Publications by authors named "Paolo Veronesi"

196 Publications

Frequency of Germline Mutations in Non-Gastric Cancers.

Cancers (Basel) 2021 May 12;13(10). Epub 2021 May 12.

Division of Breast Surgery, European Institute of Oncology (IEO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 20141 Milan, Italy.

Hereditary Diffuse Gastric Cancer (HDGC) is a complex inherited syndrome caused by germline mutations. DGC is the hallmark cancer of this genetic predisposition, but several other cancers are associated with these mutations. In this review, we revised all studies reporting mutations in non-GC patients. The selected studies included: (a) families aggregating with GC and other cancers, both, and (b) families presenting only non-gastric tumors association. Among non-gastric tumors, our results show that mutations are most frequently identified in breast cancer. The frequency of missense mutations is higher in the non-GC group, as the age at diagnosis in this group. Moreover, the predominant mutation affects the extracellular domain. Our data suggest that genetic testing should be considered also in other cancers, especially breast tumors.
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http://dx.doi.org/10.3390/cancers13102321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151827PMC
May 2021

Sex-based dimorphism of anticancer immune response and molecular mechanisms of immune evasion.

Clin Cancer Res 2021 May 20. Epub 2021 May 20.

Medicine, Weill Cornell Medicine.

Purpose: We previously demonstrated that sex influences response tovimmune-checkpoint inhibitors. Here we investigate sex-based differences in the molecular mechanisms of anticancer immune-response and immune evasion in patients with NSCLC.

Experimental Design: We analyzed a) transcriptome-data of 2575 early-stage NSCLCs from 7 different datasets; b) 327 tumor-samples extensively characterized at the molecular level from the TRACERx lung study; c) two independent cohorts of respectively 329 and 391 patients with advanced NSCLC treated with anti-PD1/anti-PDL1 drugs.

Results: As compared with men, the tumor microenvironment (TME) of women was significantly enriched for a number of innate and adaptive immune cell-types, including specific T-cell subpopulations. NSCLCs of men and women exploited different mechanisms of immune evasion. The TME of females was characterized by significantly greater T-cell dysfunction status, higher expression of inhibitory immune-checkpoint molecules and higher abundance of immune-suppressive cells, including Cancer Associated Fibroblasts, MDSCs and Regulatory T-cells. By contrast, the TME of males was significantly enriched for a T-cells excluded phenotype. We reported data supporting impaired neoantigens presentation to immune system in tumors of men, as molecular mechanism explaining the findings observed. Finally, in line with our results, we showed significant sex-based differences in the association between TMB and outcome of patients with advanced NSCLC treated with anti-PD1/PDL1 drugs.

Conclusions: We demonstrated meaningful sex-based differences of anticancer immune response and immune evasion mechanisms, that may be exploited to improve immunotherapy efficacy for both women and men.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0136DOI Listing
May 2021

CDH1 germline mutations in families with hereditary lobular breast cancer.

Eur J Cancer Prev 2021 May 7. Epub 2021 May 7.

Division of Breast Surgery, IEO European Institute of Oncology, IRCCS, Milan, Italy Department of Breast Surgery, Athens Euroclinic Hospital, Athens, Greece Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.

Pathogenic CDH1 germline mutations are associated with lobular breast cancer in the so-called hereditary lobular breast cancer (HLBC) syndrome, without apparent correlation with the classic hereditary diffuse gastric cancer (HDGC). Recent international guidelines recommend CDH1 screening also in absence of diffuse gastric cancer (DGC) history. Genomic characteristics underlying gastric and breast tumorigenesis in this varied population of patients is still unclear. In this review we revised all CDH1 germline mutations described in literature associated with lobular breast cancer (LBC). We distinguish two subgroups of CDH1 mutant carriers: (a) 'mixed' HDGC syndrome, showing both DGC plus LBC and (b) HLBC, in which DGC is absent and the LBC phenotype is predominant. A higher frequency of CDH1 mutations was identified in the HLBC syndrome with an early age at LBC diagnosis; it is possible that LBCs with CDH1 germline mutations are an independent inherited syndrome. This evidence allows us to gain biological insight into the pathophysiological mechanisms responsible for the different phenotypes of the disease and potentially tailor the prophylactic and screening procedures.
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http://dx.doi.org/10.1097/CEJ.0000000000000688DOI Listing
May 2021

Mastectomy alone for pT1-2 pN0-1 breast cancer patients: when postmastectomy radiotherapy is indicated.

Breast Cancer Res Treat 2021 Apr 27. Epub 2021 Apr 27.

Division of Breast Surgery, IEO European Institute of Oncology, IRCCS, Milan, Italy.

Purpose: To assess outcome of breast cancer (BC) stages pT1-2 N0-1 after mastectomy alone and to identify prognostic factors calling for the need of postmastectomy radiotherapy.

Methods: Patients who were not eligible for breast conserving surgery (BCS) were operated on with mastectomy between 1998 and 2008. Locoregional (LRR), distant (DM) control and breast cancer specific survival (BCSS) were retrospectively evaluated. Cumulative incidence (CI) of events was estimated according to Kalbfleisch and Prentice while Gray's test tested difference. Kaplan-Meier method for survival and Cox proportional hazards model for univariable and multivariable analysis were used. A matched pair analysis between mastectomy alone and BCS plus whole breast irradiation (WBI), using the propensity score method, was performed.

