Emerging treatments in HER2-positive advanced breast cancer: Keep raising the bar.

Patients with human epidermal receptor 2 (HER2)-positive breast cancer are experiencing a consistent shift toward better survival across the years, thanks to tremendous advancements in treatment strategies. The consistent improvements of outcomes set a high bar for new drug development and the need to explore new ways to overcome resistance mechanisms. Emerging treatments in HER2-positive breast cancer aim to tackle the disease by acting on different targets, including not only HER2 (both at the extra- and intracellular level), but also HER3, PD-(L)1, CTLA4, NKG2A, AKT, PI3K, and, in triple-positive tumors, the estrogen receptors and the cyclin-dependent kinases 4/6. This review describes the evolving treatment landscape of HER2-positive breast cancer, from the current approved therapies to the future perspectives, with a focus on the new agents which are likely to get approved in the next future.

Fertility Preservation and Assisted Reproduction in Patients With Breast Cancer Interrupting Adjuvant Endocrine Therapy to Attempt Pregnancy.

PURPOSE: We investigated time to pregnancy, efficacy and safety of fertility preservation, and assisted reproductive technologies (ARTs) in women with early hormone receptor-positive breast cancer (BC) desiring future pregnancy. PATIENTS AND METHODS: POSITIVE is an international, single-arm, prospective trial, in which 518 women temporarily interrupted adjuvant endocrine therapy to attempt pregnancy. We evaluated menstruation recovery and factors associated with time to pregnancy and investigated if ART use was associated with achieving pregnancy. The cumulative incidence of BC-free interval (BCFI) events was estimated according to the use of ovarian stimulation at diagnosis. The median follow-up was 41 months. RESULTS: Two hundred seventy-three patients (53%) reported amenorrhea at enrollment, of whom 94% resumed menses within 12 months. Among 497 patients evaluable for pregnancy, 368 (74%) reported at least one pregnancy. Young age was the main factor associated with shorter time to pregnancy with cumulative incidences of pregnancy by 1 year of 63.5%, 54.3%, and 37.7% for patients age <35, 35-39, and 40-42 years, respectively. One hundred and seventy-nine patients (36%) had embryo/oocyte cryopreservation at diagnosis, of whom 68 reported embryo transfer after enrollment. Cryopreserved embryo transfer was the only ART associated with higher chance of pregnancy (odds ratio, 2.41 [95% CI, 1.75 to 4.95]). The cumulative incidence of BCFI events at 3 years was similar for women who underwent ovarian stimulation for cryopreservation at diagnosis, 9.7% (95% CI, 6.0 to 15.4), compared with those who did not, 8.7% (95% CI, 6.0 to 12.5). CONCLUSION: In POSITIVE, fertility preservation using ovarian stimulation was not associated with short-term detrimental impact on cancer prognosis. Pregnancy rates were highest among those who underwent embryo/oocyte cryopreservation followed by embryo transfer.

Prediction of Benefit From Adjuvant Pertuzumab by 80-Gene Signature in the APHINITY (BIG 4-11) Trial.

