Neoadjuvant trastuzumab deruxtecan (T-DXd) with response-directed definitive therapy in early stage HER2-positive breast cancer: a phase II study protocol (SHAMROCK study).

BACKGROUND: The current standard of care in the neoadjuvant setting for high-risk HER2-positive (HER2 +) breast cancer is to combine systemic chemotherapy with dual HER2 blockade, trastuzumab and pertuzumab. Targeted therapies have significantly improved outcomes for patients with HER2-positive breast cancer. To improve treatment-associated toxicity, chemotherapy-sparing approaches are currently being investigated. Trastuzumab deruxtecan (T-DXd) is an HER2-directed antibody-drug-conjugate (ADC) with promising results in the metastatic setting for HER2-positive breast cancer. The SHAMROCK study investigates neoadjuvant T-DXd in early stage HER2-positive breast cancer, using pathological complete response (pCR) rate as the primary endpoint. METHODS: This is a phase II open-label, single arm, adaptive multi-centre trial of T-DXd in the neoadjuvant setting in stage 2-3 HER2-positive breast cancer. Eligible patients will receive 5.4 mg/kg of T-DXd intravenously every 3 weeks for up to 6 cycles. A repeat biopsy will performed after 2 cycles for the RNA disruption index (RDI) score assessment. According to their likelihood of pCR, as determined by the RDI score, patients will either undergo 4 or 6 cycles of T-DXd prior to imaging. Patients with imaging complete response (iCR) after either 4 or 6 cycles will proceed to surgery. Patients who do not achieve iCR will either undergo further systemic therapy or proceed to surgery. DISCUSSION: The SHAMROCK study is a chemotherapy-sparing approach to curative intent treatment, investigating neoadjuvant T-DXd. We hypothesise that neoadjuvant T-DXd will have a high pCR rate and be associated low toxicity in early stage HER2-positive breast cancer. TRIAL REGISTRATION: EudraCT Number: 2022-002485-32; ClinicalTrials.gov identifier: NCT05710666; Cancer Trials Ireland study number: CTRIAL-IE 22-01.

Assessing Mode of Recurrence in Breast Cancer to Identify an Optimised Follow-Up Pathway: 10-Year Institutional Review.

BACKGROUND: Breast cancer surveillance programmes ensure early identification of recurrence which maximises overall survival. Programmes include annual clinical examination and radiological assessment. There remains debate around the value of annual clinical exam in diagnosing recurrent disease/second primaries. The aim was to assess diagnostic modalities for recurrent breast cancer with a focus on evaluating the role of annual clinical examination. PATIENTS AND METHODS: A prospectively maintained database from a symptomatic breast cancer service between 2010-2020 was reviewed. Patients with biopsy-proven recurrence/second breast primary were included. The primary outcome was the diagnostic modality by which recurrences/secondary breast cancers were observed. Diagnostic modalities included (i) self-detection by the patient, (ii) clinical examination by a breast surgeon or (iii) radiological assessment. RESULTS: A total of 233 patients were identified and, following application of exclusion criteria, a total of 140 patients were included. A total of 65/140 (46%) patients were diagnosed clinically, either by self-detection or clinical examination, while 75/140 (54%) were diagnosed radiologically. A total of 59/65 (91%) of patients clinically diagnosed with recurrence presented to the breast clinic after self-detection of an abnormality. Four (6%) patients had cognitive impairment and recurrence was diagnosed by a carer. Two (3%) patients were diagnosed with recurrence by a breast surgeon at clinical examination. The median time to recurrence in all patients was 48 months (range 2-263 months). CONCLUSION: Clinical examination provides little value in diagnosing recurrence (< 5%) and surveillance programmes may benefit from reduced focus on such a modality. Regular radiological assessment and ensuring patients have urgent/easy access to a breast clinic if they develop new symptoms/signs should be the focus of surveillance programmes.

Clinically guided core biopsy and cutaneous punch biopsy in the evaluation of breast lesions: a necessary test or an obsolete skill?

