Clipping a Positive Lymph Node Improves Accuracy of Nodal Staging After Neoadjuvant Chemotherapy for Breast Cancer Patients, but Does It Drive Management Changes?

BACKGROUND: Sentinel lymph node (SLN) biopsy for cN+ breast cancer patients after neoadjuvant chemotherapy (NAC) is controversial because the false-negative rate (FNR) is high. Identification of three or more SLNs with a dual tracer improves these results, and inclusion of a clipped lymph node (CLN) (targeted axillary dissection [TAD]) may be even more effective. METHODS: A retrospective, single-institution analysis of consecutive cN+ patients undergoing NAC from 2019 to 2021 was performed. Patients routinely underwent placement of a clip in the positive lymph node before NAC, and TAD was performed after completion of therapy. RESULTS: The study analyzed 73 patients, and the identification rate for CLN was 98.6% (72/73). A complete response in the lymph nodes was achieved for 43 (59%) of the 73 patients. Overall, the CLN was not a SLN in 18 (25%) of 73 cases, and for women who had one or two and those who had three or more SLNs identified, this occurred in 11 (32%) and 7 (21%) of 34 cases, respectively. Failure of SLN or TAD to identify a positive residual lymph node status after NAC occurred in 10 (15%) of 69 and 2 (3%) of 73 cases, respectively (p = 0.01). In four cases, a SLN was not retrieved (5.5%), and two of these cases had a positive CLN. In three cases, the CLN was the only positive node and did not match with a SLN, directing lymphadenectomy and oncologic management change in two cases. Therefore, 7 (10%) of 73 cases had a change in surgical or oncologic management with TAD. CONCLUSIONS: For a conservative axillary treatment in this setting, TAD is an effective method. It is more accurate than SLN alone and allows management changes. Further studies are warranted.

Nipple-Sparing Mastectomy After Neoadjuvant Chemotherapy: Definitive Results with a Long-Term Follow-Up Evaluation.

BACKGROUND: Nipple-sparing mastectomy (NSM) is increasingly used for women with breast cancer who are not candidates for conservative surgery. The authors previously reported satisfying results with NSM after neoadjuvant chemotherapy (NACT). METHODS: From 2010 to 2020, 1072 women underwent mastectomy at the authors' institution. In this group, 433 NSMs were performed (40%). The only contraindications to NSM were close proximity to the nipple-areola complex (NAC), bloody discharge, and Paget disease. RESULTS: In 112 cases involving 111 women, NSM followed NACT (group 1), whereas it was performed as primary surgery in 321 instances involving 306 women (group 2). At 5 years, local relapse was 7% in group 1 and 2% in group 2, although in the multivariate analysis, locoregional relapses (LRRs) did not differ between the two groups. An increased incidence of local relapse was associated with higher tumor stage (stage III; p = 0.046) and age younger than 51 years (p = 0.038). For 34 (30.3%) of the 111 women in group 1 with a pathologic complete response (pCR), no LRRs were recorded. Only one NAC recurrence was observed. Overall survival with each tumor stage did not differ between the two groups. No differences in complications were observed. Cosmetic results were satisfying in 83.8% of the cases and did not get worse after NACT. CONCLUSIONS: The study data definitively confirm that NSM is safe even after NACT, with good cosmetic results and complications comparable with those in the primary surgery setting. Tumor stage and age were the only independent factors for local relapse. Patients with pCR enjoyed optimal locoregional control.

Breast cancer subtypes affect the nodal response after neoadjuvant chemotherapy in locally advanced breast cancer: Are we ready to endorse axillary conservation?

We evaluated the impact of breast cancer subtypes on pathologic complete response (pCR) in 181 patients with positive nodes undergoing neoadjuvant chemotherapy (NAC). After NAC, patients underwent surgery, with sentinel lymph node biopsy (SLNB) or axillary dissection (ALND). In 28.2% of cases a pCR was achieved, with the highest rate in Her2+ and triple negative tumors. Overall, nodal pCR was more frequent than breast pCR (P = 0.003) with higher percentages in Her2+ and LLB-Her2+ (P < 0.05). In the Her2+ group, nodal pCR was observed only with breast pCR. Thus, in Her2+ tumors, breast pCR predicts node pCR, supporting the use of SLNB in this subgroup to stage the axilla avoiding ALND.

Breast Reconstruction using the Anterior Approach Scarless Latissimus Dorsi Muscular flap: A Single Center Retrospective Study.