PURPOSE: At the primary analysis, the APHINITY trial reported a statistically significant but modest benefit of adding pertuzumab to standard adjuvant chemotherapy plus trastuzumab in patients with histologically confirmed human epidermal growth factor receptor 2 (HER2)-positive early-stage breast cancer. This study evaluated whether the 80-gene molecular subtyping signature (80-GS) could identify patients within the APHINITY population who derive the most benefit from dual anti-HER2 therapy. METHODS: In a nested case-control study design of 1,023 patients (matched event to control ratio of 3:1), the 80-GS classified breast tumors into functional luminal type, HER2 type, or basal type. Additionally, 80-GS distinguished tumor subtypes that exhibited a single-dominant functional pathway versus tumors with multiple activated pathways. The primary end point was invasive disease-free survival (IDFS). Hazard ratios (HRs) were evaluated by Cox regression. After excluding patients without appropriate consent and those with missing data, 964 patients were included. RESULTS: The 80-GS classified 50% (n = 479) of tumors as luminal type, 28% (n = 275) as HER2 type, and 22% (n = 209) as basal type. Most luminal-type tumors (86%) displayed a single-activated pathway, whereas 49% of HER2-type and 42% of basal-type tumors were dual activated. There was no significant difference in IDFS among different conventional 80-GS subtypes (single- and dual-activated subtypes combined). However, basal single-subtype tumors were significantly more likely to have an IDFS event (hazard ratio, 1.69 [95% CI, 1.12 to 2.54]) compared with other subtypes. HER2 single-subtype tumors displayed a trend toward greater beneficial effect on the addition of pertuzumab (hazard ratio, 0.56 [95% CI, 0.27 to 1.16]) compared with all other subtypes. CONCLUSION: The 80-GS identified subgroups of histologically confirmed HER2-positive tumors with distinct biological characteristics. Basal single-subtype tumors exhibit an inferior prognosis compared with other subgroups and may be candidates for additional therapeutic strategies. Preliminary results suggest patients with HER2-positive, genomically HER2 single-subtype tumors may particularly benefit from added pertuzumab, which warrants further investigation.

Locoregional Breast Cancer Recurrence in the European Organisation for Research and Treatment of Cancer 10041/BIG 03-04 MINDACT Trial: Analysis of Risk Factors Including the 70-Gene Signature.

PURPOSE: A number of studies are currently investigating de-escalation of radiation therapy in patients with a low risk of in-breast relapses on the basis of clinicopathologic factors and molecular tests. We evaluated whether 70-gene risk score is associated with risk of locoregional recurrence (LRR) and estimated 8-year cumulative incidences for LRR in patients with early-stage breast cancer treated with breast conservation. METHODS: In this exploratory substudy of European Organisation for Research and Treatment of Cancer 10041/BIG 03-04 MINDACT trial, we evaluated women with a known clinical and genomic 70-gene risk score test result and who had breast-conserving surgery (BCS). The primary end point was LRR at 8 years, estimated by cumulative incidences. Distant metastasis and death were considered competing risks. RESULTS: Among 6,693 enrolled patients, 5,470 (81.7%) underwent BCS, of whom 98% received radiotherapy. At 8-year follow-up, 189 patients experienced a LRR, resulting in an 8-year cumulative incidence of 3.2% (95% CI, 2.7 to 3.7). In patients with a low-risk 70-gene signature, the 8-year LRR incidence was 2.7% (95% CI, 2.1 to 3.3). In univariable analysis, adjusted for chemotherapy, five of 12 variables were associated with LRR, including the 70-gene signature. In multivariable modeling, adjuvant endocrine therapy and to a lesser extent tumor size and grade remained significantly associated with LRR. CONCLUSION: This exploratory analysis of the MINDACT trial estimated an 8-year low LRR rate of 3.2% after BCS. The 70-gene signature was not independently predictive of LRR perhaps because of the low number of events observed and currently cannot be used in clinical decision making regarding LRR. The overall low number of events does provide an opportunity to design trials toward de-escalation of local therapy.

Fine-Tuning Adjuvant Endocrine Therapy for Early-Stage Breast Cancer: An Expert Consensus on Open Issues for Future Research.

After decades of research, improving the efficacy of adjuvant endocrine therapy (ET) for early-stage breast cancer becomes increasingly difficult. Beyond technological breakthroughs and the availability of new classes of drugs, further improvement of adjuvant ET will require applying a rigorous research approach in poorly investigated areas. We critically discuss some key principles that should inform future research to improve ET efficacy, including identifying specific subgroups of patients who can benefit from escalating or de-escalating approaches, optimizing available and new treatment strategies for different clinical contexts, and dissecting the direct and indirect biological effects of therapeutic interventions. Four main issues regarding adjuvant ET were identified as relevant areas, where a better application of such principles can provide positive results in the near future: (i) tailoring the optimal duration of adjuvant ET, (ii) optimizing ovarian function suppression for premenopausal women, (iii) dissecting the biological effects of estrogen receptor manipulation, and (iv) refining the selection of patients to candidate for treatments escalation.