OBJECTIVE: The vast majority of breast cancers are diagnosed via image-guided procedures yet despite significant advances, imaging does not identify all breast malignancies. Clinically suspicious breast lesions with normal breast imaging remain a cause for concern. The aim of this study is to determine the diagnostic value of clinical core and cutaneous punch biopsies in the diagnosis of breast malignancy in clinically suspicious lesions with normal breast imaging. METHODS: All patients with suspicious clinical breast findings and normal imaging who underwent a clinical core and/or cutaneous punch biopsy from 2012 to 2019 were reviewed retrospectively. Patients with subsequent breast malignant diagnosis were analysed. RESULTS: A total of 283 biopsies (166 clinical core, 117 cutaneous punch) performed over the 7-year period were included in the analysis. A total of 263/283 (93%) yielded a benign outcome. A total of 2/283 (0.7%) yielded B3 lesions (probably benign). These lesions were benign on final surgical excision. A total of 18/283 (6.3%) yielded a malignant histopathology. Sixteen out of 18 were cutaneous punch biopsies, and 2/18 were clinical core biopsies. A total of 14/18 patients presented with nipple changes, while 4/18 had a palpable area of concern. Histopathological analysis demonstrated Paget's disease of the nipple in 8/18, invasive carcinoma in 9/18 out of which two represented a recurrence of breast malignancy. Cutaneous squamous cell carcinoma was diagnosed in 1/18. CONCLUSION: Clinical core and cutaneous punch biopsies remain a valuable tool in the diagnosis of breast cancer particularly in the management of clinically suspicious radiographically occult malignancies.

Value of Long-term Follow-up in Surgically Excised Lesions of Uncertain Malignant Potential in the Breast - Is 5 Years Necessary?

INTRODUCTION: B3 lesions are a heterogeneous group of breast lesions of uncertain malignant potential which usually require excision. The aim was to assess the efficacy of 5 years routine radiological or clinical follow-up of patients who had "high-risk" B3 lesions surgically excised, by analyzing recurrence and subsequent development of invasive/in-situ cancer. PATIENTS AND METHODS: A 10-year retrospective review from 2010 to 2019 was performed of B3 lesions diagnosed on core needle biopsy, including patients who proceeded to surgical excision with a high-risk lesion on final histology. The database recorded 6 specific B3 lesion categories: 1. Atypical ductal hyperplasia (ADH), 2. Radial scars/complex sclerosing lesions (CSLs) with epithelial atypia 3. Classical Lobular neoplasia (ALH/LCIS), 4. Papillary lesions with epithelial atypia, 5. Mixed, 6. Flat epithelial atypia (FEA), including radiological and clinical follow-up data. RESULTS: Six hundred sixteen patients had a B3 lesion after core biopsy. 110 patients had "high risk" lesions. This included 17 (15.5%) Atypical Ductal Hyperplasia (ADH), 22 (20%) radial scars/CSLs with epithelial atypia, 47 (42.7%) classical lobular neoplasia (LCIS/ALH), 7 (6.4%) papillary lesions with epithelial atypia, 13 (11.8%) mixed lesions & 4 (3.6%) Flat Epithelial Atypia (FEA) lesions. 4 of 110 (3.6%) developed invasive/in-situ disease and 4 of 110 (3.6%) developed recurrence during follow-up. 33 of 616 (5.4%) upgraded to invasive/preinvasive disease after surgical excision. CONCLUSION: Five years of routine radiological surveillance may not be necessary in patients who undergo surgical excision of "high-risk" B3 lesions. Clinical surveillance appears to be of little benefit, especially in patients with radial scars, papillary lesions, and FEA. Subsequent development of invasive/in-situ disease in patients who undergo surgical excision of atypical B3 lesions remains low.

Breast cancer patients with a negative axillary ultrasound may have clinically significant nodal metastasis.

INTRODUCTION: The non-invasive nature of the preoperative axillary ultrasound (AUS) fits the current trend of increasingly conservative axillary management. Recent publications suggest that early disease patients with clinically and radiologically negative axillae do not require sentinel lymph node biopsy (SLNB). This study aims to determine the true extent of axillary node disease in negative preoperative AUS patients. METHODS: A 10-year breast cancer registry was reviewed to identify women with pathologically confirmed T1-2 invasive breast cancer and a negative preoperative AUS. Patients who received neoadjuvant chemotherapy were excluded. Combined positive lymph node count of SLNB ± ALND was used to determine total nodal burden (TNB). Axillae were classified into low nodal burden (LNB) defined as 1-2 positive nodes and high nodal burden (HNB) defined as ≥ 3 positive nodes. RESULTS: 762 patients with negative AUS were included. There were 46.9% and 53.0% T1 and T2 tumours, respectively. 76.9% were node negative (0 LN +), 18.9% had LNB (1-2 LN +) and 4.2% had HNB (≥ 3LN +). Specifically, HNB disease was seen in 2% of T1 tumours and 6.2 % of T2 tumours with a negative AUS. In multivariate analysis, T2 strongly associated with ≥ 3 positive ALNs (OR 2.66 CI 1.09-6.51 p = 0.03) as did lymphovascular invasion (OR 3.56 CI 1.52-8.30 p = < 0.01). CONCLUSION: This study shows that AUS in its current form cannot exclude HNB axillary metastasis to the extent of eliminating the need for surgical staging of the axilla. This may impact axillary local-regional recurrence and disease-free survival. We caution that a negative AUS has a rate of 4.2% of HNB. Therefore, in cases of negative AUS with a T2 tumour, we advocate continued use of SLNB.