Results: 1281 pT1-2 N0 and 1081 pT1-2 N1 were identified. Median follow-up was 8.2 years (9.2 years for survival). Overall, LRR rate was low for both N0 and N1 subgroups (10-year CI, 8.8% and 10.9%, respectively). Young age, lymphovascular invasion and Ki-67 ≥ 20% were proved to be statistically significant prognostic factors at multivariable analysis. The combination of ≥ 2 risk factors increased LRR rate to ≥ 15%. Risk factors combination weighed on LRR rate more than nodal status itself. DM rate doubled moving from negative to positive nodal status (10-year CI 10.5% versus 20.3%, respectively). BCSS remained high in both N0 and N1 subgroups (10-year CI 92.4% versus 84.5%, respectively). Remarkably, all the molecular subtypes except Luminal A significantly affected DM and BCSS both in the N0 and N1 subgroups. Nodes number significantly impacted on DM and BCSS but not on locoregional control. In the matched pair analysis, WBI decreased nodal recurrence rate and improved distant control, without affecting survival.

Conclusions: Selected patients, namely those with at least two additional risk factors, presented high enough LRR risk to support the use of postmastectomy radiotherapy in both N0 and N1 subgroups. Moreover, the observation that radiotherapy may provide benefits that go beyond local control deserves to be further investigated.
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http://dx.doi.org/10.1007/s10549-021-06227-2DOI Listing
April 2021

Intraoperative irradiation for early breast cancer (ELIOT): long-term recurrence and survival outcomes from a single-centre, randomised, phase 3 equivalence trial.

Lancet Oncol 2021 05 9;22(5):597-608. Epub 2021 Apr 9.

Division of Breast Surgery, IEO European Institute of Oncology IRCCS, Milan, Italy.

Background: In the randomised, phase 3 equivalence trial on electron intraoperative radiotherapy (ELIOT), accelerated partial breast irradiation (APBI) with the use of intraoperative radiotherapy was associated with a higher rate of ipsilateral breast tumour recurrence (IBTR) than whole-breast irradiation (WBI) in patients with early-stage breast cancer. Here, we aimed to examine the planned long-term recurrence and survival outcomes from the ELIOT trial.

Methods: This single-centre, randomised, phase 3 equivalence trial was done at the European Institute of Oncology (Milan, Italy). Eligible women, aged 48-75 years with a clinical diagnosis of a unicentric breast carcinoma with an ultrasound diameter not exceeding 25 mm, clinically negative axillary lymph nodes, and who were suitable for breast-conserving surgery, were randomly assigned (1:1) via a web-based system, with a random permuted block design (block size of 16) and stratified by clinical tumour size, to receive post-operative WBI with conventional fractionation (50 Gy given as 25 fractions of 2 Gy, plus a 10 Gy boost), or 21 Gy intraoperative radiotherapy with electrons (ELIOT) in a single dose to the tumour bed during surgery. The trial was open label and no-one was masked to treatment group assignment. The primary endpoint was the occurrence of IBTR. The trial was designed assuming a 5-year IBTR rate of 3% in the WBI group and equivalence of the two groups, if the 5-year IBTR rate in the ELIOT group did not exceed a 2·5 times excess, corresponding to 7·5%. Overall survival was the secondary endpoint. The main analysis was done by intention to treat. The cumulative incidence of IBTR events and overall survival were assessed at 5, 10, and 15 years of follow-up. This trial is registered with ClinicalTrials.gov, NCT01849133.

Findings: Between Nov 20, 2000, and Dec 27, 2007, 1305 women were enrolled and randomly assigned: 654 to the WBI group and 651 to the ELIOT group. After a median follow-up of 12·4 years (IQR 9·7-14·7), 86 (7%) patients developed IBTR, with 70 (11%) cases in the ELIOT group and 16 (2%) in the WBI group, corresponding to an absolute excess of 54 IBTRs in the ELIOT group (HR 4·62, 95% CI 2·68-7·95, p<0·0001). In the ELIOT group, the 5-year IBTR rate was 4·2% (95% CI 2·8-5·9), the 10-year rate was 8·1% (6·1-10·3), and the 15-year rate was 12·6% (9·8-15·9). In the WBI group, the 5-year IBTR rate was 0·5% (95% CI 0·1-1·3), the 10-year rate was 1·1% (0·5-2·2), and the 15-year rate was 2·4% (1·4-4·0). At final follow-up on March 11, 2019, 193 (15%) women had died from any cause, with no difference between the two groups (98 deaths in the ELIOT group vs 95 in the WBI group; HR 1·03, 95% CI 0·77-1·36, p=0·85). In the ELIOT group, the overall survival rate was 96·8% (95% CI 95·1-97·9) at 5 years, 90·7% (88·2-92·7) at 10 years, and 83·4% (79·7-86·4) at 15 years; and in the WBI group, the overall survival rate was 96·8% (95·1-97·9) at 5 years, 92·7% (90·4-94·4) at 10 years, and 82·4% (78·5-85·6) at 15 years. We did not collect long-term data on adverse events.

Interpretation: The long-term results of this trial confirmed the higher rate of IBTR in the ELIOT group than in the WBI group, without any differences in overall survival. ELIOT should be offered to selected patients at low-risk of IBTR.

Funding: Italian Association for Cancer Research, Jacqueline Seroussi Memorial Foundation for Cancer Research, Umberto Veronesi Foundation, American Italian Cancer Foundation, The Lombardy Region, and Italian Ministry of Health.
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http://dx.doi.org/10.1016/S1470-2045(21)00080-2DOI Listing
May 2021

Geographical Distribution of E-cadherin Germline Mutations in the Context of Diffuse Gastric Cancer: A Systematic Review.