Progression-free survival assessment by local investigators versus blinded independent central review in randomized clinical trials in metastatic breast cancer: A systematic review and meta-analysis.

INTRODUCTION: In randomized clinical trials (RCTs), blinded independent central review (BICR) is used to minimize heterogeneity and bias associated with radiological response evaluation by local investigators. However, BICR adds costs and complexity to the trial management. We assessed the discrepancy index between progression-free survival (PFS) assessment by local investigators and by BICR in RCTs conducted in patients with metastatic breast cancer (MBC). METHODS: A systematic search of PubMed, Embase, Cochrane databases and conference proceedings (ASCO, SABCS, ESMO) was performed up to January 4, 2023 (PROSPERO: CRD42021229865). All RCTs published from 2000 to 2022, including MBC patients treated in first- or second-line, and reporting PFS assessed by local investigators and BICR were included. A discrepancy index between BICR-assessed and investigator-assessed HR was calculated for each trial and an overall combined DI was obtained using a fixed-effects model. The agreement between hazard ratios (HR) of PFS assessed by local investigators and BICR was measured using intraclass correlation coefficient (ICC). RESULTS: We analyzed 24 studies including 13,168 patients. Among them, 19 (79%) were in first-line, 18 (75%) were phase III trials and 23 (96%) had PFS as primary endpoint. The overall combined discrepancy index was 0.97 (95%CI 0.85-1.10; ICC 0.831, p < 0.001) suggesting no statistically significant difference in PFS assessment between local investigators and BICR. This result was consistent across all analyzed subgroups. CONCLUSIONS: The good concordance between local investigator and BICR assessments supports the reliability of local investigator-assessed PFS as primary endpoint for RCTs in MBC and questions the practical utility of implementing BICR in all RCTs.

Immunological and clinicopathological features predict HER2-positive breast cancer prognosis in the neoadjuvant NeoALTTO and CALGB 40601 randomized trials.

The identification of prognostic markers in patients receiving neoadjuvant therapy is crucial for treatment optimization in HER2-positive breast cancer, with the immune microenvironment being a key factor. Here, we investigate the complexity of B and T cell receptor (BCR and TCR) repertoires in the context of two phase III trials, NeoALTTO and CALGB 40601, evaluating neoadjuvant paclitaxel with trastuzumab and/or lapatinib in women with HER2-positive breast cancer. BCR features, particularly the number of reads and clones, evenness and Gini index, are heterogeneous according to hormone receptor status and PAM50 subtypes. Moreover, BCR measures describing clonal expansion, namely evenness and Gini index, are independent prognostic factors. We present a model developed in NeoALTTO and validated in CALGB 40601 that can predict event-free survival (EFS) by integrating hormone receptor and clinical nodal status, breast pathological complete response (pCR), stromal tumor-infiltrating lymphocyte levels (%) and BCR repertoire evenness. A prognostic score derived from the model and including those variables, HER2-EveNT, allows the identification of patients with 5-year EFS > 90%, and, in those not achieving pCR, of a subgroup of immune-enriched tumors with an excellent outcome despite residual disease.

DECRESCENDO: de-escalating chemotherapy in HER2-positive, estrogen receptor-negative, node-negative early breast cancer.

