Breast surgery after neoadjuvant chemotherapy in patients with lobular carcinoma: surgical and oncologic outcome.

INTRODUCTION: Breast cancer patients with invasive lobular carcinoma (ILC) have an increased risk of positive margins after surgery and often show little response to neoadjuvant chemotherapy (NAC). We aimed to investigate surgical outcomes in patients with ILC treated with NAC. METHODS: In this retrospective cohort study, all breast cancer patients with ILC treated with NAC who underwent surgery at the Netherlands Cancer Institute from 2010 to 2019 were selected. Patients with mixed type ILC in pre-NAC biopsies were excluded if the lobular component was not confirmed in the surgical specimen. Main outcomes were tumor-positive margins and re-excision rate. Associations between baseline characteristics and tumor-positive margins were assessed, as were complications, locoregional recurrence rate (LRR), recurrence-free survival (RFS), and overall survival (OS). RESULTS: We included 191 patients. After NAC, 107 (56%) patients had breast conserving surgery (BCS) and 84 (44%) patients underwent mastectomy. Tumor-positive margins were observed in 67 (35%) patients. Fifty five (51%) had BCS and 12 (14%) underwent mastectomy (p value < 0.001). Re-excision was performed in 35 (33%) patients with BCS and in 4 (5%) patients with mastectomy. Definitive surgery was mastectomy in 107 (56%) patients and BCS in 84 (44%) patients. Tumor-positive margins were associated with cT ≥ 3 status (OR 4.62, 95% CI 1.26-16.98, p value 0.021) in the BCS group. Five-year LRR (4.7%), RFS (81%), and OS (93%) were not affected by type of surgery after NAC. CONCLUSION: Although 33% of ILC breast cancer patients undergoing BCS after NAC required re-excision for positive resection margins, it is considered safe given that five-year RFS remained excellent and LRR and OS did not differ by extent of surgery.

Biopsy-Guided Pathological Response Assessment in Breast Cancer is Insufficient: Additional Pathology Findings of the MICRA Trial.

BACKGROUND: Neoadjuvant systemic treatment (NST) leads to pathologic complete response (pCR) in 10-89% of breast cancer patients depending on subtype. The added value of surgery is uncertain in patients who reach pCR; however, current imaging and biopsy techniques aiming to predict pCR are not accurate enough. This study aims to quantify the residual disease remaining after NST in patients with a favorable response on MRI and residual disease missed with biopsies. METHODS: In the MICRA trial, patients with a favorable response to NST on MRI underwent ultrasound-guided post-NST 14G biopsies followed by surgery. We analyzed pathology reports of the biopsies and the surgical specimens. Primary outcome was the extent of residual invasive disease among molecular subtypes, and secondary outcome was the extent of missed residual invasive disease. RESULTS: We included 167 patients. Surgical specimen showed residual invasive disease in 69 (41%) patients. The median size of residual invasive disease was 18 mm (interquartile range [IQR] 12-30) in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) patients, 8 mm (IQR 3-15) in HR+/HER2-positive (HER2+) patients, 4 mm (IQR 2-9) in HR-negative (HR-)/HER2+ patients, and 5 mm (IQR 2-11) in triple-negative (TN) patients. Residual invasive disease was missed in all subtypes varying from 4 to 7 mm. CONCLUSION: Although the extent of residual invasive disease is small in TN and HER2+ subtypes, substantial residual invasive disease is left behind in all subtypes with 14G biopsies. This may hamper local control and limits adjuvant systemic treatment options. Therefore, surgical excision remains obligatory until accuracy of imaging and biopsy techniques improve.

Clinical impact of molecular breast imaging as adjunct diagnostic modality in evaluation of indeterminate breast abnormalities and unresolved diagnostic concerns.

