Breast Surgery Bulletin: March 2023

 

Tailoring the optimal duration of the extended adjuvant endocrine therapy in patients with early-stage breast cancer. A systematic review and meta-analysis of randomized clinical trials

by Laura Pala, Tommaso De Pas, Eleonora Pagan, Isabella Sala, Chiara Catania, Emma Zattarin, Paolo Arnone, Massimo M. Grassi, Marco Colleoni, Antonio C. Wolff, Javier Cortes, Martine Piccart, Richard D. Gelber, Giuseppe Viale, Vincenzo Bagnardi, Fabio Conforti 

The Breast: Published: March 01, 2023

Background

Controversy exists regarding the optimal duration of the extended adjuvant endocrine treatment (ET) in patients with early-stage breast-cancer (eBC).

We performed a systematic review and trial-level meta-analysis of all randomized clinical trials (RCTs) comparing a “limited-extended” adjuvant ET (defined as more than 5 but less than 7.5 years of treatment overall) versus a “full-extended” adjuvant ET (defined as more than 7.5 years of treatment overall) in eBC.

Methods

To be eligible, RCTs had to i) compare a “limited-extended” adjuvant ET versus a “full-extended” adjuvant ET in patients with eBC; and ii) report disease-free survival (DFS) hazard ratio (HR) according to the disease nodal-status [i.e., nodal-negative (N-ve) versus nodal-positive (N + ve)].

The primary endpoint was to assess the difference in efficacy of full-versus limited-extended ET, measured in terms of the difference in DFS log-HR, according to the disease nodal-status. Secondary endpoint was the difference in efficacy of full-versus limited-extended ET according to tumor size (i.e., pT1 vs pT2/3/4), histological grade (i.e., G1/G2 vs G3), patients’ age (i.e., ≤60 vs > 60 years) and previous type of ET (i.e., aromatase inhibitors vs tamoxifen vs switch strategy).

Results

Three phase III RCTs fulfilled the inclusion criteria. A total of 6689 patients were included in the analysis, of which 3506 (53%) had N + ve disease.

The full-extended ET provided no DFS-benefit as compared with the limited-extended ET in patients with N-ve disease (pooled DFS-HR = 1.04, 95%CI: 0.89 to 1.22; I2 = 18%).

Conversely, in patients with N + ve disease the full-extended ET significantly improved DFS, with a pooled DFS-HR of 0.85 (95%CI: 0.74 to 0.97; I2 = 0%).

There was a significant interaction between the disease nodal-status and the efficacy of the full-versus limited-extended ET (p-heterogeneity = 0.048).

The full-extended ET provided no significant DFS-benefit as compared with the limited-extended ET in all the other subgroups analyzed.

Conclusions

: Patients with eBC and N + ve disease can obtain a significant DFS-benefit from the full-extended as compared with the limited-extended adjuvant ET.

 

 

Early breast cancer in women aged 35 years or younger: A large national multicenter French population-based case control-matched analysis

by Ondine Dufour, Gilles Houvenaeghel, Jean-Marc Classe, Monique Cohen, Christelle Faure, Chafika Mazouni, Marie-Pierre Chauvet, Eva Jouve, Emile Darai, Anne-Sophie Azuar, Pierre Gimbergues, Anthony Gonçalves, Alexandre de Nonneville 

The Breast: Published: February 08, 2023

Background

There is a scarcity of data exploring early breast cancer (eBC) in very young patients. We assessed shared and intrinsic prognostic factors in a large cohort of patients aged ≤35, compared to a control group aged 36 to 50.

Methods

Patients ≤50 were retrospectively identified from a multicentric cohort of 23,134 eBC patients who underwent primary surgery between 1990 and 2014. Multivariate Cox analyses for DFS and OS were built. To assess the independent impact of age, 1 to 3 case-control analysis was performed by matching ≤35 and 36–50 years patients.

Results

Of 6481 patients, 556 were aged ≤35, and 5925 from 36 to 50. Age ≤35 was associated with larger tumors, higher grade, ER-negativity, macroscopic lymph node involvement (pN + macro), lymphovascular invasion (LVI), mastectomy, and chemotherapy (CT) use. In multivariate analysis, age ≤35 was associated with worse DFS [HR 1.56, 95% CI 1.32–1.84; p < 0.001], and OS [HR 1.29, 95% CI 1.03–1.60; p = 0.025], as were high grade, large tumor, LVI, pN + macro, ER-negativity, period of diagnostic, and absence of ET or CT (for DFS). Adverse prognostic impact of age ≤35 was maintained in the case control-matched analysis for DFS [HR 1.56, 95%CI 1.28–1.91, p < 0.001], and OS [HR 1.33, 95%CI 1.02–1.73, p = 0.032]. When only considering patients ≤35, ER, tumor size, nodal status, and LVI were independently associated with survival in this subgroup.