The human epidermal growth factor receptor 2 (HER2)-enriched intrinsic subtype represents up to 75% of all HER2-positive hormone receptor (HR)-negative breast cancer (BC). Optimizing HER2-targeting therapy in this population might allow the omission of anthracycline-based chemotherapy, which is associated with potentially severe toxicities. DECRESCENDO (NCT04675827) is a large, multicenter, single-arm phase II trial in patients with HR-negative, HER2-positive, node-negative early BC evaluating a neoadjuvant pertuzumab and trastuzumab fixed-dose combination administered subcutaneously plus taxane-based chemotherapy followed by adjuvant treatment, adapted according to response to neoadjuvant therapy. The primary end point is the 3-year recurrence-free survival rate in patients with 'HER2-enriched' tumors and a pathological complete response. This flexible care substudy offers adjuvant treatment administration outside the hospital to some patients.

Breast cancer is the most frequent cancer type among women worldwide. Different types of breast cancer exist, defined by the type of proteins on the tumor cell surface: HER2-positive: overproduction of human epidermal growth factor receptor 2 (HER2); Hormone receptor-positive: overproduction of the estrogen and/or progesterone hormone receptors. In the past 30 years, effective anti-HER2 drugs have been developed. However, they are often combined with chemotherapy, which can cause serious side effects (also called toxicities). HER2-positive tumors, which are also hormone receptor-negative, respond better to HER2-targeting drugs with less toxicity than chemotherapy. The DECRESCENDO trial aims to test treating HER2-positive, hormone receptor-negative patients (with a maximum breast cancer tumor size of 5 cm, without swollen lymph nodes) with pertuzumab + trastuzumab. The combination therapy would be given presurgery to reduce the tumor size as much as possible first (known as neoadjuvant therapy). The intensity of the patient's chemotherapy would be reduced with only one chemotherapy drug instead of standard three to four drugs. Patients that respond well will require less intense treatment after their surgery. Tissue from the tumors will be tested to see if any of the HER2-positive tumors belong to a subtype known as 'HER2-enriched' ­ this subtype is predicted to be more responsive to the trastuzumab and pertuzumab combination therapy. In a separate study of the DECRESCENDO trial, patients with good responses to neoadjuvant therapy and no safety concerns may continue their postsurgery treatment outside the hospital, such as at home.

Real-world clinical outcomes of patients with stage I HER2-positive breast cancer treated with adjuvant paclitaxel and trastuzumab.

Up to 20% of breast cancer overexpress HER2 protein, making it a reliable target for antibody-based treatments. In early HER2-positive breast cancer avoiding anthracycline-based chemotherapy is a challenge. Based on the single-arm phase II APT trial results, adjuvant paclitaxel/trastuzumab is an accepted regimen for patients with stage I HER2-positive disease. In our retrospective study of 240 patients, the median tumor size was 12.0 mm (IQR 9 -15), and 204 (85%) had estrogen receptor-positive disease. After a median follow-up of 4.6 years, 3-year real-world disease-free survival, distant DFS, and overall survival were 98.8% (95% confidence interval (CI), 96.2-99.6), 99.2% (95% CI, 96.7-99.8), and 98.3% (95% CI, 96.2-99.6), respectively. In a real-world setting, an adjuvant paclitaxel/trastuzumab regimen was associated with low recurrence rates among women with stage I, HER2-positive breast cancer. Additionally, we reviewed other treatment optimization strategies attempted or ongoing in HER2-positive breast cancer.

Obesity-associated changes in molecular biology of primary breast cancer.

Obesity is associated with an increased risk of developing breast cancer (BC) and worse prognosis in BC patients, yet its impact on BC biology remains understudied in humans. This study investigates how the biology of untreated primary BC differs according to patients' body mass index (BMI) using data from >2,000 patients. We identify several genomic alterations that are differentially prevalent in overweight or obese patients compared to lean patients. We report evidence supporting an ageing accelerating effect of obesity at the genetic level. We show that BMI-associated differences in bulk transcriptomic profile are subtle, while single cell profiling allows detection of more pronounced changes in different cell compartments. These analyses further reveal an elevated and unresolved inflammation of the BC tumor microenvironment associated with obesity, with distinct characteristics contingent on the estrogen receptor status. Collectively, our analyses imply that obesity is associated with an inflammaging-like phenotype. We conclude that patient adiposity may play a significant role in the heterogeneity of BC and should be considered for BC treatment tailoring.