Patient demographics and management challenges in an Irish symptomatic breast cancer unit.

BACKGROUND: Breast cancer is the most common cancer in women. Beaumont Hospital is a nationally designated symptomatic breast cancer unit, independent of the national screening programme, BreastCheck. AIMS: We hypothesised that patients attending symptomatic breast cancer units differ from national registry data and aimed to characterise this in a retrospective study. METHODS: A prospective database of patients diagnosed with breast cancer was maintained between 2014 and 2017. Multiple patient and tumour demographics were analysed retrospectively and compared with data from the National Cancer Registry. RESULTS: In total, 944 patients were diagnosed with breast cancer, 379 (40%) were aged < 50, 206 (22%) 50-64, 208 (22%) 65-75 and 151 (16%) > 75 years respectively. Expectedly, older patients (≥ 65 years) had a higher proportion of oestrogen receptor-positive, HER2-negative breast cancer (72%). Triple negative breast cancer was relatively more common (17%) among younger patients. These patients received more intensive chemotherapy: 118 (64%) received combination anthracycline-taxane chemotherapy, in comparison with only 14 (21%) of older patients. Patients generally presented at a later stage compared with national registry data: stage II 491 (52%) and stage III 179 (19%) versus stage II (50%) and stage III (13%). CONCLUSION: Patients attending the symptomatic breast cancer unit Beaumont Hospital have different demographics compared with the national registry data. This presents particular challenges for management.

Impact of somatic PI3K pathway and ERBB family mutations on pathological complete response (pCR) in HER2-positive breast cancer patients who received neoadjuvant HER2-targeted therapies.

BACKGROUND: The Cancer Genome Atlas analysis revealed that somatic EGFR, receptor tyrosine-protein kinase erbB-2 (ERBB2), Erb-B2 receptor tyrosine kinase 3 (ERBB3) and Erb-B2 receptor tyrosine kinase 4 (ERBB4) gene mutations (ERBB family mutations) occur alone or co-occur with somatic mutations in the gene encoding the phosphatidylinositol 3-kinase (PI3K) catalytic subunit (PIK3CA) in 19% of human epidermal growth factor receptor 2 (HER2)-positive breast cancers. Because ERBB family mutations can activate the PI3K/AKT pathway and likely have similar canonical signalling effects to PI3K pathway mutations, we investigated their combined impact on response to neoadjuvant HER2-targeted therapies. METHODS: Baseline tumour biopsies were available from 74 patients with HER2-positive breast cancer who were enrolled in the phase II TCHL neoadjuvant study (ICORG 10-05) assessing TCH (docetaxel, carboplatin, trastuzumab) (n = 38) versus TCL (docetaxel, carboplatin, lapatinib) (n = 10) versus TCHL (docetaxel, carboplatin, trastuzumab, lapatinib) (n = 40), each for six cycles. Activating mutations in PIK3CA and ERBB family genes were identified using mass spectrometry-based genotyping. Phosphatase and tensin homolog (PTEN) expression was assessed by immunohistochemistry. RESULTS: PIK3CA and/or ERBB family mutations were detected in 23 (31.1%) tumour samples tested, whereas PTEN expression was low in 31.1% of cases tested. Mutation frequency was similar in each treatment arm (31.3% in TCH arm, 30% in TCL arm and 31.3% in TCHL arm) and was not influenced by oestrogen receptor (ER) status (27.6% in ER-negative patients, 33.3% in ER-positive patients) or progesterone receptor (PR) status (32.6% in PR-negative patients, 29% in PR-positive patients). There was no significant difference in pathological complete response (pCR) rates between 47 patients with wild-type (WT) tumours and 22 patients whose tumours carried mutations (in either PIK3CA or ERBB family genes) (42.5% vs. 54.5%; p = 0.439). Similarly, there was no significant difference in pCR rates between patients with PIK3CA/ERBB family mutated/PTEN-low (i.e., PI3K-activated) tumours and patients without PI3K activation (50% vs. 44%; p = 0.769). However, in the TCHL (but not the TCH) group, the pCR rate was higher for 9 patients with PIK3CA/ERBB family mutated tumours than for 20 patients with PIK3CA/ERBB family WT tumours (77.8% vs. 35%; p = 0.05). CONCLUSIONS: Our results indicate that patients who receive neoadjuvant TCHL and have PIK3CA/ERBB family mutated tumours may be more likely to have a pCR than patients with WT tumours. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01485926 . Registered on 2 December 2011.

