First-line Therapy For Metastatic Disease Research Articles

Transarterial chemoembolization for renal cell carcinoma patients with liver metastases in the era of immunotherapy: A case series

Treatment for renal cell carcinoma (RCC) has changed rapidly in the past decade with the widespread implementation of immune checkpoint inhibitors (ICIs) as first-line therapy in metastatic disease. The presence of liver metastases is a poor prognostic indicator but also has the potential to be a target for localized therapy. However, there is limited knowledge on the dynamics and long-term effects of combining liver-directed transarterial chemoembolization (TACE) with ICI therapy. We identified four patients with metastatic RCC (mRCC) and liver metastases who were treated concurrently with ICIs and TACE to metastatic liver lesions from our institutional database. We assessed treatment radiological responses and toxicity in this cohort. Liver-directed TACE with concurrent ICI was associated with radiological response or stabilization in all the liver lesions in the four patients in this cohort with a median time to locoregional liver metastasis progression-free survival of 8.3 months (range 6.0–11.1). The concurrent administration of ICI therapy and TACE to liver lesions was well tolerated with no new safety signals and no immune-related toxicities. Combining TACE with ICI in patients with mRCC showed promising response with limited toxicity. Future studies are warranted to clarify treatment timing and validate benefits.

Immunotherapy for early-stage non-small cell lung cancer: A system review.

With the addition of immunotherapy, lung cancer, one of the most common cancers with high mortality rates, has broadened the treatment landscape. Immune checkpoint inhibitors have demonstrated significant efficacy in the treatment of non-small cell lung cancer (NSCLC) and are now used as the first-line therapy for metastatic disease, consolidation therapy after radiotherapy for unresectable locally advanced disease, and adjuvant therapy after surgical resection and chemotherapy for resectable disease. The use of adjuvant and neoadjuvant immunotherapy in patients with early-stage NSCLC, however, is still debatable. We will address several aspects, namely the initial efficacy of monotherapy, the efficacy of combination chemotherapy, immunotherapy-related biomarkers, adverse effects, ongoing randomized controlled trials, and current issues and future directions for immunotherapy in early-stage NSCLC will be discussed here.

Metastatic primary breast neuroendocrine neoplasms: a case series.

Breast neuroendocrine neoplasms represent a rare subtype of breast cancer which have not been well studied or characterised, particularly in the metastatic setting. To present clinicopathological characteristics, treatment and outcomes of a series of patients with metastatic neuroendocrine carcinoma of the breast and review the current literature. We performed a retrospective review to identify and describe patients with metastatic neuroendocrine carcinoma of the breast at our centre between 2011 and 2021. Medical records, pathology and imaging results were examined to evaluate the clinical and histopathological features as well as the treatment pathways and prognosis of these patients. We present a series of seven female patients with metastatic neuroendocrine carcinoma of the breast, as defined by the World Health Organization classification, over a period of 10 years (2011-2021) from a single centre. Median age at diagnosis was 48 years (range 39-63). Six of seven tissue samples expressed synaptophysin and chromogranin and were also oestrogen and progesterone receptor positive; median Ki-67 index was 50% (range 20-90%). All seven patients had demonstrated avidity on 18 F-FDG PET imaging, and the six who underwent 68 Ga-DOTATATE PET all had significant avidity. Treatment modalities and sequencing varied, but all patients received chemotherapy during their disease course. Six patients received three or more lines of treatment. Median overall survival was 31.8 months (range 3.7-108.6). Median progression-free survival (PFS) with first-line therapy for metastatic disease was 5.8 months (range 1.8-37.8). This series shows the use of multiple modalities in treating this disease, with different sequencing in different patients. Despite multiple modalities used in the first-line setting, first-line PFS remains short. Larger series and further molecular characterisation are required to aid clinicians in managing this condition and to guide optimal treatment sequencing to improve outcomes in this rare patient group.