Introduction: Scarless latissimus dorsi (LD) flap is a breast reconstruction technique, which allow to cover the lower pole of implant with a large portion of the LD muscle without skin paddle; it represents a surgical solution that transpose vascularized tissue avoiding the failure of breast reconstruction, following necrosis of mastectomy skin flaps. Material and Method: A retrospective review of patients undergoing immediate or delayed breast reconstruction using scarless LD flap reconstructions was performed. Clinical data obtained from follow-up visits were recorded. To evaluate breast shape contentment and patient satisfaction, the patients were requested to answer the Breast-Q, version 2.0 reduction module postoperative scales questionnaire at the 12-month follow-up. Results: We performed 19 scarless LD flap reconstructions between September 2019 and June 2022. The surgical time in average (considering minutes ± SD) was 130 (±15) minutes. The aesthetic assessment was good/excellent in 83% of patients. This was statistically significant (P=0.0). Conclusions: The scarless LD flap reconstruction is a valid and reliable solution, which has the advantage to reduce the risk of exposed prosthesis if native skin necrosis occurs.

Pathologic response and survival after neoadjuvant chemotherapy with or without pertuzumab in patients with HER2-positive breast cancer: the Neopearl nationwide collaborative study.

Purpose: Clinical trials have shown a significant increase in pathologic complete response (pCR) with the addition of pertuzumab to neoadjuvant chemotherapy for patients with early-stage HER-2 positive breast cancer. To date, limited studies have examined comparative outcomes of neoadjuvant pertuzumab in real-world setting. The Neopearl study aimed to assess comparative real-life efficacy and safety of neoadjuvant pertuzumab for these patients. Methods: We conducted a nationwide retrospective analysis involving 17 oncology facilities with a certified multidisciplinary breast cancer treatment committee. We identified patients with HER-2 positive stage II-III breast cancer treated with neoadjuvant chemotherapy based on trastuzumab and taxanes with or without pertuzumab. All patients underwent breast surgery and received a comprehensive cardiologic evaluation at baseline and after neoadjuvant treatment. Patients who received the combination of pertuzumab, trastuzumab, and chemotherapy constituted case cohort (PTCT), whereas those treated with trastuzumab and chemotherapy accounted for control cohort (TCT). The pCR rate and 5-year event free survival (EFS) were the primary outcomes. Secondary end-points were rates of conversion from planned modified radical mastectomy (MRM) to breast conservation surgery (BCS) and cardiotoxicities. Results: From March 2014 to April 2021, we included 271 patients, 134 (49%) and 137 (51%) in TCT and PTCT cohort, respectively. Positive axillary lymph nodes and stage III were more frequent in PTCT cohort. The pCR rate was significantly increased in patients who received pertuzumab (49% vs 62%; OR 1.74, 95%CI 1.04-2.89) and with HER-2 enriched subtypes (16% vs 85%; OR 2.94, 95%CI 1.60-5.41). After a median follow-up of 5 years, the 5-year EFS was significantly prolonged only in patients treated with pertuzumab (81% vs 93%; HR 2.22, 95%CI 1.03-4.79). The same analysis performed on propensity score matched population showed concordant results. On univariate analysis, only patients with positive lymph nodes were found to benefit from pertuzumab for both pCR and 5-year EFS. The rates of conversion from MRM to BCS and cardiologic toxicities did not differ between the cohorts. Conclusion: Our findings support previous data on improved outcomes with the addition of pertuzumab to trastuzumab-based neoadjuvant chemotherapy. This benefit seems to be more significant in patients with clinically positive lymph nodes.

CDK4/6 Inhibitor Treatments in Patients with Hormone Receptor Positive, Her2 Negative Advanced Breast Cancer: Potential Molecular Mechanisms, Clinical Implications and Future Perspectives.

Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer is the most common breast cancer subtype, and endocrine therapy (ET) remains its therapeutic backbone. Although anti-estrogen therapies are usually effective initially, approximately 50% of HR+ patients develop resistance to ET within their lifetime, ultimately leading to disease recurrence and limited clinical benefit. The recent addition of cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (palbociclib, ribociclib, abemaciclib) to ET have remarkably improved the outcome of patients with HR+ advanced breast cancer (ABC) compared with anti-estrogens alone, by targeting the cell-cycle machinery and overcoming some aspects of endocrine resistance. However, which patients are the better candidates for these drugs, which are the main characteristics for a better selection of patients or if there are predictive biomarkers of response, is still unknown. In this review we reported the mechanism of action of CDK4/6 inhibitors as well as their potential mechanism of resistance, their implications in clinical practice and the forthcoming strategies to enhance their efficacy in improving survival and quality of life of patients affected with HR+, HER2-, ABC.

Long-Term Outcomes of Once-Daily Accelerated Partial-Breast Irradiation With Tomotherapy: Results of a Phase 2 Trial.