PURPOSE: Improvements in molecular breast imaging (MBI) have increased the use of MBI as adjunct diagnostic modality and alternative to MRI. We aimed to assess the value of MBI in patients with equivocal breast lesions on conventional imaging, especially in terms of its ability to rule out malignancy. METHODS: We selected patients who underwent MBI in addition to conventional diagnostics due to equivocal breast lesions between 2012 and 2015. All patients underwent digital mammography, target ultrasound and MBI. MBI was performed using a single-head Dilon 6800 gamma camera after administration of 600 MBq 99m Tc-sestamibi. Imaging was reported according to BI-RADS classification and compared with pathology or follow-up of ≥6 months. RESULTS: Of 226 women included, pathology was obtained in 106 (47%) and (pre)malignant lesions were found in 25 (11%). Median follow-up was 5.4 years (IQR 3.9-7.1). Sensitivity was higher for MBI compared to conventional diagnostics (84% vs. 32%; P = 0.002), identifying malignancy in 21 and 6 patients, respectively, but specificity did not differ (86% vs. 81%; P = 0.161). Positive and negative predictive value were 43% and 98% for MBI and 17% and 91% for conventional diagnostics. MBI was discordant with conventional diagnostics in 68 (30%) patients and correctly changed diagnosis in 46 (20%) patients, identifying 15 malignant lesions. In subgroups with nipple discharge ( N = 42) and BI-RADS 3 lesions ( N = 113) MBI detected 7 of 8 occult malignancies. CONCLUSION: MBI correctly adjusted treatment in 20% of patients with diagnostic concerns after conventional work-up, and could rule out malignancy with a high negative predictive value of 98%.

Immediate or delayed oncoplastic surgery after breast conserving surgery at the Netherlands Cancer Institute: a cohort study of 251 cases.

PURPOSE: Oncoplastic surgery (OPS) after breast conserving surgery is preferably performed during the same operation. Offering delayed OPS instead of mastectomy to patients with a high risk of tumor-positive margins allows breast conservation with the option of margin re-excision during OPS, without having to dismantle the reconstruction. We aimed to evaluate surgical outcomes after immediate and delayed OPS. METHODS: We included early-stage breast cancer patients who underwent OPS at the Netherlands Cancer Institute between 2016 and 2019. Patients were selected for delayed OPS after multidisciplinary consultation if the risk of tumor-positive margins with immediate OPS was considered significant (> 30%). Groups were compared on baseline characteristics and short-term surgical outcomes. RESULTS: Of 242 patients with 251 OPS, 130 (52%) OPS had neoadjuvant chemotherapy. Immediate OPS was performed in 176 (70%) cases and delayed OPS in 76 (30%). Selection for delayed OPS was associated with tumor size (OR 1.03, 95% CI 1.01-1.04), ILC (OR 2.61, 95% CI 1.10-6.20), DCIS (OR 3.45, 95% CI 1.42-8.34) and bra size (OR 0.76, 95% CI 0.62-0.94). Delayed and immediate OPS differed in tissue weight (54 vs. 67 g, p = 0.034), tissue replacement (51% vs. 26%, p < .001) and tumor-positive margins (66% vs. 18%, p < .001). Re-excision was performed in 48 (63%) delayed OPS and in 11 (6%) immediate OPS. Groups did not differ in complications (21% vs. 18%, p = 0.333). Breast conservation after immediate and delayed OPS was 98% and 93%, respectively. CONCLUSION: Performing delayed OPS in selected cases facilitated simultaneous margin re-excision without increasing complications, and resulted in an excellent breast conservation rate.

Clinical impact of MRI-detected additional lesions in breast cancer patients with neoadjuvant systemic therapy at the Netherlands cancer institute.

