mutations of genes involved in the PI3K signalling pathway occur frequently in BC. We performed a phase II study of BYL719, a selective PI3Kα inhibitor, in BC to evaluate its effica...

Background Although the benefit of adjunct digital breast tomosynthesis (DBT) is established in population screening, its benefit in surveillance after breast cancer treatment is not well defined. We prospectively evaluated whether the addition of DBT to digital mammography (DM) reduced the rate of indeterminate findings compared to DM alone in patients after breast cancer treatment. Methods Patients had both DM and DBT for routine surveillance. Two-dimensional synthesised mammogram (SM) was generated for each patient from DBT data. DM, SM, and DBT images were read for each patient by one of four radiologists credentialed for DBT. We compared the rates of indeterminate findings between DM + DBT with DM alone in patients with a range of breast densities and between DM and SM. Results A total of 618 patients and 1069 breasts were analysed. The rates of indeterminate findings for DM + DBT versus DM alone were 10.5% and 13.1%, respectively (p = 0.018). In breasts treated with surgery and radiotherapy (n = 558), the corresponding rates of indeterminate findings were 4.9% and 6.9%, respectively (p = 0.039). The rate of indeterminate findings for DM + DBT increased with increasing breast density (p = 0.019). There was no significant difference in the rates of indeterminate findings between DM and SM (13.1% versus 11.5%, p = 0.1). Conclusion The addition of DBT to DM reduced the rate of indeterminate findings in surveillance of patients after breast cancer treatment. Further research is required to confirm whether DBT and SM could replace DM for patients undergoing surveillance.

This prospective study of surveillance strategies uses a whole-body screening program, including whole-body magnetic resonance imaging, in carriers of germline mutations in TP53.

Background The incremental value of 18FDG PET/CT in patients with breast cancer (BC) compared to conventional imaging (CI) in clinical practice is unclear. The aim of this study was to evaluate the management impact and prognostic value of 18 F-FDG PET/CT in this setting. Methods Sixty-three patients who were referred to our institution for suspicion of BC relapse were retrospectively enrolled. All patients had been evaluated with CI and underwent PET/CT. At a median follow-up of 61 months, serial clinical, imaging and pathologic results were obtained to validate diagnostic findings. Overall Survival (OS) was estimated using Kaplan Meier methods and analyzed using the Cox proportional hazards regression models. Results Forty-two patients had a confirmed relapse with 37 (88%) positive on CI and 40 (95%) positive on PET/CT. When compared with CI, PET/CT had a higher negative predictive value (86% versus 54%) and positive predictive value (95% versus 70%). The management impact of PET/CT was high (change of treatment modality or intent) in 30 patients (48%) and medium (change in radiation treatment volume or dose fractionation) in 6 patients (9%). Thirty-nine patients (62%) died during follow-up. The PET/CT result was a highly significant predictor of OS (Hazard Ratio [95% Confidence Interval] =4.7 [2.0-10.9] for PET positive versus PET negative for a systemic recurrence; p = 0.0003). In a Cox multivariate analysis including other prognosis factors, PET/CT findings predicted survival (p = 0.005). In contrast, restaging by CI was not significant predictor of survival. Conclusion Our study support the value of 18 F-FDG PET/CT in providing incremental information that influence patient management and refine prognostic stratification in the setting of suspected recurrent breast cancer.

Demand for screening breast magnetic resonance imaging (MRI) for women with a hereditary predisposition to breast cancer has increased since the introduction of a medicare item number. To aid future service planning, we examined the practicalities of establishing and running a breast MRI screening programme for high risk women and to describe the early outcomes of our screening programme.We undertook a retrospective audit of prospectively collected data. Women50 years of age with an inherited BRCA1 or BRCA2 gene mutation were invited to undergo annual breast screening with MRI in addition to mammography and clinical breast examination. We assessed process times for booking, performing and reporting MRIs; MRI findings and ease of interpretation; patient recall rate; MRI cancer detection rate; and patient satisfaction via questionnaire.From 2006 to 2009, 82 women completed a round one screening MRI and 45, 21 and one women completed second, third and fourth round annual MRI studies, respectively. Median MRI process times were: booking 20 min; attendance in radiology department 90 min; imaging duration 45 min; reporting by one radiologist 30 min. Of the 82 round one studies, 23 (28%) were reported as ≥Breast Imaging Reporting and Data System three requiring further investigation. Of the round two and three studies completed, 13/45 (28%) and 2/21 (9%) have been recalled, respectively. Seven malignancies were detected. Questionnaires revealed women were satisfied with the service.Significant time, staff and equipment is required to run an effective breast MRI screening programme and this must be considered by future service providers.