Interrupting Endocrine Therapy to Attempt Pregnancy after Breast Cancer.

BACKGROUND: Prospective data on the risk of recurrence among women with hormone receptor-positive early breast cancer who temporarily discontinue endocrine therapy to attempt pregnancy are lacking. METHODS: We conducted a single-group trial in which we evaluated the temporary interruption of adjuvant endocrine therapy to attempt pregnancy in young women with previous breast cancer. Eligible women were 42 years of age or younger; had had stage I, II, or III disease; had received adjuvant endocrine therapy for 18 to 30 months; and desired pregnancy. The primary end point was the number of breast cancer events (defined as local, regional, or distant recurrence of invasive breast cancer or new contralateral invasive breast cancer) during follow-up. The primary analysis was planned to be performed after 1600 patient-years of follow-up. The prespecified safety threshold was the occurrence of 46 breast cancer events during this period. Breast cancer outcomes in this treatment-interruption group were compared with those in an external control cohort consisting of women who would have met the entry criteria for the current trial. RESULTS: Among 516 women, the median age was 37 years, the median time from breast cancer diagnosis to enrollment was 29 months, and 93.4% had stage I or II disease. Among 497 women who were followed for pregnancy status, 368 (74.0%) had at least one pregnancy and 317 (63.8%) had at least one live birth. In total, 365 babies were born. At 1638 patient-years of follow-up (median follow-up, 41 months), 44 patients had a breast cancer event, a result that did not exceed the safety threshold. The 3-year incidence of breast cancer events was 8.9% (95% confidence interval [CI], 6.3 to 11.6) in the treatment-interruption group and 9.2% (95% CI, 7.6 to 10.8) in the control cohort. CONCLUSIONS: Among select women with previous hormone receptor-positive early breast cancer, temporary interruption of endocrine therapy to attempt pregnancy did not confer a greater short-term risk of breast cancer events, including distant recurrence, than that in the external control cohort. Further follow-up is critical to inform longer-term safety. (Funded by ETOP IBCSG Partners Foundation and others; POSITIVE ClinicalTrials.gov number, NCT02308085.).

Pathologic Complete Response and Individual Patient Prognosis After Neoadjuvant Chemotherapy Plus Anti-Human Epidermal Growth Factor Receptor 2 Therapy of Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer.

PURPOSE: The achievement of pathologic complete response (pCR) is strongly prognostic for event-free survival (EFS) and overall survival (OS) in patients with early breast cancer (EBC), and adapting postneoadjuvant therapy improves long-term outcomes for patients with HER2-positive disease not achieving pCR. We sought to investigate prognostic factors for EFS and OS among patients with and without pCR after neoadjuvant systemic treatment consisting of chemotherapy plus anti-HER2 therapy. MATERIALS AND METHODS: We used individual data from 3,710 patients randomly assigned in 11 neoadjuvant trials for HER2-positive EBC with ≥100 patients enrolled, available data for pCR, EFS, and OS, and follow-up ≥3 years. We assessed baseline clinical tumor size (cT) and clinical nodal status (cN) as prognostic factors using stratified (by trial and treatment) Cox models separately for hormone receptor-positive versus hormone receptor-negative disease, and for patients who had pCR (pCR+; ypT0/is, ypN0) versus patients who did not achieve a pCR (pCR-). RESULTS: The median follow-up overall was 61.2 months. In pCR+ patients, cT and cN were significant independent prognostic factors for EFS, whereas only cT was a significant predictor for OS. In pCR- patients, cT, cN, and hormone receptor status were significant independent predictors for both EFS and OS. Regardless of hormone receptor status, cT, and cN, the 5-year EFS/OS rates were higher in pCR+ patients than in pCR- patients. In most subsets with regards to hormone receptor and pCR status, cT and cN were independent prognostic factors for both EFS and OS, including pCR+ patients. CONCLUSION: These results confirm that patients achieving pCR have far better survival outcomes than patients who do not. The traditional poor prognostic features, namely tumor size and nodal status, remain important even after a pCR.

