Neoadjuvant chemotherapy in young breast cancer patients: correlation between response and relapse?

The aim of this analysis was to assess how the clinical response to chemotherapy corresponded to long-term prognosis in patients of less than 35 years of age. A retrospective analysis was made of response and survival data of 609 premenopausal patients who had been treated by four cycles of neoadjuvant chemotherapy followed by surgery and/or radiotherapy. Patients were stratified into three age groups (group 1, ≤35 years; group 2, 35–40 years; group 3, ≥41 years). Objective and complete clinical response rates were significantly higher in the youngest patients (below 35 yrs: P=0.005 and P=0.001, respectively) in stark contrast to a particularly poor outcome of this subpopulation. Five-year local recurrence rates were 31% in the youngest patients, compared with 26% and 16% in groups 2 and 3, respectively (P=0.0007). Group 1 patients also had significantly higher 5-year metastatic relapse rates (41% versus 35% and 28%; P=0.007) and 5-year survival figures were 70%, 82% and 84% for groups 1, 2 and 3 respectively (P=0.002). Finally, stratification by age and by response revealed that, whilst the outcome of the youngest patients was highly dependent on their response to primary chemotherapy, complete responders showed disease-free survival rates at 5 years that were lower than these of older patients, whatever their response. Despite a seemingly better control of the primary tumour by chemotherapy, the patients in the youngest age group remained at a high risk for local and metastatic relapse. This apparent paradox may be in part attributable to rapid disease progression of micrometastatic tumour subpopulations that are refractory to chemotherapy.     

Impact of molecular subtype and race on HR+, HER2− breast cancer survival

Purpose

There is an urgent need to understand the biological factors contributing to the racial survival disparity among women with hormone receptor-positive (HR+), HER2? breast cancer. In this study, we examined the impact of PAM50 subtype on 10-year mortality rate in women with HR+, HER2? breast cancer by race.

Methods

Women with localized, HR+, HER2? breast cancer diagnosed between 2002 and 2012 from two population-based cohorts were evaluated. Archival tumors were obtained and classified by PAM50 into four molecular subtypes (i.e., luminal A, luminal B, HER2-enriched, and basal-like). The molecular subtypes within HR+, HER2? breast cancers and corresponding 10-year mortality rate were compared between Black and Non-Hispanic White (NHW) women using Cox proportional hazard ratios and survival analysis, adjusting for covariates.

Results

In this study, 318 women with localized, HR+, HER2? breast cancer were included—227 Black (71%) and 91 NHW (29%). Young Black women (age?≤?50) had the highest proportion of HR+, non-luminal A tumors (47%), compared to young NHW (10%), older Black women (31%), and older NHW (30%). Overall, women with HR+, non-luminal A subtypes had a higher 10-year mortality rate compared to HR+, luminal A subtypes after adjustment for age, stage, and income (HR 4.21 for Blacks, 95% CI 1.74–10.18 and HR 3.44 for NHW, 95% CI 1.31–9.03). Among HR+, non-luminal A subtypes there was, however, no significant racial difference in 10-yr mortality observed (Black vs. NHW: HR 1.23, 95% CI 0.58–2.58).

Conclusion

Molecular subtype classification highlights racial disparities in PAM50 subtype distribution among women with HR+, HER2? breast cancer. Among women with HR+, HER2? breast cancer, racial survival disparities are ameliorated after adjusting for molecular subtype.

     

Dose modifications of ribociclib and endocrine therapy for treatment of ER+ HER2− metastatic breast cancer

Breast Cancer Research and Treatment - Treatment for estrogen receptor positive (ER+), human epidermal receptor 2 negative (HER2?) metastatic breast cancer (MBC) has improved with the...     

Neoadjuvant chemotherapy in breast cancer—insights from the German experience

New insights into neoadjuvant treatment of breast cancer have shown that the prognostic value of pathological complete response has to be rated differently according to subtype. Whereas in triple-negative, HER2-positive (non-luminal) and luminal B (HER2-negative) patients with a pCR after neoadjuvant chemotherapy show a significantly better outcome than patients without a pCR, this prognostic impact cannot be seen in patients with luminal A or luminal B (HER2-positive) tumors. Patients can therefore only avoid an initially high-risk prognosis if they have a pCR of these first mentioned subtypes. For patients with those tumors or with high Ki-67 levels in residual disease, new treatment options have to be found. Contrarily, response-guided chemotherapy, i.e., changing the regimen in case of no early response or intensification in case of early response, showed significant survival advantages only in the latter group. Strategies are currently being developed on how locoregional treatment can be reduced in patients with a pathological complete response. These aim to reduce the extent of surgery or even avoid surgery completely.     