BACKGROUND: In breast cancer patients treated with neoadjuvant systemic therapy (NST), MRI is used pre- and post-NST for response monitoring. The relevance of additional MRI-detected lesions in these patients is unclear. Therefore, we aimed to assess the impact of pre-NST MRI-detected additional lesions on surgical treatment and outcome. METHODS: We retrospectively selected all early-stage breast cancer patients with MRI pre-NST at our institute from January 2010-2015. MRI-detected lesions were defined as separated from the index tumor and occult at conventional mammography and ultrasound. Outcomes were change in surgical treatment and five-year recurrence-free and overall survival. RESULTS: Overall, MRI detected additional lesions in 206 (31%) of 656 patients: in 160 patients in the ipsilateral breast and in 78 contralateral breasts, including 32 bilateral cases. Ipsilateral lesions were mostly categorized BI-RADS 5 (54 %) and contralateral lesions BI-RADS 3 (64%). Targeted ultrasound was performed in 115 (56%) patients: in 70 ipsilateral and in 64 contralateral cases. Biopsy was obtained in 44 (28% of 160) ipsilateral and 50 (64% of 78) contralateral breasts, containing tumor foci in 20 (13% of 160) and 11 (14% of 78) cases, respectively. Surgical treatment changed in 54 (26% of 206) patients: 19 (9%) had mastectomy, 24 (12%) had wider local excision and 11 (5%) underwent contralateral surgery. Five-year recurrence-free and overall survival did not differ for patients with local excision or mastectomy. CONCLUSION: Pre-NST MRI-detected additional lesions in 31% of patients, resulting in more extensive surgery in 26% of these patients, including 5% contralateral surgeries.

Three-year follow-up of de-escalated axillary treatment after neoadjuvant systemic therapy in clinically node-positive breast cancer: the MARI-protocol.

PURPOSE: In clinically node-positive (cN+) breast cancer patients, evidence supporting response-guided treatment after neoadjuvant systemic therapy (NST) instead of axillary lymph node dissection (ALND) is increasing, but follow-up results are lacking. We assessed three-year axillary recurrence-free interval (aRFI) in cN+ patients with response-adjusted axillary treatment according to the 'Marking Axillary lymph nodes with Radioactive Iodine seeds' (MARI)-protocol. METHODS: We retrospectively assessed all stage II-III cytologically proven cN+ breast cancer patients who underwent the MARI-protocol between July 2014 and November 2018. Pre-NST axillary staging with FDG-PET/CT (less- or more than four suspicious axillary nodes; cALN < 4 or cALN ≥ 4) and post-NST pathological axillary response measured in the pre-NST largest tumor-positive axillary lymph node marked with an iodine seed (MARI-node; ypMARI-neg or ypMARI-pos) determined axillary treatment: no further treatment (cALN < 4, ypMARI-neg), axillary radiotherapy (ART) (cALN < 4, ypMARI-pos and cALN ≥ 4, ypMARI-neg) or ALND plus ART (cALN ≥ 4, ypMARI-pos). RESULTS: Of 272 women included, the MARI-node was tumor-negative in 56 (32%) of 174 cALN < 4 patients and 43 (44%) of 98 cALN ≥ 4 patients. According to protocol, 56 (21%) patients received no further axillary treatment, 161 (59%) received ART and 55 (20%) received ALND plus ART. Median follow-up was 3.0 years (IQR 1.9-4.1). Five patients (one no further treatment, four ART) had axillary metastases. Three-year aRFI was 98% (95% CI 96-100). The overall recurrence risk remained highest for patients with ALND (HR 4.36; 95% CI 0.95-20.04, p = 0.059). CONCLUSIONS: De-escalation of axillary treatment according to the MARI-protocol prevented ALND in 80% of cN+ patients with an excellent three-year aRFI of 98%.

[18F]FDG-PET/CT in prone compared to supine position for optimal axillary staging and treatment in clinically node-positive breast cancer patients with neoadjuvant systemic therapy.