PIK3CA copy-number gain and inhibitors of the PI3K/AKT/mTOR pathway in triple-negative breast cancer.

As wider insights are gained on the molecular landscape of triple-negative breast cancer (TNBC), novel targeted therapeutic strategies might become an option in this setting as well. Activating mutations of PIK3CA represent the second most common alteration in TNBC after the TP53 mutation, with a prevalence of ∼10%-15%. Considering the well-established predictive role of PIK3CA mutations for response to agents targeting the PI3K/AKT/mTOR pathway, several clinical trials are currently evaluating these drugs in patients with advanced TNBC. However, much less is known regarding the actionability of PIK3CA copy-number gains, which represent a thoroughly common molecular alteration in TNBC, with a prevalence estimated at 6%-20%, and are listed as "likely gain-of-function" alterations in the OncoKB database. In the present paper, we describe two clinical cases in which patients harboring PIK3CA-amplified TNBC received a targeted treatment with the mTOR-inhibitor everolimus and the PI3K-inhibitor alpelisib, respectively, with evidence of disease response on 18F-FDG positron-emission tomography (PET) imaging. Hence, we discuss the evidence presently available regarding a possible predictive value of PIK3CA amplification for response to targeted treatment strategies, suggesting that this molecular alteration might represent an intriguing biomarker in this sense. Considering that few of the currently active clinical trials assessing agents targeting the PI3K/AKT/mTOR pathway in TNBC select patients based on tumor molecular characterization, and none of these based on PIK3CA copy-number status, we urge for the introduction of PIK3CA amplification as a criterion for patient selection in future clinical trials in this setting.

Re-Evaluation of Pathologic Complete Response as a Surrogate for Event-Free and Overall Survival in Human Epidermal Growth Factor Receptor 2-Positive, Early Breast Cancer Treated With Neoadjuvant Therapy Including Anti-Human Epidermal Growth Factor Receptor 2 Therapy.

PURPOSE: Pathologic complete response (pCR) has prognostic importance and is frequently used as a primary end point, but doubts remain about its validity as a surrogate for event-free survival (EFS) and overall survival (OS) in human epidermal growth factor receptor 2 (HER2)-positive, early breast cancer. METHODS: We obtained individual-patient data from randomized trials of neoadjuvant anti-HER2 therapy that enrolled at least 100 patients, had data for pCR, EFS, and OS, and a median follow-up of at least 3 years. We quantified the patient-level association between pCR (defined as ypT0/Tis ypN0) and both EFS and OS using odds ratios (ORs, with ORs >1.00 indicating a benefit from achieving a pCR). We quantified the trial-level association between treatment effects on pCR and on EFS and OS using R2 (with values above 0.75 considered as indicating strong associations). RESULTS: Eleven of 15 eligible trials had data for analysis (3,980 patients, with a median follow-up of 62 months). Considering all trials, we found strong patient-level associations, with ORs of 2.64 (95% CI, 2.20 to 3.07) for EFS and 3.15 (95% CI, 2.38 to 3.91) for OS; however, trial-level associations were weak, with an unadjusted R2 of 0.23 (95% CI, 0 to 0.66) for EFS and 0.02 (95% CI, 0 to 0.17) for OS. We found qualitatively similar results when grouping trials according to different clinical questions, when analyzing only patients with hormone receptor-negative disease, and when using a more stringent definition of pCR (ypT0 ypN0). CONCLUSION: Although pCR may be useful for patient management, it cannot be considered as a surrogate for EFS or OS in neoadjuvant trials of HER2-positive, operable breast cancer.