Abstract IA11: Chemotherapy remodels the bladder cancer immune microenvironment

Abstract In the United States urothelial carcinoma (UC) of the bladder is the 4th and 9th most frequent malignancy in men and women, respectively, with around 74,000 new cases and 16,000 deaths in 2017. High-grade (HG), muscle-invasive bladder tumors account for the majority of those deaths as patients with metastatic disease have a 5-year survival rate of only 15%. The current standard-of-care first-line therapy for metastatic disease is cisplatin-based combination chemotherapy or immune checkpoint inhibition in patients who are platinum ineligible. Novel immune checkpoint (IC) inhibitors, including anti-PD1 and anti-PD-L1, represent a paradigm shift in cancer therapy and have demonstrated substantial clinical benefits in patients with advanced UC. Despite the enthusiasm engendered by PD-1/PD-L1 axis blockade in metastatic UC, only 15-25% of patients treated in published trials had objective responses. Preliminary studies from our laboratory show that chemotherapy remodels the immune microenvironment of muscle-invasive bladder cancers. We have begun to investigate the mechanisms by which chemotherapy drives a heightened immune response using our recently described genetically engineered murine (GEM) models of bladder cancer. Citation Format: William Y. Kim. Chemotherapy remodels the bladder cancer immune microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr IA11.

Clinical outcomes of patients with breast cancer relapsing after (neo)adjuvant trastuzumab and receiving trastuzumab rechallenge or lapatinib-based therapy: a multicentre retrospective cohort study

BackgroundIn the prepertuzumab era, we evaluated the clinical outcomes of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer who underwent first-line trastuzumab-based or lapatinib-based therapy according to prior exposure to (neo)adjuvant trastuzumab.Materials and methodsIn this multicentre retrospective cohort study conducted in 14 Italian centres of the Gruppo Italiano Mammella, consecutive patients undergoing first-line trastuzumab or lapatinib-based therapy were included. Analyses were performed according to the type of first-line therapy for metastatic disease (trastuzumab or lapatinib). Dichotomous clinical outcomes were analysed using logistic regression and time-to-event outcomes using Cox proportional hazard models controlling for relevant demographic, clinicopathological and therapy characteristics.ResultsOut of 450 patients included in the study, 416 (92%) received trastuzumab and 34 (7.5%) lapatinib. As compared with the trastuzumab cohort, more patients in the lapatinib cohort had a trastuzumab-free interval <1 month (37% vs 13.9%; p=0.017) and brain metastasis as first site of relapse (38.2% vs 9.4%; p<0.001). Among the 128 patients who relapsed after prior (neo)adjuvant trastuzumab, 101 (78.9%) received first-line trastuzumab and 27 (21.1%) first-line lapatinib. The following outcomes were observed with first-line lapatinib or trastuzumab, respectively: overall response rate 45.5% vs 61.3% (p=0.184), clinical benefit rate 68.2% vs 72.5% (p=0.691), median progression-free survival (PFS) 11.4 vs 12.0 months (p=0.814) and median overall survival (OS) 34.7 vs 48.2 months (p=0.722). In patients with brain metastasis as first site of relapse, median PFS was 12.2 vs 9.9 months (p=0.093) and median OS 33.7 vs 28.5 months (p=0.280), respectively.ConclusionsIn patients with HER2-positive breast cancer relapsing after prior (neo)adjuvant trastuzumab, first-line treatment with trastuzumab or lapatinib was not associated with a significant difference in the clinical outcomes. A non-significant trend favouring the use of lapatinib was observed in patients with brain metastasis as the first site of relapse.