Cancers (Basel) 2021 Mar 12;13(6). Epub 2021 Mar 12.

i3S-Instituto de Investigação e Inovação em Saúde, University of Porto, 4200-135 Porto, Portugal.

Hereditary diffuse gastric cancer (HDGC) is a complex and multifactorial inherited cancer predisposition syndrome caused by germline mutations. Nevertheless, current genetic screening recommendations disregard an unbalanced worldwide distribution of variants, impacting testing efficacy and patient management. In this systematic review, we collected and analyzed all studies describing variants in gastric cancer patients originating from both high- and low-prevalence countries. Selected studies were categorized as family study, series study, and unknown study, according to the implementation of HDGC clinical criteria for genetic testing. Our results indicate that mutations are more frequently identified in gastric cancer low-incidence countries, and in the family study group that encompasses cases fulfilling criteria. Considering the type of alterations, we verified that the relative frequency of mutation types varies within study groups and geographical areas. In the series study, the missense variant frequency is higher in high-incidence areas of gastric cancer, when compared with non-missense mutations. However, application of variant scoring for putative relevance led to a strong reduction of variants conferring increased risk of gastric cancer. Herein, we demonstrate that criteria for genetic screening are critical for identification of individuals carrying mutations with clinical significance. Further, we propose that future guidelines for testing should consider GC incidence across geographical regions for improved surveillance programs and early diagnosis of disease.
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http://dx.doi.org/10.3390/cancers13061269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001745PMC
March 2021

Impact of radiation and hormonal therapy on the locoregional recurrence of elderly breast cancer: Are these necessary after breast-conserving surgery?

Cancer 2021 Apr 1. Epub 2021 Apr 1.

Division of Breast Surgery, European Institute of Oncology, IRCCS, Milan, Italy.

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http://dx.doi.org/10.1002/cncr.33550DOI Listing
April 2021

Chest wall infiltration is a critical prognostic factor in breast implant-associated anaplastic large-cell lymphoma affected patients.

Eur J Cancer 2021 May 23;148:277-286. Epub 2021 Mar 23.

Directorate General of Medical Device and Pharmaceutical Service - Italian Ministry of Health, Rome, Italy; Group of Experts on BIA-ALCL at the Italian Ministry of Health, Italy.

Background: Breast implant-associated anaplastic large-cell lymphoma is a rare disease with a favourable prognosis if adequately treated. Same staged patients have usually a similar prognosis and outcomes, but in our experience, IIA-staged patients have a wider prognosis with outcomes that vary from complete disease response to death. This study aimed to understand and identify all the factors that could influence the prognosis of this group of patients and verify if their prognosis matches the stage they belong to.

Material And Methods: Patients in stage IIA have been divided into two subgroups: IIAb with lymphoma extension towards the glandular tissue and IIAcw with tumour extension towards the chest-wall. The overall survival (OS) and event-free survival (EFS) of 64 BIA-ALCL cases were evaluated for each staged group.

Results: Significant differences of OS and EFS between IIAb and IIAcw patients (log-rank p = 0.046 and log-rank p = 0.018, respectively) were observed and poor prognosis joined IIAcw- and IV-staged patients.

Conclusion: Chest-wall infiltration is a critical prognostic factor in BIA-ALCL patients as it influences the possibility of performing a surgical radical tumour extirpation. Our results could represent valid assistance for the physicians in choosing the most appropriate BIA-ALCL prognostic category and treatment and could promote further wider studies to provide stronger evidence on a possible revision of the MDA TNM classification.
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http://dx.doi.org/10.1016/j.ejca.2021.01.041DOI Listing
May 2021

Long-term outcome and axillary recurrence in elderly women (≥70 years) with breast cancer: 10-years follow-up from a matched cohort study.

Eur J Surg Oncol 2021 Jul 3;47(7):1593-1600. Epub 2021 Mar 3.

Division of Breast Surgery, IEO European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Italy.

Background And Objectives: The oncological benefit of axillary surgery (AS), with sentinel lymph node biopsy (SLNB) or axillary dissection (ALND), in elderly women affected by breast cancer (BC) is controversial. We evaluated AS trends over a 10-year follow-up period as well as locoregional and survival outcomes in this subset of patients.

Methods: Patients aged 70 years or older, treated between 1994 and 2008, were selected and divided in two groups, depending on whether or not AS was performed. A (1:1) matched analysis for all relevant clinicopathological features was performed. Outcomes were analyzed using the Kaplan-Meier method and univariate Cox-proportional hazard ratio analysis.

Results: A total of 1.748 patients were identified and stratified by age (70-74, 75-79, 80-84). A matched analysis was performed for 252 patients: 122 who underwent AS and 122 who did not. At 10-year follow-up, ipsilateral breast tumor recurrence, distant metastasis and contralateral BC were similar, p = 0.83, p = 0.42 and p = 0.28, respectively. In the no-AS group, a significant increased risk of axillary lymph-node recurrence was identified at 5- and confirmed at 10-years (p = 0.038), without impact on overall survival at 5- and 10-years (p = 0.52). In the non-AS group, higher rate of axillary recurrence at 10-years was observed in patients with poorly differentiated (24.1%, 95% CI 7.2-46.2), highly proliferative (Ki67 ≥ 20%: 17.1%, 95% CI 0.6-33.3) and luminal B tumors (16.8%, 95% CI 5.9-35.5).