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.

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.

Impact of Anti-HER2 Therapy Alone and With Weekly Paclitaxel on the Ovarian Reserve of Young Women With HER2-Positive Breast Cancer.

BACKGROUND: The potential gonadotoxicity of anti-HER2 agents remains largely unknown, and limited, conflicting evidence exists for taxanes. Antimüllerian hormone (AMH) is an established biomarker of ovarian reserve that may aid in quantifying anticancer treatment-induced gonadotoxicity. PATIENTS AND METHODS: The present biomarker analysis of the randomized phase III neoadjuvant NeoALTTO trial included premenopausal women aged ≤45 years at diagnosis of HER2-positive early breast cancer with available frozen serum samples at baseline (ie, before anticancer treatments), at week 2 (ie, the "biological window" of anti-HER2 therapy alone), and/or at the time of surgery (ie, after completing paclitaxel + anti-HER2 therapy, before starting adjuvant chemotherapy). RESULTS: The present analysis included 130 patients with a median age of 38 years (interquartile ratio [IQR], age 33-42 years). AMH values at the 3 time points differed significantly (P<.001). At baseline, median AMH levels were 1.29 ng/mL (IQR, 0.56-2.62 ng/mL). At week 2, a small but significant reduction in AMH levels was observed (median, 1.10 ng/mL; IQR, 0.45-2.09 ng/mL; P<.001). At surgery, a larger significant decline in AMH levels was observed (median, 0.01 ng/mL; IQR, 0.01-0.03 ng/mL; P<.001). Although the type of anti-HER2 treatment (trastuzumab and/or lapatinib) did not seem to impact the results, age and pretreatment ovarian reserve had a major influence on treatment-induced gonadotoxicity risk. CONCLUSIONS: This NeoALTTO biomarker analysis showed that anti-HER2 therapies alone had limited gonadotoxicity but that the addition of weekly paclitaxel resulted in marked AMH decline with possible negative implications for subsequent ovarian function and fertility.

Ten-year survival of neoadjuvant dual HER2 blockade in patients with HER2-positive breast cancer.

BACKGROUND: Dual anti-HER2-targeted therapy in breast cancer (BC) significantly increased the rate of pathological complete response (pCR) compared to single blockade when added to chemotherapy. However, limited data exist on the long-term impact on survival of the additional increase in pCR. METHODS: Neoadjuvant lapatinib and/or trastuzumab treatment optimisation (NCT00553358) is an international, randomised, open-label, phase III study investigating the addition of lapatinib to chemotherapy plus trastuzumab in HER2-positive early BC. Ten-year event-free survival (EFS), overall survival (OS) and safety were assessed on intention-to-treat population. The association between pCR and EFS or OS was investigated in landmark population. RESULTS: A total of 455 patients were randomised to receive lapatinib (154), trastuzumab (149) or the combination (152). Ten-year EFS estimates were 63% (95% confidence interval [CI], 54%-71%) in the lapatinib group, 64% (95% CI, 55%-72%) in the trastuzumab group and 67% (95% CI, 58%-74%) in the combination group. Ten-year OS rates were 76% (95% CI, 67%-83%), 75% (95% CI, 66%-82%) and 80% (95% CI, 73%-86%) in the lapatinib, trastuzumab and combination groups, respectively. Women who achieved a pCR had improved EFS (hazard ratio 0.48, 95% CI, 0.31-0.73) and OS (hazard ratio 0.37, 95% CI, 0.20-0.63) compared with those who did not. The numerical difference in survival according to pCR status was greater in women treated with the combination and those with hormone-receptor-negative tumours. There were no new or long-term safety concerns. CONCLUSIONS: Patients with HER2-positive BC showed a durable survival benefit of neoadjuvant anti-HER2, irrespective of treatment arm. Patients who achieve pCR have significantly better outcomes than patients without pCR.