Conclusions

Age ≤35 is associated with less favorable presentation and more aggressive treatment strategies. Our results support the poor prognosis value of young age, which independently persisted when adjusting for other prognostic factors and treatments.

 

Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial

 

by Stephen R D Johnston, Masakazu Toi, Joyce O'Shaughnessy, Priya Rastogi, Mario Campone, Patrick Neven, Chiun-Sheng Huang, Jens Huober, Georgina Garnica Jaliffe, Irfan Cicin, Sara M Tolaney, Matthew P Goetz, Hope S Rugo, Elzbieta Senkus, Laura Testa, Lucia Del Mastro, Chikako Shimizu, Ran Wei, Ashwin Shahir, Maria Munoz, Belen San Antonio, Valérie André, Nadia Harbeck, Miguel Martin, monarchE Committee Members 

 

The Lancet Oncology: VOLUME 24, ISSUE 1, P77-90, JANUARY 2023

 

Background

Adjuvant abemaciclib plus endocrine therapy previously showed a significant improvement in invasive disease-free survival and distant relapse-free survival in hormone receptor-positive, human epidermal growth factor receptor 2 (HER2; also known as ERBB2)-negative, node-positive, high-risk, early breast cancer. Here, we report updated results from an interim analysis to assess overall survival as well as invasive disease-free survival and distant relapse-free survival with additional follow-up.

Methods

In monarchE, an open-label, randomised, phase 3 trial, adult patients (aged ≥18 years) who had hormone receptor-positive, HER2-negative, node-positive, early breast cancer at a high risk of recurrence with an Eastern Cooperative Oncology Group performance status of 0 or 1 were recruited from 603 sites including hospitals and academic and community centres in 38 countries. Patients were randomly assigned (1:1) by means of an interactive web-based response system (block size of 4), stratified by previous chemotherapy, menopausal status, and region, to receive standard-of-care endocrine therapy of physician's choice for up to 10 years with or without abemaciclib 150 mg orally twice a day for 2 years (treatment period). All therapies were administered in an open-label manner without masking. High-risk disease was defined as either four or more positive axillary lymph nodes, or between one and three positive axillary lymph nodes and either grade 3 disease or tumour size of 5 cm or larger (cohort 1). A smaller group of patients were enrolled with between one and three positive axillary lymph nodes and Ki-67 of at least 20% as an additional risk feature (cohort 2). This was a prespecified overall survival interim analysis planned to occur 2 years after the primary outcome analysis for invasive disease-free survival. Efficacy was assessed in the intention-to-treat population. Safety was assessed in all treated patients. The study is registered with ClinicalTrials.gov, NCT03155997, and is ongoing.

Findings

Between July 17, 2017, and Aug 12, 2019, 5637 patients were randomly assigned (5601 [99·4%] were women and 36 [0·6%] were men). 2808 were assigned to receive abemaciclib plus endocrine therapy and 2829 were assigned to receive endocrine therapy alone. At a median follow-up of 42 months (IQR 37–47), median invasive disease-free survival was not reached in either group and the invasive disease-free survival benefit previously reported was sustained: HR 0·664 (95% CI 0·578–0·762, nominal p<0·0001). At 4 years, the absolute difference in invasive disease-free survival between the groups was 6·4% (85·8% [95% CI 84·2–87·3] in the abemaciclib plus endocrine therapy group vs 79·4% [77·5–81·1] in the endocrine therapy alone group). 157 (5·6%) of 2808 patients in the abemaciclib plus endocrine therapy group died compared with 173 (6·1%) of 2829 patients in the endocrine therapy alone group (HR 0·929, 95% CI 0·748–1·153; p=0·50). The most common grade 3–4 adverse events were neutropenia (in 548 [19·6%] of 2791 patients receiving abemaciclib plus endocrine therapy vs 24 [0·9%] of 2800 patients in the endocrine therapy alone group), leukopenia (318 [11·4%] vs 11 [0·4%]), and diarrhoea (218 [7·8%] vs six [0·2%]). Serious adverse events occurred in 433 (15·5%) of 2791 patients receiving abemaciclib plus endocrine therapy versus 256 (9·1%) of 2800 receiving endocrine therapy. There were two treatment-related deaths in the abemaciclib plus endocrine therapy group (diarrhoea and pneumonitis) and none in the endocrine therapy alone group.