Conclusions: Axillary staging in elderly women does not impact long-term survival. Tailoring surgery according to tumor biology and age may improve locoregional outcome.
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http://dx.doi.org/10.1016/j.ejso.2021.02.027DOI Listing
July 2021

Schwannoma of the axillary region. Imaging findings, clinical pitfalls, and misdiagnosis.

Breast J 2021 Mar 15;27(3):273-275. Epub 2021 Feb 15.

Division of Breast Surgery, European Institute of Oncology, IRCCS, Milan, Italy.

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http://dx.doi.org/10.1111/tbj.14196DOI Listing
March 2021

A Novel Method of Implant Coverage for Post-Mastectomy Reconstruction after Previous Augmentation: A Case Report.

Breast Care (Basel) 2020 Oct 28;15(5):534-537. Epub 2020 Jan 28.

Division of Breast Cancer Reconstruction, European Institute of Oncology, IRCCS, Milan, Italy.

Background: Breast augmentation is the most common -cosmetic surgical procedure in the USA, with nearly 300,000 women undergoing surgery annually. National incidence rates predict that among women undergoing breast augmentation each year, approximately 35,000 will eventually be diagnosed with breast cancer, in particular individual / germline mutant carriers.

Case Report: Our case introduces a novel method of implant coverage after immediate post-mastectomy reconstruction in augmented patients. A novel "capsular flap" (flap of the pre-existing old capsule) is isolated and refolded to cover the outer lower portion of the implant.

Conclusion: Tailored surgical approaches can be offered to those patients previously augmented and requiring mastectomy after breast cancer diagnosis.
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http://dx.doi.org/10.1159/000505226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650099PMC
October 2020

Axillary surgery in breast cancer: An updated historical perspective.

Semin Oncol 2020 12 23;47(6):341-352. Epub 2020 Oct 23.

Division of Breast Cancer Surgery, IEO, European Institute of Oncology, IRCCS, Milan, Italy; Faculty of Medicine, University of Milan, Milan, Italy.

This historical surgical retrospection focuses on the temporal de-escalation axillary surgery, focusing on the unceasing efforts of researchers toward new challenges, as documented by extensive studies and trials. Axillary surgery has evolved, aiming to offer the best oncologic treatment and improve the quality of life of women. Axillary lymph-node dissection (ALND) has been replaced by sentinel lymph-node biopsy (SLNB) in women with early clinically node-negative breast cancer, providing adequate axillary nodal staging information with minimal morbidity, and becoming the standard of care in the management of breast cancer. However, this is only the beginning. Strategies in defining systemic and radiotherapeutic treatments have gradually been optimized, offering increasingly refined and targeted breast cancer treatment tools. In recent years, the paradigm of completion ALND after a positive SLNB has been questioned, and several studies have led to revolutionary changes in clinical practice. Moreover, the increasingly pivotal role played by neoadjuvant chemotherapy (NAC) has had a profound effect on the extent of axillary surgery, paving the way to a more finite "targeted" procedure in women with node-positive breast cancer who convert to negative nodes clinically after NAC. The utility of SLNB itself and its subsequent omission in women with negative nodes clinically and breast conservative surgery is also under scientific evaluation. The changes over time in the surgical approach to breast cancer have been numerous and significant. The novel emerging perspective characterized by recent advances in biology and genetics, in dedicated axillary ultrasound imaging and chemotherapy regimens, is the present reality that points to the future of axillary node treatment in breast cancer.
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http://dx.doi.org/10.1053/j.seminoncol.2020.09.001DOI Listing
December 2020

Long-term standard sentinel node biopsy after neoadjuvant treatment in breast cancer: a single institution ten-year follow-up.

Eur J Surg Oncol 2021 Apr 15;47(4):804-812. Epub 2020 Oct 15.

Division of Breast Cancer Surgery, IEO, European Institute of Oncology, IRCCS, Milan, Italy.

Introduction: In patients with positive lymph nodes (cN+) prior to neoadjuvant treatment (NAT), which convert to a clinically negative axilla (cN0) after treatment, the use of sentinel node biopsy (SNB) is still debatable, since the false-negative rate (FNR) is significantly high (12.6-14.2%). The objective of this retrospective mono-institutional study, with a long follow-up, aimed to evaluate the outcome in patients undergoing NAT who remained or converted to cN0 and received SNB independent of target axillary dissection (TAD) or the removal of at least 3 sentinel nodes (SNs).

Methods: This study analyzed 688 consecutive cT1-3, cN0/1/2 patients, operated at the European Institute of Oncology, Milan, from 2000 to 2015 who became or remained cN0 after NAT and underwent SNB with a least one SN found. Axillary dissection (AD) was not performed if the SN was negative. Nodal radiotherapy (RT) was not mandatory.

Results: Axillary failure occurred in 1.8% of the initially cN1/2 patients and in 1.5% of the initially cN0 patients. After a median follow-up of 9.2 years (IQR 5.3-12.3), the 5- and 10-year overall survival (OS) were 91.3% (95% CI, 88.8-93.2) and 81.0% (95% CI, 77.2-84.2) in the whole cohort, 92.0% (95% CI, 89.0-94.2) and 81.5% (95% CI, 76.9-85.2) in those initially cN0, 89.8% (95% CI, 85.0-93.2) and 80.1% (95% CI, 72.8-85.7) in those initially cN1/2.

Conclusion: The 10-year follow-up confirmed our preliminary data that the use of standard SNB is acceptable in cN1/2 patients who become cN0 after NAT and will not translate into a worse outcome.
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http://dx.doi.org/10.1016/j.ejso.2020.10.014DOI Listing
April 2021

Metaplastic breast cancer: Prognostic and therapeutic considerations.