PCN316 TREATMENT PATTERNS OF ADVANCED SOFT-TISSUE SARCOMA IN ARGENTINA

To describe the treatment patterns of patients with advanced soft-tissue sarcomas who received chemotherapy or radiotherapy in Argentina. Patients with advanced soft-tissue sarcoma (locally advanced, inoperable, or metastatic disease) who received chemotherapy or radiotherapy from 2013-2018 were selected from the Instituto de Especialidades Médicas S.A. (IEMSA) clinical database, which collects the information of several insurance providers (Social Security System and Health Maintenance Organizations). Cases with osteosarcoma, Kaposi’s Sarcoma and gastrointestinal stromal tumors were excluded. A total of 99 patients were analysed. There was a high variability in histological type, with leiomyosarcoma (N=17; 17%), pleomorphic sarcoma (N=12; 12%), liposarcoma (N=10; 10%), and rhabdomyosarcoma (N=10; 10%) being the most frequent. The most frequent locations were leg (33%), abdomen (16%), and arm (14%). At the time of diagnosis, 46% of the cases were localized, 26% were loco-regionally advanced and 27% were metastatic. Of the 99 patients, 50.5% received adjuvant/neoadjuvant therapy, and of them, 50% received only chemotherapy, 30% received only adjuvant/neoadjuvant radiotherapy, and 20% received both therapies. There were 86 patients who received first-line therapy for metastatic disease. Seventy-nine percent of them received chemotherapy. The most frequent chemotherapy was doxorubicin-ifosfamide-mesna (N=22; 32%), and docetaxel-gemcitabine (N=6, 9%), and epirubicin-ifosfamide-mesna (N=3; 4%). There was a high variability in the rest of the treatments. During the first-line therapy, twenty-one patients (24%) had surgery, and fifteen patients (17%) received radiotherapy. Only one patient had a complete response after first-line chemotherapy. Forty-five patients received second-line therapy, 93% of whom received chemotherapy. Again, the most frequent treatments were doxorubicin-ifosfamide-mesna (N=13; 31%) and docetaxel-gemcitabine (N=9; 21%). Two patients experienced a complete response with second-line therapy. There is a high variability in the treatment of advanced soft-tissue sarcomas in Argentina. Response to current chemotherapy treatments is very poor. There is a large need for more effective treatments.

Validation of Immunohistochemistry for the Detection of BRAF V600E-Mutated Lung Adenocarcinomas.

BRAF V600E mutation, a missense mutation in exon 15 resulting in valine substitution for glutamate at position 600 within the kinase domain of BRAF oncogene, is found in a subset of lung adenocarcinoma (ADC). The usefulness of immunohistochemistry (IHC) as an alternative diagnostic tool has not been validated. Moreover, the clinical information of patients with BRAF V600E-mutated lung ADC is limited. We retrospectively identified 31 lung ADCs diagnosed with BRAF V600E mutation by standard molecular sequencing methods and reviewed their clinical characteristics and pathological features. An anti-BRAF V600E monoclonal VE1 antibody for IHC was used to confirm the expression patterns. The series was comprised of 99 cases, 29 with BRAF V600E mutation and 70 without BRAF V600E but with other types or undetected mutations. The majority of BRAF V600E-mutated biopsied tissues were poorly differentiated and micropapillary patterns. Application of the IHC VE1 assay was highly feasible in primary/metastatic sites or effusion blocks, yielding positive findings in 28 of 29 (96.6%) BRAF V600E-mutated tumors and negative results in 69 of 70 (98.6%) tumors harboring other types or undetected mutations. Patients who received pemetrexed/platinum-based rather than mutation-targeted chemotherapy as the first-line therapy for metastatic disease showed median overall survival of 15.5 months. Our findings indicated that VE1 antibody-based IHC analysis demonstrated high sensitivity and specificity to detect BRAF V600E-mutated lung ADCs in tissues from primary or metastatic sites.

The Treatment of Metastatic and Castration-Resistant Prostate Cancer Patients in Korea

The treatment of advanced prostate cancer has rapidly evolved. Androgen deprivation therapy is recognized as the first-line therapy for metastatic disease; however, a substantial proportion of patients will eventually progress to develop castration-resistance. For the past several years, docetaxel-based chemotherapy has shown significant therapeutic benefit in castration-resistant prostate cancer. Over the last 5 years, several new agents such as the enzalutamide, abiraterone, cabazitaxel, and 223 radium have been developed which have all been associated with improved quality of life, pain palliation, and an increase in survival. Unfortunately, there are no Korean treatment guideline for metastatic prostate cancer and/or castration-resistant prostate cancer which has been developed based on adequate review and assessment of evidences. Thus, a guideline adequate for domestic circumstances is eagerly needed. The Korean Association for Clinical Oncology, the Korean Prostate Society, the Korean Urological Oncology Society, and the Korean Society of Pathologists reviewed and endorsed the guidelines. Key Words: Prostatic neoplasms; Castration-resistant; Korea.