Interpretation

Adjuvant abemaciclib reduces the risk of recurrence. The benefit is sustained beyond the completion of treatment with an absolute increase at 4 years, further supporting the use of abemaciclib in patients with high-risk hormone receptor-positive, HER2-negative early breast cancer. Further follow-up is needed to establish whether overall survival can be improved with abemaciclib plus endocrine therapy in these patients.

 

 

 

Antibody-drug conjugates targeting Trop-2: Clinical developments in early breast cancer therapy

 

by Jae Ho Jeong, Sung-Bae Kim / October 26, 2022

 

The Breast: VOLUME 66, P199-203, DECEMBER 01, 2022

 

Although breast cancer has a good prognosis compared with various cancers, metastatic breast cancer has an aggressive disease course and remains incurable. Therefore, treatment of early breast cancer to prevent recurrence and metastasis is crucial. Recently, the development of anti-cancer drugs, such as targeted agents and immuno-oncology, has been accelerating. Antibody-drug conjugates (ADCs) are also building a new paradigm. Particularly, ADCs targeting Trop-2 were approved for their efficacy in metastatic triple-negative breast cancer patients who received ≥2 prior systemic therapies and showed significant results in heavily pretreated hormone receptor-positive/HER2-negative breast cancer. In this brief review, we provide an overview of ongoing clinical trials of ADCs targeting Trop-2 in early breast cancer, specifically sacituzumab govitecan.

 

Immune checkpoint inhibition in the treatment of early stage triple negative breast cancer: 2021 update

 

by Lauren C. Brown, Sherene Loi 

 

The Breast: Published: December 31, 2021

 

Abstract

There is an emerging body of evidence regarding the use of immunotherapy in early-stage triple negative breast cancer (TNBC), with the recent publication of several phase III and randomised phase II studies examining the role of immune checkpoint inhibitors (ICI) in the neoadjuvant setting in combination with chemotherapy. Evidence to date suggests that the addition of PD-1/PD-L1 inhibitors results in slight increases in the rate of pathologic complete response (pCR) seen at the time of surgery, and improved event free survival (EFS) has now been reported. However, a number of questions remain such as the optimal chemotherapy backbone; whether traditional third generation chemotherapy regimens can safely be de-escalated in the presence of an ICI; and the most appropriate sequencing of treatment in order to best harness a durable immune response and if continuation of post operative ICI is needed if one achieves a pCR. A predictive biomarker is also yet to be established, given that PD-L1 protein expression does not seem discriminatory. Given that long-term clinical outcome improvements seen thus far in early stage trials do not seem to be mediated through small changes in pathological complete response rates, new approaches in early stage trial design are now needed.

Adjuvant CDK4/6 inhibitors combined with endocrine therapy in HR-positive, HER2-negative early breast cancer: A meta-analysis of randomized clinical trials

 

Adjuvant CDK4/6 inhibitors combined with endocrine therapy in HR-positive, HER2-negative early breast cancer: A meta-analysis of randomized clinical trials

 

by Hong-Fei Gao, Ying-Yi Lin, Teng Zhu, Fei Ji, Liu-Lu Zhang, Ci-Qiu Yang, Mei Yang, Jie-Qing Li, Min-Yi Cheng, Kun Wang 

 

The Breast: VOLUME 59, P165-175, OCTOBER 01, 2021

 

Background

The benefit of adjuvant cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors with endocrine therapy (ET) in hormone receptor-positive, human epidermal growth factor 2 receptor-negative (HR+/HER2-) early breast cancer (EBC) is uncertain. Hence, we performed a meta-analysis to determine the efficacy and safety of adjuvant CDK4/6 inhibitors plus ET and to identify potential preferred subpopulations for this regimen.

Methods

A literature search was conducted in PubMed, Embase, Cochrane databases up to Jan 15, 2021. Hazard ratios (HRs) for invasive disease-free survival (IDFS) and risk ratios (RRs) for grade 3/4 adverse events (AEs) and treatment discontinuation were extracted. Analysis with predefined subgroup variables was done. Trial sequential analysis (TSA) was performed to assess the conclusiveness of survival outcomes.