J Surg Oncol 2021 Jan 12;123(1):61-70. Epub 2020 Oct 12.

Division of Breast Surgery, European Institute of Oncology, IRCCS, Milan, Italy.

Introduction: Metaplastic breast cancer (MBC) is a rare condition of breast tumor with different subtypes, considered a disease with worse prognosis; treatments and survival are often unclear and conflicting.

Methods: We consecutively collected 153 primary MBCs of different subtypes. Breast surgery, neoadjuvant or adjuvant treatment, clinic-pathological factors, number and type of events during follow-up were considered to evaluate overall survival (OS) and invasive disease-free survival (IDFS).

Results: The majority of MBC was triple-negative (TN) subtype (88.7%), G3 (95.3%), pN0 (70.6%), and with high levels of Ki-67 (93.5%). For OS and IDFS, no significant associations were seen between the different MBC subtypes. The matched triple-negative MBC (TNMBC) and ductal TNBC cohorts had similar prognosis both in terms of OS (p = .411) and IDFS (p = .981). We observed a positive trend for TNMBC patients treated in the adjuvant setting with the cyclofosfamide, methotrexate, 5-fluorouracil protocol for better OS (p = .090) and IDFS (p = .087). A poor or absent response rate was observed in the neoadjuvant setting.

Conclusion: Our results demonstrate that metaplastic and ductal breast cancers with TN phenotype are similar in terms of overall and disease-free survival. Metaplastic cancers are poorly responsive to neoadjuvant treatment, and in the absence of novel targeted therapies, surgical treatment remains the first choice.
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http://dx.doi.org/10.1002/jso.26248DOI Listing
January 2021

Axillary surgery in breast cancer: evolution and de-escalation.

Minerva Chir 2020 12 2;75(6):383-385. Epub 2020 Oct 2.

Division of Breast Surgery, IRCCS European Institute of Oncology, Milan, Italy.

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http://dx.doi.org/10.23736/S0026-4733.20.08598-3DOI Listing
December 2020

Impact of COVID-19 pandemic on clinical and surgical breast cancer management.

EClinicalMedicine 2020 Sep 20;26:100523. Epub 2020 Sep 20.

Division of Breast Surgery, European Institute of Oncology, IRCCS, Milan, Italy.

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http://dx.doi.org/10.1016/j.eclinm.2020.100523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502176PMC
September 2020

Sentinel node biopsy in conservative surgery for breast cancer: a changing role in clinical practice.

Minerva Chir 2020 Dec 25;75(6):386-391. Epub 2020 Sep 25.

Division of Breast Cancer Surgery, European Institute of Oncology (IEO), IRCCS, Milan, Italy.

Recent studies have demonstrated that the extent of surgical treatment in both breast and axilla can be minimized through a multimodal and personalized management, based on assessment of breast cancer (BC) molecular subtypes, genetics and on the prevailing relevance of systemic therapies. Axillary lymph-nodes dissection (ALND) represents the older surgical modality for appropriate staging and for adjuvant systemic and radiation therapies planning. Thanks to findings from extensive and crucial clinical trials, sentinel lymph node biopsy (SLNB) replaced this approach, obviating the need for ALND in node-negative disease patients, both in mastectomy and conservative surgery, and becoming a crucial turning point in BC managing. Furthermore, recent clinical trials have established that ALND can be avoided in those patients with low axillary disease burden in the sentinel nodes who are undergoing breast-conserving surgery (BCS) with radiotherapy. Several studies also proved that neoadjuvant chemotherapy (NAC) increases the BCS rates, as well reducing the extent of axillary surgery. The potential oncological safety of axillary observation choice in early BC patients undergoing BCS, in the recent perspective of the prevailing value of BC biology, is also under scientific evaluation. This study explores the current role of SLNB in BC patients eligible for BCS, providing a view into future directions in BC care.
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http://dx.doi.org/10.23736/S0026-4733.20.08481-3DOI Listing
December 2020

Prognosis of selected triple negative apocrine breast cancer patients who did not receive adjuvant chemotherapy.

Breast 2020 Oct 24;53:138-142. Epub 2020 Jul 24.

Division of Medical Senology, IEO, European Institute of Oncology IRCCS, Milan, Italy.

Background: Triple negative breast cancer encompasses several biological entities with different outcomes and is a priority to identify which patients require more treatment to reduce the risk of recurrence and which patients need less treatment.

Patients And Methods: Among the 210 women with first primary invasive apocrine non metastatic breast cancer operated on between January 1998 and December 2016 at the European Institute Oncology, Milan, we identified 24 patients with a pT1-pT2, node-negative, triple negative subtype and Ki-67 ≤ 20% who did not receive adjuvant chemotherapy (CT). We compared the outcome of this cohort with a similar group of 24 patients with ductal tumors who received adjuvant chemotherapy, matched by pathological stage and biological features and also with a similar group of 12 patients with apocrine tumors who received adjuvant chemotherapy.

Results: The median age was 64 and 61 years in the apocrine (w/o CT) and ductal group, respectively. The median value of Ki-67 expression was 12% in the apocrine group (w/o CT) and 16% in the ductal group (p < 0.001). After a median follow-up of 7.5 years, no patients in the apocrine group (w/o CT) experienced a breast cancer related event compared with 4 events in the ductal carcinoma group (Gray test p-value = 0.11).