Response and Prognosis of Docetaxel and Cyclophosphamide as Neoadjuvant Chemotherapy in ER+ HER2− Breast Cancer: A Prospective Phase II Study

BackgroundAlthough a docetaxel and cyclophosphomide (TC) regimen without anthracycline as adjuvant therapy became one of the standard regimens especially for ER-positive (ER⁺)/human epidermal growth factor receptor 2-negative (HER2⁻) primary breast cancer, the efficacy of TC as neoadjuvant chemotherapy (NAC) is not known. We conducted the prospective trial to assess the efficacy of a TC regimen in the neoadjuvant setting for stage II to III ER⁺/HER2⁻ primary breast cancer.Patients and MethodsA TC regimen that included 75 mg/m² of docetaxel and 600 mg/m² of cyclophosphamide for 4 cycles every 3 weeks was administered as NAC. Primary endpoints are the rate of clinical response (clinical partial response and clinical complete response) and pathologic complete response; secondary endpoints are the disease-free survival and overall survival rates.ResultsThirty (71.4%) of 42 tumors had clinical response. No patient achieved pathologic complete response. At the median follow-up period of 105.2 months (range, 12.1-119.7 months), the disease-free survival rate was 81.6%, and the distant disease-free survival rate was 86.8%. In terms of survival, only 1 patient died during the study period. The overall survival rate was 97.4% during the study period. Patients who developed distant recurrence had a trend to have progesterone receptor-negative or weakly positive compared with those who did not develop any recurrence (85.7% vs. 45.2%; P = .05).ConclusionsOur prospective study showed that a TC regimen as NAC achieved a high clinical response rate in stage II to III ER⁺/HER2⁻ breast cancer. A TC regimen without anthracycline as NAC might be one of the options for patients with ER⁺/HER2⁻ breast cancer without high-risk factors including progesterone receptor negativity.     

Relapse after complete response to anthracycline‐based combination chemotherapy in metastatic breast cancer

The aim of this study was to assess the applicability of histopathological grading according to the protocol of Elston/Ellis and the Nottingham Prognostic Index (NPI) to a defined breast cancer population. The NPI is the sum of the individual scores concerning grade, tumour size, and lymph node status, each weighted according to regression coefficients of a Cox proportional hazard analysis and calculated for each individual breast cancer patient. 630 consecutive patients with invasive breast cancer diagnosed 1988–91 were retrospectively followed up and their tumours reviewed and graded. A Cox proportional hazard analysis was performed. Grade, lymph node status, and tumour size were statistically significant predictors of survival within the follow up period (median 7.2 years). Similar to NPI, a temporary index (Kalmar Prognostic Index, KPI) was derived and normalised to NPI for comparison (KPI(norm)). NPI and KPI(norm) gave similar prognostic power in spite of the differences of the patient populations from which the 2 indices were derived. Patients with NPI 4 or less had 0.66% breast cancer specific mortality during the follow up time. 14% of the patients with NPI 4.1–5 and 32% of those with an index sum 5.1–6 died from breast cancer during this time. Younger patients tended to have higher grade tumours. We advocate the common use of grade and the NPI in order to increase the comparability of groups of patients receiving different therapies.     

Effect of neoadjuvant chemotherapy on breast cancer phenotype,ER/PR and HER2 expression – Implications for the practising oncologist

PurposeTo assess the effect of neoadjuvant chemotherapy (NACT) on breast cancer characteristics, hormone receptors and human epidermal growth factor receptor 2 (HER2) expression and whether testing should be repeated on residual tumours.Material and methodsPatients with primary operable breast cancer who received NACT at a single United Kingdom tertiary referral centre were included. Tumour type, grade (including details of mitotic grade, tubule formation and pleomorphism), oestrogen receptor (ER), progesterone receptor (PR) and HER2 status were compared between pre-treatment and post-treatment residual samples using tissue microarrays. A control group of paired core and excision tumours from patients who did not receive NACT was also assessed.ResultsTwo hundred forty-six cases and 113 controls were included. Pathological complete response (path CR) was achieved in 21.5% of patients. In those patients failing to achieve a path CR, a change in the histological type was noted in 29 out of 178 cases (16.3%, p < 0.001) with increase in the lobular and metaplastic types. Downgrading occurred in 28.8%, due to significant reduction in mitotic rate and prominent tubule formation. A change in ER/PR/HER2 status occurred in 12%, 14.5% and 7.1% of cases, respectively, predominantly as a switch from negative to positive status for ER and from positive to negative status for HER2. Further alterations in expression levels were also noted. Minimal changes in the low ER/PR expressors and the HER2 2+ tumours were found in the control group.ConclusionSignificant changes in tumour morphology, grade, hormone receptors and HER2 status occur following NACT. We recommend testing on residual invasive carcinoma. A switch from negative to positive status warrants offering endocrine/trastuzumab-based therapy to this group of patients.     