PURPOSE: We report long-term outcomes of phase 2 trial on patients with invasive breast cancer treated with accelerated partial-breast irradiation (APBI) using tomotherapy after breast conservative surgery. METHODS AND MATERIALS: From December 2010 to December 2018, we treated 338 women with APBI-tomotherapy: 38.5 Gy in 10 once-daily fractions. Patients selected were age ≥50 years old, with ≤3 cm in size unifocal tumor and at least 2 mm of clear margins. Disease outcomes were analyzed by clinicopathologic characteristics, molecular phenotypes, and American Society for Radiation Oncology (ASTRO) 2017 updated consensus groupings. RESULTS: The median age was 65 years (range, 50-86). The invasive ductal (87.5%) and the luminal A-like molecular phenotype (70%) were the most common tumors. Overall 242 patients (71.6%) were considered "suitable" for enrollment in APBI according to the eligibility criteria of the ASTRO-2017 consensus statement. With a median follow-up of 76 months (range, 17-113), 2 patients (0.6%) had an invasive ipsilateral breast tumor recurrence (IBTR), and 2 patients (0.6%) had an axillary ipsilateral failure. The rate of local control in terms of free of IBTR was 99.4% and locoregional control (no recurrence in ipsilateral breast as well as in regional nodes) was 98.8%. Progression-free survival was 98.4% and 92% at 5 and 10 years, respectively. Acute and late skin toxicity, graded according to the Common Terminology Criteria for Adverse Events, were 7.7% (G1) and 0.6% (G2) and 4.4% (G1) and 1.1% (G2), respectively. There were no grade 3/4 toxicities, however. Very few patients (2%) or physicians (2%) assessed cosmetic outcome as fair or poor at the 2-year follow-up. CONCLUSIONS: This phase 2 trial on APBI-tomotherapy shows excellent long-term results. Once-daily fractionation schedule was well tolerated with a low rate of adverse events and worse cosmetic outcome. In this series, even among those deemed cautionary or unsuitable for APBI by ASTRO criteria, we demonstrated a low rate of IBTR.

PONDx: real-life utilization and decision impact of the 21-gene assay on clinical practice in Italy.

Clinicopathological prognostic features have limited value to identify with precision newly diagnosed patients with hormone receptor (HR)-positive, HER2-negative breast cancer (BC), who would benefit from chemotherapy (CT) in addition to adjuvant hormonal therapy (HT). The 21-gene Oncotype DX Breast Recurrence Score® (RS) assay has been demonstrated to predict CT benefit, hence supporting personalized decisions on adjuvant CT. The multicenter, prospective, observational study PONDx investigated the real-life use of RS® results in Italy and its impact on treatment decisions. Physicians' treatment recommendations (HT ± CT) were documented before and after availability of RS results, and changes in recommendations were determined. In the HR+ HER2- early BC population studied (N = 1738), physicians recommended CT + HT in 49% of patients pre-RS. RS-guided treatment decisions resulted in 36% reduction of CT recommendations. PONDx confirms that RS results provide clinically relevant information for CT recommendation in early-stage BC, resulting in a reduction of more than a third of CT use.

PANHER study: a 20-year treatment outcome analysis from a multicentre observational study of HER2-positive advanced breast cancer patients from the real-world setting.

BACKGROUND: The evolution of therapeutic landscape of human epidermal growth factor receptor-2 (HER2)-positive breast cancer (BC) has led to an unprecedented outcome improvement, even if the optimal sequence strategy is still debated. To address this issue and to provide a picture of the advancement of anti-HER2 treatments, we performed a large, multicenter, retrospective study of HER2-positive BC patients. METHODS: The observational PANHER study included 1,328 HER2-positive advanced BC patients treated with HER2 blocking agents since June 2000 throughout July 2020. Endpoints of efficacy were progression-free survival (PFS) and overall survival (OS). RESULTS: Patients who received a first-line pertuzumab-based regimen showed better PFS (p < 0.0001) and OS (p = 0.004) than those receiving other treatments. Median PFS and mOS from second-line starting were 8 and 28 months, without significant differences among various regimens. Pertuzumab-pretreated patients showed a mPFS and a mOS from second-line starting not significantly affected by type of second line, that is, T-DM1 or lapatinib/capecitabine (p = 0.80 and p = 0.45, respectively). Conversely, pertuzumab-naïve patients receiving second-line T-DM1 showed a significantly higher mPFS compared with that of patients treated with lapatinib/capecitabine (p = 0.004). Median OS from metastatic disease diagnosis was higher in patients treated with trastuzumab-based first line followed by second-line T-DM1 in comparison to pertuzumab-based first-line and second-line T-DM1 (p = 0.003), although these data might be partially influenced by more favorable prognostic characteristics of patients in the pre-pertuzumab era. No significant differences emerged when comparing patients treated with 'old' or 'new' drugs (p = 0.43), even though differences in the length of the follow-up between the two cohorts should be taken into account. CONCLUSION: Our results confirmed a relevant impact of first-line pertuzumab-based treatment and showed lower efficacy of second-line T-DM1 in trastuzumab/pertuzumab pretreated, as compared with pertuzumab-naïve patients. Our findings may help delineate a more appropriate therapeutic strategy in HER2-positive metastatic BC. Prospective randomized trials addressing this topic are awaited.