PURPOSE: Axillary staging before neoadjuvant systemic therapy in clinically node-positive breast cancer patients with tailored axillary treatment according to the Marking Axillary lymph nodes with radioactive iodine seeds (MARI)-protocol, a protocol developed at the Netherlands Cancer Institute, is performed with [18F] fluorodeoxyglucose (FDG) positron emission tomography and computed tomography (PET/CT). We aimed to assess the value of FDG-PET/CT in prone compared to standard supine position for axillary staging. METHODS: We selected patients with FDG-PET/CT in supine and prone position who underwent the MARI-protocol. One hour after administration of 3.5 MBq/kg, [18F]FDG-PET was performed with a low-dose prone position CT-thorax followed by a supine whole-body scan. Scans were separately reviewed by two nuclear medicine physicians and categorized by number of FDG-positive axillary lymph nodes (ALNs; cALN<4 or cALN≥4). Main outcome was axillary up- or downstaging. RESULTS: Of 153 patients included, 24 (16%) patients were up- or downstaged at evaluation of prone images: One observer upstaged 14 patients, downstaged 3  patients and reported a higher number of ALNs (3.6 vs. 3.2, p < 0.001), while staging (4 up- and 5 downstaged) and number of ALNs (2.8 vs. 2.8) did not differ for the other. Observers agreed on up- or downstaging in only 1 (1%) patient. Irrespective of supine or prone position scanning, observers agreed on axillary staging in 124 (81%) patients and disagreed in 5 (3%). Interobserver agreement was lower with prone assessments (86%, K = 0.67) than supine (92%, K = 0.80). CONCLUSIONS: Axillary staging with FDG-PET/CT in prone compared to supine position did not result in concordant up- or downstaging. Therefore, FDG-PET/CT in supine position only can be considered sufficient for axillary staging.

Minimally Invasive Complete Response Assessment of the Breast After Neoadjuvant Systemic Therapy for Early Breast Cancer (MICRA trial): Interim Analysis of a Multicenter Observational Cohort Study.

BACKGROUND: The added value of surgery in breast cancer patients with pathological complete response (pCR) after neoadjuvant systemic therapy (NST) is uncertain. The accuracy of imaging identifying pCR for omission of surgery, however, is insufficient. We investigated the accuracy of ultrasound-guided biopsies identifying breast pCR (ypT0) after NST in patients with radiological partial (rPR) or complete response (rCR) on MRI. METHODS: We performed a multicenter, prospective single-arm study in three Dutch hospitals. Patients with T1-4(N0 or N +) breast cancer with MRI rPR and enhancement ≤ 2.0 cm or MRI rCR after NST were enrolled. Eight ultrasound-guided 14-G core biopsies were obtained in the operating room before surgery close to the marker placed centrally in the tumor area at diagnosis (no attempt was made to remove the marker), and compared with the surgical specimen of the breast. Primary outcome was the false-negative rate (FNR). RESULTS: Between April 2016 and June 2019, 202 patients fulfilled eligibility criteria. Pre-surgical biopsies were obtained in 167 patients, of whom 136 had rCR and 31 had rPR on MRI. Forty-three (26%) tumors were hormone receptor (HR)-positive/HER2-negative, 64 (38%) were HER2-positive, and 60 (36%) were triple-negative. Eighty-nine patients had pCR (53%; 95% CI 45-61) and 78 had residual disease. Biopsies were false-negative in 29 (37%; 95% CI 27-49) of 78 patients. The multivariable associated with false-negative biopsies was rCR (FNR 47%; OR 9.81, 95% CI 1.72-55.89; p = 0.01); a trend was observed for HR-negative tumors (FNR 71% in HER2-positive and 55% in triple-negative tumors; OR 4.55, 95% CI 0.95-21.73; p = 0.058) and smaller pathological lesions (6 mm vs 15 mm; OR 0.93, 95% CI 0.87-1.00; p = 0.051). CONCLUSION: The MICRA trial showed that ultrasound-guided core biopsies are not accurate enough to identify breast pCR in patients with good response on MRI after NST. Therefore, breast surgery cannot safely be omitted relying on the results of core biopsies in these patients.