Ultrasound-guided core biopsy: an effective method of detecting axillary nodal metastases.

BACKGROUND: Axillary nodal status is an important prognostic predictor in patients with breast cancer. This study evaluated the sensitivity and specificity of ultrasound-guided core biopsy (Ax US-CB) at detecting axillary nodal metastases in patients with primary breast cancer, thereby determining how often sentinel lymph node biopsy could be avoided in node positive patients. STUDY DESIGN: Records of patients presenting to a breast unit between January 2007 and June 2010 were reviewed retrospectively. Patients who underwent axillary ultrasonography with or without preoperative core biopsy were identified. Sensitivity, specificity, positive predictive value, and negative predictive value for ultrasonography and percutaneous biopsy were evaluated. RESULTS: Records of 718 patients were reviewed, with 445 fulfilling inclusion criteria. Forty-seven percent (n = 210/445) had nodal metastases, with 110 detected by Ax US-CB (sensitivity 52.4%, specificity 100%, positive predictive value 100%, negative predictive value 70.1%). Axillary ultrasonography without biopsy had sensitivity and specificity of 54.3% and 97%, respectively. Lymphovascular invasion was an independent predictor of nodal metastases (sensitivity 60.8%, specificity 80%). Ultrasound-guided core biopsy detected more than half of all nodal metastases, sparing more than one-quarter of all breast cancer patients an unnecessary sentinel lymph node biopsy. CONCLUSIONS: Axillary ultrasonography, when combined with core biopsy, is a valuable component of the management of patients with primary breast cancer. Its ability to definitively identify nodal metastases before surgical intervention can greatly facilitate a patient's preoperative integrated treatment plan. In this regard, we believe our study adds considerably to the increasing data, which indicate the benefit of Ax US-CB in the preoperative detection of nodal metastases.

Indeterminate or suspicious breast lesions detected initially with MR imaging: value of MRI-directed breast ultrasound.

RATIONALE AND OBJECTIVES: To retrospectively determine the value of magnetic resonance imaging (MRI)-directed breast ultrasonography (US) in the evaluation of indeterminate or suspicious lesions identified on contrast-enhanced, breast MRI. MATERIALS AND METHODS: A total of 395 patients presenting for breast MRI during a 4-year period was retrospectively reviewed. Seventy-one patients were recommended for MRI-directed US for further characterization of indeterminate or suspicious breast lesions detected on MRI. Fifty-five patients (all female; age 31-80 years) had US. Their MRI and US were reviewed and tested for correlations with histologic results or long term follow-up. Logistic regression analyses were used to test for associations between MRI lesion characteristics and US detection rate. RESULTS: US identified 46 of 97 (47%) lesions depicted at MRI from 55 patients (47 [85%] of these patients had histories of breast malignancies). Twelve cancers were found from the 97 lesions (12%). Biopsy was avoidable in 10 lesions (10%). The detection rate with US was slightly higher with "mass" (55% [23/42]) lesions described in MRI than "non-mass" lesions or lymph nodes (42% [23/55]). There was a significant positive association (odd ratio = 1.23: 95% CI = 1.05-1.43, P = .01) between US detection rate and MRI mass lesion size. There was no statistical significance between US detection rate and the presence of malignancies; 42% (5/12) of MRI malignant lesions were not visualized with US. CONCLUSIONS: MRI-directed US reduced the number of biopsies required for indeterminate or suspicious MRI lesions. Nevertheless, the lesions which were biopsied had a low rate of malignancy.

Correlation between core biopsy and excisional biopsy in breast high-risk lesions.