Abstract PD6-10: KEYNOTE-086 cohort B: Pembrolizumab monotherapy for PD-L1–positive, previously untreated, metastatic triple-negative breast cancer (mTNBC)

Abstract Background: Patients with previously untreated mTNBC typically receive cytotoxic chemotherapy as first-line therapy for metastatic disease. However, efficacy and safety are suboptimal. KEYNOTE-086 (NCT02447003) is a multicohort, single-arm, phase 2 study of pembrolizumab monotherapy for mTNBC. In cohort B, we assessed the safety and antitumor activity of pembrolizumab as first-line therapy for patients with PD-L1-positive mTNBC. Methods: Key eligibility criteria for cohort B were age ≥18 y, centrally confirmed TNBC, no prior systemic anticancer therapy for metastatic disease, ECOG performance status 0-1, measurable disease per RECIST v1.1 by central review, no radiographic evidence of brain metastases, and a tumor PD-L1 combined positive score (CPS) ≥1. Pembrolizumab 200 mg was given once every 3 wk for 24 mo or until disease progression, intolerable toxicity, or investigator or patient decision. Tumor imaging was performed every 9 wk for 12 mo and every 12 wk thereafter. Clinically stable patients with radiologic progression could remain on pembrolizumab until progression was confirmed on subsequent assessment. Primary end point was safety. Secondary end points included ORR, duration of response, and PFS (all RECIST v1.1 by central review) and OS. Results: Of the 206 patients with tumors evaluable for PD-L1 expression, 128 (62%) had PD-L1 CPS ≥1. Of these, 84 met all eligibility criteria and enrolled. All patients were women, median age was 52.5 y, 29 (35%) had ECOG PS 1, 40 (48%) had elevated LDH, 55 (65%) had visceral ± nonvisceral metastases, and 73 (87%) received prior (neo)adjuvant therapy. All patients received ≥1 pembrolizumab dose, and after median follow-up of 10.6 mo, 18 (21%) remained on pembrolizumab. Treatment-related AEs occurred in 53 (63%) patients and were of grade 3-4 severity in 7 (8%); no patients died or discontinued pembrolizumab because of treatment-related AEs. The most common treatment-related AEs were fatigue (26%), nausea (13%), and diarrhea (12%). No grade 3-4 treatment-related AE occurred in &amp;gt;1 patient. The most common immune-mediated AE was hypothyroidism (10%). Three patients had complete response and 16 had partial response for an ORR of 23% (95% CI 15-33). Of the 11 patients with a best response of stable disease, 1 had stable disease for ≥24 wk, leading to a disease control rate of 24% (95% CI 16-34). 12 of 19 (63%) responses were ongoing at data cutoff, and median duration of response was 8.4 mo (range 2.1+ to 13.9+). Median PFS was 2.1 mo (95% CI 2.0-2.2), with an estimated 6-mo PFS rate of 26%. Median OS was 16.1 mo (95% CI 11.3-NR), with an estimated 6-mo OS rate of 83%. Conclusions: Pembrolizumab monotherapy continues to demonstrate a favorable safety profile and robust, durable antitumor activity in patients with PD-L1-positive, previously untreated mTNBC. Citation Format: Adams S, Loi S, Toppmeyer DL, Cescon DW, De Laurentiis M, Nanda R, Winer EP, Mukai H, Tamura K, Armstrong AC, Liu MC, Iwata H, Ryvo L, Wimberger P, Rugo HS, Tan A, D'Aquanno C, Ding Y, Karantza V, Schmid P. KEYNOTE-086 cohort B: Pembrolizumab monotherapy for PD-L1–positive, previously untreated, metastatic triple-negative breast cancer (mTNBC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD6-10.