Conclusions: The outcome of selected apocrine triple negative breast cancer patients who did not received adjuvant chemotherapy is excellent and supports a treatment de-escalation. Multicenter projects focusing on the possibility of avoiding adjuvant chemotherapy in selected subtypes of triple negative breast cancers with favorable outcome are warranted.
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http://dx.doi.org/10.1016/j.breast.2020.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424227PMC
October 2020

High-dose-rate Brachytherapy as Adjuvant Local rEirradiation for Salvage Treatment of Recurrent breAst cancer (BALESTRA): a retrospective mono-institutional study.

J Contemp Brachytherapy 2020 Jun 30;12(3):207-215. Epub 2020 Jun 30.

Department of Radiotherapy, IEO European Institute of Oncology IRCCS, Milan, Italy.

Purpose: To evaluate clinical results of catheter-based interstitial high-dose-rate (HDR) brachytherapy (BT) as adjuvant treatment in previously irradiated recurrent breast cancer.

Material And Methods: Between January 2011 and September 2015, 31 consecutive patients with histologically confirmed recurrent breast cancer after conservative surgery and conventional whole breast radiotherapy, were retreated with a second conservative surgical resection and reirradiated with adjuvant interstitial HDR-BT. None of the brachytherapy implant was performed during the quadrantectomy procedure. A dose of 34 Gy in 10 fractions, 2 fractions per day, with a minimal interval of 6 hours was delivered.

Results: At the time of the implant, the median age of patients was 59.7 years (range, 39.3-74.9 years). The median time from first treatment until BT for local recurrence was 11.9 years (range, 2.5-27.8 years). The median interval between salvage surgery and BT was 3.6 months (range, 1-8.2 months). No acute epidermitis or soft tissue side effects higher than grade 2 were recorded, with good cosmetic results in all patients. Most of the patients presented grade 1-2 late side effects. Only one patient developed grade 3 liponecrosis. After a median follow-up of 73.7 months (range, 28.8-102.4 months), the overall survival and cancer specific survival were 87.1% and 90.3%, respectively; 5-year local control and 5-year progression-free survival rate were 90.3% and 83.9%, respectively.

Conclusions: Our preliminary analysis showed that HDR-BT is a feasible treatment for partial breast reirradiation offering very low complications rate and fast procedure. Higher patients' cohort is warranted in order to define the role of this treatment modality in the breast conservative management of local recurrence.
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http://dx.doi.org/10.5114/jcb.2020.96860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366017PMC
June 2020

How Useful Are Tumor Markers in Detecting Metastases with FDG-PET/CT during Breast Cancer Surveillance?

Oncology 2020 9;98(10):714-718. Epub 2020 Jun 9.

Division of Breast Surgery, European Institute of Oncology, IRCCS, Milan, Italy.

Background: To assess the clinical usefulness of serum tumor markers for early detection of distant breast cancer recurrence using FDG-PET/CT.

Methods: We retrospectively analyzed 561 consecutive patients who underwent surgery for invasive primary breast cancer and had increased tumor markers (CA 15-3 and CEA) after completion of locoregional therapy. FDG-PET/CT data were reviewed for all cases. CA 15-3 and CEA were evaluated both in a continuous and in a quartile (Q) distribution. The Wilcoxon rank-sum test and logistic regression models were used to evaluate the association between increased tumor marker values and the presence (and type) of distant metastases.

Results: The median value of CA 15-3 was 35.0 U/mL (IQR, 29.5-43.0) in cases where no distant metastases were detected, and it was 58.9 U/mL (IQR, 40.0-108.0) in cases where metastases were detected (p < 0.001). The median value of CEA was 6.6 U/mL (IQR, 4.4-10.0) in cases of no metastases and 12.4 U/mL (IQR, 6.9-30.0) in cases of metastases (p < 0.001). Increased levels of both tumor markers (Q3 and Q4) were strongly associated with the presence of distant metastases. The association between CA 15-3 and bone/liver metastases was stronger compared with other types of metastases (p heterogeneity between odds ratios [ORs] = 0.03 for Q3 and <0.001 for Q4), while no relevant heterogeneity between ORs emerged for CEA.

Conclusion: Increased tumor marker levels detected in asymptomatic breast cancer patients during adjuvant therapies and follow-up are significantly predictive of distant metastases identified on FDG-PET/CT.
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http://dx.doi.org/10.1159/000507707DOI Listing
October 2020

Feasibility and surgical impact of Z0011 trial criteria in a single-Institution practice.

Breast J 2020 07 7;26(7):1330-1336. Epub 2020 Jun 7.

Division of Breast Surgery, IEO, European Institute of Oncology IRCCS, Milan, Italy.

The purpose of this study is the evaluation of clinical and surgical impact of the Z0011 trial criteria on the management of breast cancer (BC) patients undergoing breast conservative surgery (BCS) at the European Institute of Oncology (IEO). We studied 1386 patients who underwent BCS and sentinel lymph node biopsy (SLNB) from July 2016 to July 2018. Clinical evaluation, breast ultrasound, mammogram, and cyto/histological examination were performed for all patients at the time of diagnosis. Frozen sections of the sentinel lymph node (SLN) were not performed for any patient. Patients who underwent neo-adjuvant therapy were excluded. To evaluate the results before and after the introduction of Z0011 criteria, a group of 1425 patients with the same characteristics who underwent BCS and SLNB from July 2013 to July 2015 were analyzed. We studied the characteristics of the patients by nodal status, and we observed that T stage, tumor grade, and lymphovascular invasion were statistically related with the highest rate of positive SLN. Of the 1386 patients who underwent surgery after the introduction of the Z011 trial, 1156 patients (83.4%) had negative SLN, 230 patients (16.6%) had positive SLN. Subsequent axillary lymph node dissection (ALND) was performed in only 7 cases (3.0%). Of the 1425 patients operated before the introduction of the Z0011 trial, 216 patients had subsequent ALND (15%). The reduction in the number of ALND performed after the introduction of Z0011 is statistically significant, and this could result in a remarkable reduction of the comorbidities of our patients.
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http://dx.doi.org/10.1111/tbj.13851DOI Listing
July 2020

COVID-19: The European institute of oncology as a "hub" centre for breast cancer surgery during the pandemic in Milan (Lombardy region, northern Italy) - A screenshot of the first month.