Neoadjuvant chemotherapy for operable breast cancer: is this the future?

The idea of using preoperative or neoadjuvant chemotherapy in patients with operable breast cancer originated from experimental and clinical observations as well as theoretical hypotheses on tumor cell growth and dissemination. Initially, nonrandomized studies demonstrated considerable rates of clinical tumor response, low rates of pathologic complete response (pCR), and increased rates of breast-conserving procedures. However, nonrandomized studies could not address the relative efficacy of neoadjuvant versus adjuvant chemotherapy on disease-free and overall survival. Similarly, earlier randomized trials were not designed as straightforward comparisons of neoadjuvant versus adjuvant chemotherapy and therefore could not adequately address the relative efficacy of neoadjuvant versus adjuvant chemotherapy on outcome. These answers were eventually provided by larger randomized trials that directly compared neoadjuvant with adjuvant chemotherapy, which are reviewed in more detail in this article. Potential advantages and disadvantages of the neoadjuvant approach and surgical considerations in the breast and axilla after neoadjuvant chemotherapy are also discussed. Finally, several recently reported trials of neoadjuvant therapy incorporating newer agents such as taxanes in sequence with anthracycline-containing regimens have shown further increases in pCR rates. Although outcome data are not available yet from these studies, it is hoped that the observed increase in pCR rates will be associated with improved outcome. If the previously observed significant correlation between the achievement of pCR and improved outcome continues to be demonstrated with these newer regimens, it will substantially strengthen the rationale for using neoadjuvant rather that adjuvant chemotherapy in the clinical setting as well as in future research studies.     

Neoadjuvant chemotherapy in head and neck cancer: should it be revisited?

Locally advanced SCCHN (LA-SCCHN) is generally treated by a combination of chemotherapy, irradiation and/or surgery. Timing of the chemotherapy has for long been a matter of debate but concurrent chemoradiation was widely adopted as standard of care for locally advanced squamous cell carcinoma of the head and neck after the publication of a large meta-analysis which demonstrated that concurrent chemoradiation confers an absolute survival benefit of 8% at 2 and 5 years. Induction chemotherapy has some appealing advantages including the opportunity of assessing tumor response and selecting the patients who are candidates for organ preservation. The cisplatin-fluorouracil combination has been the induction regimen of choice for two decades but has recently been superseded by a combination of cisplatin, fluorouracil and a taxane which can be considered the standard regimen when induction chemotherapy is appropriate. Multiple large randomized trials designed to compare sequential induction, i.e., chemotherapy followed by CRT to CRT alone are currently underway. New challenges are the integration of targeted therapies into the current treatment strategies and the identification of prognostic biomarkers and of factors predicting the response to treatment which would help to select patients who are likely to benefit most from induction chemotherapy.     

The multigene signature MammaPrint impacts on multidisciplinary team decisions in ER+, HER2? early breast cancer

Background:

Validated multigene signatures (MGS) provide additional prognostic information when evaluating clinical features of ER⁺, HER2⁻ early breast cancer. We have studied the quantitative and qualitative impact of MGS on multidisciplinary team (MDT) recommendations.

Methods:

We prospectively recruited 75 ER⁺, HER2⁻ breast cancer patients. Inclusion was based on biopsy assessment of grade, hormone receptor status, HER2, clinical tumour and nodal status. A fresh tissue sample was sent for MammaPrint (MP), TargetPrint analysis at surgery. Clinical risk was decided by the MDT in the absence of MP results and repeated following the collection of MP results. Decision changes were recorded and a health technology assessment was undertaken to compare cost effectiveness.

Results:

The majority of patients were assigned low to intermediate clinical risk by the MDT. According to MP, 76% were low risk. A very high correlation between local IHC and the TargetPrint assessment was shown. In over a third of patients, discordance between clinical and molecular risk was observed. Decision changes were recorded in half of these cases (18.6%) and resulted in two out of three patients not requiring chemotherapy. The use of MP was also found to be more cost effective.

Conclusions:

The multigene signature MP revealed clinical and molecular risk discordance in a third of patients. The impact of this on MDT recommendations was most profound in cases where few clinical risk factors were observed and enabled some women to forgo chemotherapy. The use of MGS is unlikely to have an impact in either clinically low-risk women or in patients with more than one relative indication for chemotherapy.     