Immediate Breast Reconstruction after mastectomy with polyurethane implants versus textured implants: A retrospective study with focus on capsular contracture.

BACKGROUND: Capsular contracture (CC) is the most common complication following Immediate Breast Reconstruction (IBR) with breast implants. Different implant surfaces were developed aiming to reduce the incidence of CC. We evaluated the incidence and degree of CC after Direct-to-Implant (DTI) IBR with insertion of textured (TE) or polyurethane (PU) covered implants. METHODS: A retrospective review of consecutive patients treated at our Institution with mastectomy and one-stage IBR and implant reconstruction between 2013 and 2018, with or without post mastectomy radiation therapy (PMRT), was conducted. Immediate breast reconstruction was performed by implanting 186 PU covered implants and 172 TE implants. RESULTS: Three-hundred-twelve women underwent 358 DTI IBR with PU or TE implants, were analyzed with a median follow-up time of 2.3 years (range 1.0-3.0). The overall rate of CC Baker grade III and IV was 11.8% (95%CI: 8.4-16.3), while, after PU and TE implant placement it was 8.1% (95% CI: 4.1-15.7) and 15.8% (95% CI: 4.1-15.7) [p = 0.009]), respectively. Irradiated breasts developed CC more frequently rather than non-irradiated breasts (HR = 12.5, p < 0.001), and the relative risk was higher in the TE group compared with the PU group (HR = 0.3, p = 0.003). CONCLUSIONS: After mastectomy and one-stage IBR, the use of PU covered implants is associated with a lower incidence of CC compared to TE implants. This advantage is amplified several folds for patients who necessitate PMRT. Footnote: Capsular contracture (CC); Immediate Breast Reconstruction (IBR); Directto- Implant (DTI); Textured (TE); Polyurethane (PU); Post mastectomy radiation therapy (PMRT); Nipple Sparing mastectomy (NSM).

Once Daily Accelerated Partial Breast Irradiation: Preliminary Results with Helical Tomotherapy®.

BACKGROUND: Accelerated partial breast irradiation (APBI) is becoming an option for patients with low-risk breast cancer. The current practice is 38.5 Gy in 10 fractions b.i.d. over 5 days. This fractionation has a higher bioequivalent dose compared to the standard schedule. We report on preliminary results of once-daily APBI in patients treated with TomoTherapy®. PATIENTS AND METHODS: Patients with unifocal-breast disease who underwent breast-conserving surgery were enrolled in the study. Treatment was administered with TomoTherapy, by contouring in accordance with the NSABP B-39/RTOG 0413 APBI protocol. Treatment schedule was 38.5 Gy in 10 once-daily fractions. EORTC Cosmetic Rating System was adopted for cosmetic outcome. RESULTS: From 2010 to 2013, 111 patients were treated. With a median follow-up of 34 months, no ipsilateral breast recurrence was observed. Very few patients (1-4%) assessed their cosmetic outcome as fair or poor during follow-up. CONCLUSION: Once-daily APBI with TomoTherapy yielded good cosmetic results without compromising local control efficacy.

Neoadjuvant chemotherapy is not a contraindication for nipple sparing mastectomy.

BACKGROUND: Nipple-sparing mastectomy (NSM) has been recently implemented to improve cosmetic outcome after mastectomy, but it is rarely considered today after neoadjuvant chemotherapy (NCH). PATIENTS AND METHODS: Among 275 NSMs performed from January 2007 to January 2015, 186 cases, with a minimum follow-up of 12 months, were carried out for invasive or intraductal carcinoma. Patients were considered for NSM if there were no clinical and radiological evidence of invasion or close proximity (<1 cm) to the nipple-areola complex (NAC). We compared patients operated with NSM after NCH (Group I N = 51) with those who underwent primary surgery (Group II, N = 135). RESULTS: At a median follow-up of 35 months, 166/186 patients were alive and disease-free (89.7%). Three local relapses (1.6%) were observed, all in the skin flap outside the NAC in Group I: (6%; p < 0.01). No NAC recurrences have been recorded, in either group. Nipple loss due to full thickness necrosis or resection for insufficient margins was recorded in 31 cases (17%); 12 in Group I (24%) and 19 in Group II (14%) (P = 0.1). This event decreased by half in the second part of the study (21/93 vs 10/93) (P = 0.03). CONCLUSIONS: NSM after NCH is not associated with a statistically significant difference in terms of post-operative complications, total nipple loss for necrosis or margins, and results improve with experience. The loco-regional relapse rate was higher after NCH, yet it was consistent with traditional mastectomy in the high-risk setting. There is no need to avoid NSM after NCH for locally advanced cancers, if the retro-areolar margins of resection are clear at the time of surgery.