A Korean single-center, real-world, retrospective study of first-line weekly paclitaxel in patients with metastatic angiosarcoma.

BackgroundAngiosarcoma is a rare subgroup of soft tissue sarcomas associated with poor prognosis, but paclitaxel has been shown to be active in pretreated metastatic disease. We investigated the efficacy and safety of weekly paclitaxel as first-line chemotherapy in adult patients with metastatic angiosarcoma.MethodsA retrospective study using the Samsung Medical Center (Seoul, Korea) cancer chemotherapy registry was performed on 21 consecutive patients with angiosarcoma who were treated with weekly paclitaxel as first-line therapy for metastatic disease between Oct. 2008 and Dec. 2014. We excluded patients who were enrolled in clinical trials to ensure the results would reflect the real-world outcomes obtained in a daily clinical setting. Endpoints included efficacy in terms of response rate, progression-free survival (PFS), overall survival (OS) and safety.ResultsAmong 21 patients, 15 (71 %) were male and the median age was 53 years (range, 24–76). Primary sites of angiosarcoma were the visceral organs (33 %), scalp (29 %) and heart (23 %). The median number of metastatic sites was two (range, 1–5) with the lungs being the most frequently involved site. Weekly paclitaxel was generally well tolerated: the major hematologic toxicity was grade 1/2 anemia (24 %). Among non-hematologic toxicities, grade 1/2 peripheral neuropathy was most commonly observed (67 %). Objective response was observed in 11 (52 %) patients (4 complete and 7 partial responses). With a median follow-up of 21 months, the estimated median PFS and OS were 5.7 months (95 % CI 5.1–6.3) and 18.6 months (95 % CI 9.9–27.3), respectively.ConclusionsIn this retrospective study, first-line chemotherapy with weekly paclitaxel demonstrated clinically relevant efficacy and tolerability in unselected Korean patients with metastatic angiosarcoma. It is encouraging that response rate and PFS for Korean patients were similar to those reported in Western reports.

Statistical controversies in clinical research: end points other than overall survival are vital for regulatory approval of anticancer agents

There is an ongoing debate about the relative merits of overall survival (OS) and other metrics that can be used as primary end points in cancer clinical trials. Although survival time is arguably the most objective metric for assessing the efficacy of anticancer treatment, OS as a clinical-trial end point needs to be conceptually distinguished from increased survival time as a goal desired by patients, clinicians and public-health policy makers. OS presents several drawbacks as a primary end point that threatens to hamper further drug development, including the increase in the number of patients and the much longer follow-up required in a clinical trial. In many settings of first-line therapy for metastatic disease, median OS is currently two to four times longer than median progression-free survival. As a result, the analysis of OS may be increasingly confounded by the effect of salvage therapies used after disease progression. In this review, we use straightforward statistical reasoning and examples from the oncology literature to argue that OS should no longer be the primary end point of most future phase III cancer clinical trials that aim at assessing the efficacy of novel therapies in the setting of metastatic disease.

Defining a Role and Predicting Benefit From Platinum-Based Therapy in Breast Cancer: An Evolving Story