Complete response in HER2+ leptomeningeal carcinomatosis from breast cancer with intrathecal trastuzumab

Trastuzumab, a monoclonal antibody against the HER2 receptor, is a major breakthrough in the treatment of HER2+ breast cancer. However, its high molecular weight precludes it from crossing the intact blood–brain barrier, making the central nervous system a sanctuary to HER2+ breast cancer metastases. We prospectively assessed functional outcome and toxicity of administering trastuzumab directly into the cerebrospinal fluid of a patient with leptomeningeal carcinomatosis (LC) and brain metastases from HER2+ breast cancer that had already been treated with other intrathecal chemotherapy, with no benefit. Upon signed informed consent, weekly lumbar puncture with administration of trastuzumab 25 mg was begun to a 44 year-old women with metastatic breast cancer (lymph node, bone, lung, and liver involvement) previously treated with tamoxifen, letrozole, anthracyclines, taxanes, capecitabine, intravenous trastuzumab, and lapatinib. She received 67 weekly administrations of intrathecal trastuzumab with marked clinical improvement and no adverse events. She survived 27 months after LC diagnosis. A complete leptomeningeal response, with no evidence of leptomeningeal metastasis at necropsy, was achieved. We believe that intrathecal trastuzumab administration should be prospectively evaluated to confirm clinical activity and optimize dose, schedule, and duration of treatment.     

High serum TGF-�� predicts poor response to lapatinib and capecitabine in HER2-positive breast cancer

Lapatinib and capecitabine combination therapy is effective in trastuzumab-resistant human epidermal growth factor receptor 2 (HER2)-positive breast cancer. We investigated the biomarkers from serum of patients receiving lapatinib and capecitabine Patients received lapatinib 1,250 mg once daily and capecitabine 2,000 mg/m(2)/day, day 1-14, every 3 weeks. Serum samples were obtained before treatment initiation. Levels of transforming growth factor-α (TGF-α), epidermal growth factor (EGF), extracellular domains of EGFR and HER2 were measured by enzyme-linked immunosorbent assay. The effect of TGF-α on in vitro sensitivity of SK-BR-3 cells to lapatinib was investigated. Sixty-four patients were included. Response rate was significantly higher in patients with low serum TGF-α (≤ 3.75 pg/ml) compared to high TGF-α (>3.75 pg/ml) [61.1% (11/18) vs. 17.4% (8/46), respectively; P = 0.001]. Low serum TGF-α was independently associated with better response in multivariate analysis [adjusted odds ratio, 8.96; 95% confidence interval (CI) 2.4-34.2]. Time-to-progression tended to be shorter in patients with high serum TGF-α compared to low TGF-α [median 3.8 months (95% CI 2.3-5.4) vs. 6.5 (95% CI 6.1-6.8), respectively; P = 0.067]. We confirmed that TGF-α diminished the sensitivity of SK-BR3-cells to lapatinib in vitro. The in vitro antiproliferative effect of cetuximab in combination with lapatinib was higher than that of lapatinib alone in SK-BR3-cells exposed to TGF-α. These data suggest that TGF-α plays a role in resistance to lapatinib and capecitabine therapy among HER2-positive breast cancer.     

In situ detection of HER2:HER2 and HER2:HER3 protein–protein interactions demonstrates prognostic significance in early breast cancer

HER2 overexpression/amplification is linked with poor prognosis in early breast cancer. Co-expression of HER2 and HER3 is associated with endocrine and chemotherapy resistance, driven not simply by expression but by signalling via HER2:HER3 or HER2:HER2 dimers. Proximity ligation assays (PLAs) detect protein–protein complexes at a single-molecule level and allow study of signalling pathways in situ. A cohort of 100 tumours was analyzed by PLA, IHC and FISH. HER complexes were analyzed by PLA in a further 321 tumours from the BR9601 trial comparing cyclophosphamide, methotrexate and fluorouracil (CMF) with epirubicin followed by CMF (epi-CMF). The relationships between HER dimer expression and RFS and OS were investigated, and multivariate regression analysis identified factors influencing patient prognosis. PLA successfully and reproducibly detected HER2:HER2 and HER2:HER3 protein complexes in vivo. A significant association (P < 0.00001) was identified between HER2 homodimerization and HER2 gene amplification. Following a minimum p value approach high levels of HER2:HER2 dimers were significantly associated with reduced relapse-free (RFS; hazard ratio = 1.72, 95% confidence interval 1.15–2.56, P = 0.008) and overall survival (OS HR = 1.69 95% CI = 1.09–2.62, P = 0.019). Similarly, high levels of HER2:HER3 dimers were associated with reduced RFS (HR = 2.18, 95% CI = 1.46–3.26, P = 0.00016) and OS (HR = 2.21, 95% CI = 1.41–3.47, P = 0.001). This study demonstrates that in situ detection of HER2 and HER2:3 protein:protein complexes can be performed robustly and reproducibly in clinical specimens, provides novel prognostic information and opens a significant novel opportunity to probe the clinical impact of cellular signalling processes.