Eur J Surg Oncol 2020 Jun 24;46(6):1180-1181. Epub 2020 Apr 24.

Division of Breast Surgery, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141, Milan, Italy; Faculty of Medicine, University of Milan, via Festa del Perdono 7, 20122 Milan, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.ejso.2020.04.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180348PMC
June 2020

E-cadherin deregulation in breast cancer.

J Cell Mol Med 2020 06 16;24(11):5930-5936. Epub 2020 Apr 16.

Department of Experimental Oncology, European Institute of Oncology IRCCS, Milan, Italy.

E-cadherin protein (CDH1 gene) integrity is fundamental to the process of epithelial polarization and differentiation. Deregulation of the E-cadherin function plays a crucial role in breast cancer metastases, with worse prognosis and shorter overall survival. In this narrative review, we describe the inactivating mechanisms underlying CDH1 gene activity and its possible translation to clinical practice as a prognostic biomarker and as a potential targeted therapy.
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http://dx.doi.org/10.1111/jcmm.15140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294130PMC
June 2020

Multicentric breast cancer with heterogeneous histopathology: a multidisciplinary review.

Future Oncol 2020 Mar 6;16(8):395-412. Epub 2020 Feb 6.

Division of Radiation Oncology, European Institute of Oncology, IRCCS, Milan, Italy.

Multiple synchronous (multifocal or multicentric) ipsilateral breast cancers with heterogeneous histopathology are a rare clinical occurrence, however, their incidence is increasing due to the use of MRI for breast cancer screening and staging. Some studies have demonstrated poorer clinical outcomes for this pattern of breast cancer, but there is no evidence to guide clinical practice. In this multidisciplinary review, we reflect on pathology and molecular characteristics, imaging findings, surgical management including conservation and reconstructive options and approach to the axilla, and the role of chemotherapy and radiotherapy. Multidisciplinary discussions appear decisive in planning an appropriate surgical choice and defining the correct systemic treatment tailored to each clinical condition.
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http://dx.doi.org/10.2217/fon-2019-0540DOI Listing
March 2020

Long-Term Results and Reconstruction Failure in Patients Receiving Postmastectomy Radiation Therapy with a Temporary Expander or Permanent Implant in Place.

Plast Reconstr Surg 2020 Feb;145(2):317-327

From the Division of Radiation Oncology, Division of Epidemiology and Biostatistics, Unit of Medical Physics, Division of Plastic and Reconstructive Surgery, Division of Breast Surgery, and the Scientific Directorate, IEO, European Institute of Oncology IRCCS; and the Department of Oncology and Hemato-oncology, University of Milan.

Background: This study investigated the risk of reconstruction failure after mastectomy, immediate breast reconstruction, and radiotherapy to either a temporary tissue expander or permanent implant.

Methods: Records of women treated at a single institution between June of 1997 and December of 2011 were reviewed. Two patient groups were identified based on type of immediate breast reconstruction: tissue expander followed by exchange with a permanent implant and permanent implant. The study endpoint was rate of reconstruction failure, defined as a replacement, loss of the implant, or conversion to flap.

Results: The tissue expander/permanent implant and the permanent implant groups consisted of 63 and 75 patients, respectively. The groups were well balanced for clinical and treatment characteristics. With a median follow-up of 116 months, eight implant losses, 50 implant replacements, and four flap conversions were recorded. Reconstruction failure occurred in 22 of 63 patients in the expander/implant group and in 40 of 75 patients in the permanent implant group. A traditional proportional hazards model showed a higher risk of reconstruction failure for the expander/implant group (hazard ratio, 2.01) and a significantly shorter time to reconstruction failure compared with the permanent implant group (109.2 months versus 157.7 months; p = 0.03); however, according to a competing risk model, the between-groups cumulative incidences were not significantly different (hazard ratio, 1.09).

Conclusions: Radiotherapy to either a tissue expander or a permanent implant presented a fairly large risk of reconstruction failure over time. The expander/implant group was not more likely to develop reconstruction failure compared to permanent implant group, but the timing of onset was shorter. More complex techniques should be investigated to lower the risk of reconstruction failure.

Clinical Question/level Of Evidence: Therapeutic, III.
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http://dx.doi.org/10.1097/PRS.0000000000006441DOI Listing
February 2020

Validation of a Novel Nomogram for Prediction of Local Relapse after Surgery for Invasive Breast Carcinoma.

Ann Surg Oncol 2020 Jun 21;27(6):1864-1874. Epub 2020 Jan 21.

Division of Breast Surgery, IEO European Institute of Oncology IRCCS, Milan, Italy.

Background: Around 7% of women who undergo breast-conserving surgery (BCS) or mastectomy are at risk of developing ipsilateral breast tumor recurrence (IBTR). When assessing risks that, like that of IBTR, depend on multiple clinicopathological variables, nomograms are the predictive tools of choice. In this study, two independent nomograms were constructed to estimate the individualized risk of IBTR after breast surgery.