Background: The aim was to investigate the correlation between 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) metabolic response to chemoradiotherapy and clinical outcomes in squamous cell carcinoma (SCC) of the anus. Methods: A total of 48 patients with biopsy-proven anal SCC underwent FDG-PET scans at baseline and post chemoradiotherapy (54 Gy, concurrent 5-FU/mitomycin). Kaplan–Meier analysis was used to determine survival outcomes according to FDG-PET metabolic response. Results: In all, 79% patients (n=38) had a complete metabolic response (CMR) at all sites of disease, 15% (n=7) had a CMR in regional nodes but only partial response in the primary tumour (overall partial metabolic response (PMR)) and 6% (n=3) had progressive distant disease despite CMR locoregionally (overall no response (NR)). The 2-year progression-free survival (PFS) was 95% for patients with a CMR, 71% for PMR and 0% for NR (P

Aim To illustrate imaging manifestations of unusual side effects of some new anti-cancer medications. Many of the new anti-cancer medications target specific biologic pathways and are expected to cause less adverse effects on healthy tissues. Some of these agents are associated with unusual side effects, recognition of which is clinically important. Ipilimumab is a monoclonal antibody against cytotoxic T lymphocyte-associated antigen (CTLA)-4 used for the treatment of metastatic melanoma. Though it has been shown to increase overall survival rates, it also results in various immune-related adverse effects, one of which is hypophysitis. Crizotinib is an anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 inhibitor, approved for treatment of non-small cell lung carcinoma. Its side effects include the unusual formation of complex renal cysts which mimic renal abscesses or malignancy. In this presentation, we illustrate the imaging manifestations of Ipilimumab associated hypophysitis, early recognition of which is important as cessation of the drug in affected patients leads to resolution of hypophysitis, and also demonstrate complex renal cysts associated with the use of Crizotinib, knowledge of which is important to avoid misdiagnosis of renal abscess/ malignancy and consequent inappropriate treatment or stoppage of Crizotinib.

Background Novel therapeutic agents recently introduced for the treatment of cancer have several unusual side effects. An increased incidence of renal cystic lesions, often with features concerning for malignancy or infection, has been reported in patients with anaplastic lymphoma kinase (ALK) - rearranged advanced non-small cell lung cancer (NSCLC) treated with Crizotinib. Many of these lesions undergo spontaneous resolution despite developing complex features on imaging. We assess the incidence and patterns of evolution of Crizotinib Associated Renal Cysts [CARCs] at our institute and provide histopathology correlation of their benign nature. Methods A retrospective analysis of renal lesions in computerised tomography (CT) scans of 35 patients with advanced ALK-rearranged NSCLC who had been prescribed crizotinib at our institution was performed by three radiologists, who analysed the evolution of these lesions, particularly for pre-defined significant and complex changes. Results Of 26 patients eligible for this analysis, 4 (15%) had cysts at baseline that remained stable on crizotinib treatment while 11(42%) developed significant change in 28 renal cysts. Commonest pattern of cyst evolution was enlargement from baseline followed by spontaneous regression (17/28 lesions) while other patterns noted were stable lesions, regression from baseline and ongoing enlargement. The median maximum size reached was 23 mm (range 9 – 67 mm) after a median of 178 days (160 to 1342) on crizotinib. Complex change occurred in 12 cysts, in 7/26 (27%) patients and within 60 days of starting Crizotinib in 10 cysts. Imaging features were falsely concerning for malignancy or abscess in 4/26 patients. Conclusion Most CARCs resolve spontaneously, or have a benign evolution despite enlargement and other features concerning for malignancy or infection on imaging. This unusual manifestation of chemotherapy should be recognised, particularly by radiologists, so that inappropriate treatment decisions are avoided.