BACKGROUND: The purpose of the current study was to compare the prevalence of invasive or in situ cancer at excisional biopsy in patients with image-guided core needle biopsy (CNB)-proven atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), or lobular carcinoma-in-situ (LCIS). Factors affecting the upgrade rate to malignancy were also identified. METHODS: Patients diagnosed with ADH, ALH, or LCIS on image-guided CNB (stereotactic or ultrasound) from 1995 to 2005 were identified through radiologic and surgical databases. Patients who subsequently underwent excisional biopsy of their lesion were included in the study. The imaging, medical records, and pathology of these patients were reviewed. RESULTS: Ninety-six patients with either ADH (61/96, 63%), ALH (19/96, 20%), or LCIS (16/96, 17%) on image-guided CNB proceeded to excisional biopsy. Malignancy was detected on excisional biopsy in 31% of patients with ADH, 16% of patients with ALH, and 25% of patients with LCIS. There were no significant differences between the 2 groups in terms of age, parity, hormonal status, or previous benign breast biopsies. The presence of a mass on mammography was associated with an increased upgrade rate to malignancy, while biopsies performed using vacuum-assisted devices, larger gauge biopsy needles, and greater number of cores were associated with a lower upgrade rate. CONCLUSIONS: Our data suggest that excisional biopsy is warranted in all patients with CNB diagnoses of ADH, ALH, or LCIS to exclude the presence of cancer.

Coronal oblique turbo STIR imaging of the sacrum and sacroiliac joints at routine MR imaging of the lumbar spine.

The objective of the study was to evaluate the clinical impact of coronal oblique imaging of the lumbrosacral junction and the sacrum at initial presentation for MR imaging of the lumbar spine in patients presenting with low back pain or sciatic pain. Two hundred and sixty consecutive patients attending for MRI of the lumbar spine underwent simultaneous coronal oblique turbo short tau inversion recovery (STIR; TR 2500, TE 40, TI 150, echo train length 7, number of scan acquisitions 2) imaging of the sacrum and the sacroiliac joints with a field of view of 30-cm and 3-mm slices (acquisition time 3 min and 20 s). Images were reviewed by two experienced radiologists to determine the cause of back pain, with and without images of the sacrum and sacroiliac joints. The added value of the additional sequence was assessed. Correlation was made with surgery, response to nerve root injection or clinical follow-up at 3 months. Subgroup analysis was performed to determine if patient stratification according to sex or symptoms would be useful. In total, in 19 of 260 patients (7.3%), abnormalities were identified at coronal STIR imaging. In 7 of 260 patients (2.7%), pathology was identified in the sacrum thought to account for back pain, altering the diagnosis made on the standard sequences. These diagnoses were sacroiliitis (n=2), sacral stress fracture (n=1), degenerative sacroiliac joints (n=1), degenerative accessory articulation between the lumbar spine and the sacrum (n=1), Tarlov cyst of nerve root (n=1) and retroverted uterus causing sciatic pain (n=1). Patient stratification according to sex or the presence or absence of sciatic symptoms was not useful in predicting the added benefit of the additional sequence. Routine coronal STIR imaging of the sacrum as part of lumbar spine MRI improves assessment of patients presenting with low back pain or sciatica in only a small number of patients.

De novo placement of button gastrostomy catheters in an adult population: experience in 53 patients.

PURPOSE: To investigate the feasibility of primary button gastrostomy insertion with the aid of T-fastener gastropexy. MATERIALS AND METHODS: Fifty-three consecutive patients (33 men, 20 women; mean age, 63.4 years) referred for percutaneous radiologic gastrostomy (PRG) underwent primary button gastrostomy insertion over an 18-month period in two centers. Nine of the patients (17%) were referred after failed endoscopic gastrostomy and 44 (83%) were primarily referred for PRG. Indications for gastrostomy included esophageal/head and neck malignancy (n = 33) and neurologic disorders (n = 20). Gastropexy with three or four T-fasteners was performed in all patients and angioplasty balloon catheters (6 mm x 40 mm) were used to measure tract length and dilate the tract. An 18-F dilator was used for final tract dilation. Button gastrostomy catheters with retention balloons were inserted in all patients. Patient follow-up was performed by the department of dietetics, which contacted patients on a weekly basis. RESULTS: Primary button gastrostomy insertion was successful in 52 of 53 patients (98%). The mean gastrostomy button catheter survival was 13.3 weeks (range, 1-28 weeks). No episodes of button occlusion occurred. Since the beginning of this study, 33 patients (63%) have had their gastrostomy buttons replaced. The reasons for button replacement include burst retention balloons (n = 27; 52%), dislodgment of the catheter (n = 4; 8%), and continuing pain/discomfort at the gastrostomy site (n = 2; 4%). CONCLUSION: Button-type gastrostomy catheters can be placed de novo by interventional radiologists without the need for a mature tract, provided a T-fastener gastropexy is used. The balloon retention button devices are not compromised by occlusion but do tend to become dislodged.