Patients And Methods: In this retrospective study, 18,717 consecutive patients with primary invasive breast cancer were enrolled. The training set used for building the nomograms comprised 15,124 patients (11,627 treated with BCS and 3497 with mastectomy), while the validation set included 3593 women (2565 BCS and 1028 mastectomy). Median follow-up time was 8 years in the training set and 6 years in the validation set. Multivariable Cox proportional hazards regression was used to identify independent factors for IBTR. Two separated nomograms were constructed on multivariate models for BCS and mastectomy.

Results: The factors that associated with IBTR after either BCS or mastectomy were identified. The two multivariable models were used to build nomograms for the prediction of IBTR 1 year, 5 years, and 10 years after BCS or after mastectomy. Five-year and 10-year IBTR rates in the BCS training set were equal to 3.50% and 7.00%, respectively, and to 5.39% and 7.94% in the mastectomy training set. The nomograms were subsequently validated with c-index values of 0.77 and 0.69 in the BCS and mastectomy validation sets, respectively.

Conclusions: The nomograms presented in this study provide clinicians and patients with a valuable decision-making tool for choosing between different treatment options for invasive breast cancer.
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http://dx.doi.org/10.1245/s10434-019-08160-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523878PMC
June 2020

Breast implant-associated anaplastic large cell lymphoma: A comprehensive review.

Cancer Treat Rev 2020 Mar 13;84:101963. Epub 2020 Jan 13.

Division of Early Drug Development for Innovative Therapies, IEO, European Institute of Oncology IRCCS, Milan, Italy; Department of Oncology and Haemato-Oncology, University of Milano, Milan, Italy. Electronic address:

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a recently recognized non-Hodgkin lymphoma of T-cell origin. Despite the low incidence of this new disease, the increasing use of breast implants for cosmetic or post-mastectomy reconstruction purposes places BIA-ALC as an emerging and compelling medical challenge. The real BIA-ALCL pathogenesis has not been fully uncovered so far, while different putative causal factors have been proposed. Breast implants with textured surfaces seem to be associated with nearly all cases of BIA-ALCL, while the real the risk of disease development has not been well estimated so far. Late onset, persistent seroma around breast implant represents the classical clinical presentation. Most of the BIA-ALCL patients presents with localized disease, which confers an excellent prognosis. Unlike other non-Hodgkin lymphomas, surgical excision of the mass has a key role in the treatment. For patients with advanced and disseminated diseases, the treatment did not differ from other types of T-cell lymphoma. For these reasons, BIA-ALCL represents an emerging disease which requires multidisciplinary team approach to well define diagnostic workup and treatment for each patient. This review article aims to summarize available data on BIA-ALCL. First, we will outline available data on BIA-ALCL epidemiology, pathogenesis, diagnostic work-up, and treatment. Second, we will point out the potential psychological implications as well as the risk of perception distortion for women with breast implants, especially for those with previous breast cancer. Lastly, we will summarize the current national recommendations regarding textured breast implants and discuss the diagnostic-therapeutic algorithm for BIA-ALCL management.
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http://dx.doi.org/10.1016/j.ctrv.2020.101963DOI Listing
March 2020

Local Failure After Accelerated Partial Breast Irradiation with Intraoperative Radiotherapy with Electrons: An Insight into Management and Outcome from an Italian Multicentric Study.

Ann Surg Oncol 2020 Mar 15;27(3):752-762. Epub 2019 Nov 15.

Division of Radiation Oncology, European Institute of Oncology, IEO, IRCCS, Milan, Italy.

Background: The aim of this work is to evaluate pattern of care and clinical outcome in a large series of patients with in-breast recurrence (IBR), after quadrantectomy and intraoperative radiation therapy with electrons (IOERT) as partial breast irradiation.

Patients And Methods: Patients with IBR after IOERT, treated with salvage surgery ± adjuvant reirradiation (re-RT), were selected from a multiinstitution database. Disease-free survival (DFS), overall survival (OS), cumulative incidence of second IBR, and distant metastases (DM) were estimated.

Results: A total of 224/267 patients from seven institutions were included. Primary tumors received 21 Gy. Median time to first IBR was 4.3 years (range 2.6-6.1 years). Salvage mastectomy and repeat quadrantectomy were performed in 135 (60.3%) and 89 (39.7%) patients, followed by adjuvant re-RT in 21/135 (15.5%) and 63/89 (70.8%), respectively. Median follow-up after salvage treatment was 4.1 years. Overall, 5- and 8-year outcomes were as follows: cumulative incidence of second IBR: 8.4% and 14.8%; cumulative incidence of DM: 17.1% and 22.5%; DFS: 67.4% and 52.5%; OS: 89.3% and 74.7%. The risk of second IBR was similar in the salvage mastectomy and repeat quadrantectomy + RT groups [hazard ratio (HR) 1.41, p = 0.566], while salvage mastectomy patients had greater risk of DM (HR 3.15, p = 0.019), as well as poorer DFS (HR 2.13, p = 0.016) and a trend towards worse OS (HR 3.27, p = 0.059). Patients who underwent repeat quadrantectomy alone had worse outcomes (second IBR, HR 5.63, p = 0.006; DFS, HR 3.21, p = 0.003; OS, HR 4.38, p = 0.044) than those adding re-RT.

Conclusions: Repeat quadrantectomy + RT represents an effective salvage approach and achieved local control comparable to that of salvage mastectomy.
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http://dx.doi.org/10.1245/s10434-019-08075-3DOI Listing
March 2020