Internal Mammary Chain Sentinel Nodes in Early-Stage Breast Cancer Patients: Toward Selective Removal.

BACKGROUND: Removal of internal mammary chain sentinel nodes (IMCSNs) affects prognosis and treatment of breast cancer, and internal mammary chain radiotherapy (IMCRT) can improve survival for selected patients. This study aimed to determine the effect of IMCSN biopsy on recurrence-free survival (RFS) and overall survival (OS) and to identify predictive factors for IMCSN and distant metastasis. METHODS: Patients with IMCSNs were selected from a prospective database for the period 1999-2007. Lymphoscintigraphy was performed after intratumoral technetium-99 m injection, and all sentinel nodes were removed. Both RFS and OS were calculated for subgroups with tumor-positive, tumor-negative, or non-removed IMCSNs. Predictive factors were identified for tumor-positive IMCSNs and distant metastasis by regression analysis. RESULTS: For 287 (85%) of 336 patients, IMCSN biopsy was performed, and metastasis was detected in 38 patients (13%). The patients with tumor-positive IMCSNs had poorer OS than the patients with no IMCSN metastasis or non-removed IMCSNs (p = 0.002). These patients also had worse RFS due to distant metastasis (p = 0.002). Axillary metastasis was predictive for tumor-positive IMCSNs (positive predictive value, 38.5%). The predictive factors for distant metastasis were tumor-positive IMCSNs (hazard ratio [HR], 2.5), non-removed IMCSNs (HR, 2.3), tumor diameter greater than 1.5 cm (HR, 3.5), and age older than 65 years (HR, 3.1; reference, < 50 years). CONCLUSIONS: Patients with IMCSNs have worse survival due to distant metastasis. The clinically relevant predictive factor for distant metastasis is tumor larger than 1.5 cm. According to the authors' current protocol, IMCSN biopsy is performed for patients younger than 70 years who have a tumor larger than 1.5 cm, with the cardiotoxicity of the adjuvant IMCRT weighed against the survival benefit.

[Gastrografin as a prognostic and therapeutic medium; use for small bowel obstruction, but not for closed loop obstruction]. / Gastrografin als prognostisch en therapeutisch medium.

Timely recognition and treatment of small bowel obstruction is of great importance for the course of the disease. Complete obstruction of the small bowel can lead to serious complications such as bowel ischaemia and perforation. Gastrografin, which is traditionally used as an oral contrast agent in imaging diagnostics, is of prognostic and therapeutic value in patients presenting with adhesive small bowel obstruction. CT is necessary to rule out closed loop obstruction or other than adhesive causes of the bowel obstruction before using Gastrografin. Patients with closed loop obstruction can rapidly develop bowel ischaemia and immediate surgery is indicated once diagnosed. Awaiting clinical resolution of the small bowel obstruction without surgery is justified when closed loop obstruction has been ruled out, there are no signs of bowel ischaemia and an abdominal radiograph within 4-24 hours after administration of Gastrografin shows the oral contrast in the colon.

[Breast-specific gamma imaging in breast cancer]. / 'Breast-specific gamma imaging' bij borstkanker.

Breast-specific gamma imaging (BSGI) is a new technique in nuclear medicine for the diagnosis of breast cancer. After intravenous injection of the radioactive substance 99mTc-sestamibi the breasts are imaged with a gamma camera. The radionuclide assimilates into intracellular mitochondria, which are present in greater numbers in breast cancer cells than in normal cells. This causes a relatively high uptake of the radionuclide in tumours. Along with mammography and ultrasound, MRI is the current gold standard in breast imaging diagnostics. However, MRI is a complex and expensive procedure and has low specificity leading to high false-positive rates. BSGI has equally high sensitivity but is more specific, cheaper and much simpler to interpret. BSGI could replace MRI as a complementary technique to show, exclude or indicate the extent of breast cancer.