Results

Three trials were eligible (N = 12647). Compared with ET, adjuvant CDK4/6 inhibitors with ET prolonged IDFS in patients with HR+/HER2- EBC (HR 0.87, 95% CI 0.76–0.98, p = 0.03, I2 = 19%), with positive therapeutic responses observed in patients with N2/N3 nodal status (HR 0.83, 95% CI 0.71–0.97, p = 0.02, I2 = 0%). None of the cumulative z-curves crossed the trial monitoring boundaries in TSA, and no reliable conclusion could be drawn. The combination treatment carried a higher risk of grade 3/4 AEs (RR 4.14, 95% CI 3.33–5.15, p < 0.00001) and an increase in treatment discontinuation due to AEs (RR 19.16, 95% CI 9.27–39.61, p < 0.00001).

Conclusions

Adjuvant CDK4/6 inhibitors with ET might provide survival benefit in HR+/HER2- EBC. A statistically significantly improved IDFS was only observed in N2/N3 subgroup. However, overall evidence favoring the use of this combination regimen was inadequate.

The role of CDK4/6 inhibitors in early breast cancer

 

The role of CDK4/6 inhibitors in early breast cancer

 

by Miguel Gil-Gil, Emilio Alba, Joaquín Gavilá, Juan de la Haba-Rodríguez, Eva Ciruelos, Pablo Tolosa, Daniele Candini, Antonio Llombart-Cussac 

 

The Breast: VOLUME 58, P160-169, AUGUST  01, 2021

 

The use of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) has proven to be a successful strategy in the treatment of advanced hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2 -) breast cancer (BC), leading to a strong interest in their possible role in the treatment of early luminal BC. In this review we collect the most relevant and recent information on the use of CDK4/6i for the treatment of early BC in the neoadjuvant and adjuvant settings. Specifically, we evaluate the results of the large phase 3 adjuvant trials recently released, which have yielded apparently divergent results.

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

 

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

by Roberto Orecchia, Umberto Veronesi, Patrick Maisonneuve, Viviana Enrica Galimberti, Roberta Lazzari, Paolo Veronesi, Barbara Alicja Jereczek-Fossa, Federica Cattani, Claudia Sangalli, Alberto Luini, Pietro Caldarella, Marco Venturino, Daniele Sances, Stefano Zurrida, Giuseppe Viale, Maria Cristina Leonardi, Mattia Intra 

The Lancet Oncology : VOLUME 22, ISSUE 5, P597-608, MAY 01, 2021

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.

Clinical predictors of cardiac toxicity in HER2-positive early breast cancer patients treated with adjuvant s.c. versus i.v. trastuzumab

 Clinical predictors of cardiac toxicity in HER2-positive early breast cancer patients treated with adjuvant s.c. versus i.v. trastuzumab

by Rita De Sanctis, Laura Giordano, Federica D’Antonio, Elisa Agostinetto, Arianna Marinello, Daniela Guiducci, Giovanna Masci, Agnese Losurdo, Monica Zuradelli, Rosalba Torrisi, Armando Santoro 

 

The Breast: VOLUME 57, P80-85, JUNE 01, 2021 (Published: March 17, 2021)

 

Background

Few data are available about real-life cardiotoxicity associated with s.c. versus i.v. trastuzumab treatment of early-stage, HER2-positive breast cancer, and little is known about its predisposing factors.

Patients and methods

We retrospectively reviewed data of 363 adult patients treated with adjuvant trastuzumab for HER2-positive breast cancer. Univariate statistical analysis was performed, and a multivariable logistic model was developed to identify independent risk factors of cardiac toxicity.

Results

Within 5 years, the overall incidence of events meeting our criteria was 11.8%, and an early discontinuation of trastuzumab was recorded in 20 patients (5.5%). No cases of congestive heart failure occurred, neither multiple events per patient were observed. A total of 184 patients received i.v. and 179 received s.c. trastuzumab. Compared with the s.c. formulation, a higher cardiotoxicity rate for the i.v. administration (15.2% vs 8.4%) was found, and particularly in those patients with cardiovascular risk factors (19.3% vs 8.7%), at the univariate and multivariate analyses. Although more patients with prior anthracycline-based chemotherapy experienced cardiac events, the association of this therapy with cardiac events was not significant. The incidence of cardiac events was not influenced by anthropometric data (e.g. body mass index) or a diagnosis of diabetes mellitus. 5-year event-free survival was 91.7% in the overall population; event-free survival rates were similar between the s.c. and the i.v. groups.

Conclusion

Our study shows a more favorable safety profile of s.c. versus i.v trastuzumab administration. The use of s.c. trastuzumab could be advisable in at-risk patients.