There are three evolving stories that have the potential to improve outcomes for patients with localized triple-negative breast cancer (TNBC), a phenotypically defined breast cancer subtype that often occurs in individuals harboring germline BRCA1 mutations, including up to 20% of unselected individuals and 50% with a strong family history. When occurring sporadically without a germline mutation, TNBC shares many clinical and molecular features with BRCA1associated cancers, including defective DNA repair, which may be a result of methylation-induced silencing of BRCA or mutations in other genes that encode proteins involved in DNA repair. The first story, as exemplified in the article by Sikov et al that accompanies this editorial, is that the DNA–damaging agent carboplatin significantly improves the pathologic complete response (pCR) rate when added to a neoadjuvant chemotherapy regimen that includes a taxane, anthracycline, and alkylating agent, confirming the results of a similar trial. The second story involves using predictive biomarkers to identify tumors that are particularly sensitive to DNA-damaging agents, including germline mutations in genes that encode proteins that are essential for DNA damage repair and somatic markers that identify so-called BRCAness in sporadic cancers. The third story centers on using response to neoadjuvant therapy as a pharmacodynamic biomarker, exemplified by the strong inverse association between pCR in the breast and axilla and risk of recurrence. Although it is clear that platinum-containing agents are potentially useful in TNBC, it is unclear which patients benefit from them and how to best use them. The platinum story in breast cancer dates back to 1988, when Sledge et al noted partial responses in seven of 19 patients (47%) unselected for breast cancer subtype who received cisplatin as first-line therapy for metastatic disease. Other reports followed, confirming activity for cisplatin and carboplatin when used as first-line cytotoxic therapy in otherwise unselected patients, although efficacy was limited when used beyond first-line treatment, and attempts to combine platinum-containing agents with taxanes met with variable success. On the basis of preclinical data indicating synergy when platinum-based drugs were combined with trastuzumab in human epidermal growth factor receptor 2 (HER2)/neu positive disease, the carboplatin-docetaxel-trastuzumab regimen was found to be an effective adjuvant regimen, although adding carboplatin to a trastuzumab-taxane regimen in metastatic disease produced only modest clinical benefit. This brings us to the next chapter in the evolving platinum story, which includes two randomized phase II neoadjuvant trials in TNBC. The first report of the GeparSixto trial by von Minckwitz et al included 293 patients with operable and locally advanced TNBC who received weekly paclitaxel and liposomal doxorubicin plus bevacizumab, either alone or in combination with weekly carboplatin (area under the curve [AUC] 2, then reduced to AUC 1.5) for up to 18 weeks. The addition of carboplatin significantly improved the pCR rate in the breast and axilla (58% v 37%; P .05), although it also substantially increased toxicity without affecting breast conservation rates. The second study, by Sikov et al from the Alliance Clinical Trials Group, included 493 patients with operable and locally advanced TNBC who received weekly paclitaxel for 12 weeks followed by doxorubicin-cyclophosphamide every 2 weeks. Paclitaxel was given alone or in combination with carboplatin (AUC 6 every 3 weeks for four cycles); using a 2 2 factorial design, patients were also randomly assigned to receive chemotherapy alone or in combination with bevacizumab. The addition of carboplatin was associated with an improved pCR rate in the breast and axilla (54% v 41%; P .0029); similar benefits were observed in the absence (49% v 39%) and presence (60% v 43%) of bevacizumab. Although numerically more patients who were not initially considered candidates for breast conservation were deemed potential candidates after therapy when carboplatin was used (57% v 44%), the difference was not statistically significant, and the actual rates were not reported. Neither trial was adequately powered to determine carboplatin-reduced recurrence, nor were patients observed long enough to observe such a difference if it existed. Why use platinum-containing agents in TNBC? This brings us to our second evolving story, dating back to 2000, when it was recognized that BRCA-mutant cells were sensitized to the antineoplastic effects of DNA-damaging agents such as platinum, and that neoadjuvant platinum monotherapy was highly effective in BRCA mutation– associated breast cancer. It was also recognized that sporadic TNBC JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 1 JANUARY 1 2015

Cost-utility analysis of adjuvant chemotherapy in patients with stage III colon cancer in Thailand

Background: In Thailand, there has been no economic evaluation study of adjuvant chemotherapy for stage III colon cancer patients after resection. Objective: This study aims to evaluate the cost-utility of all chemotherapy regimens currently used in Thailand compared with the adjuvant 5-fluorouracil/leucovorin (5-FU/LV) plus capecitabine as the first-line therapy for metastatic disease in patients with stage III colon cancer after resection. Methods: A cost-utility analysis was performed to estimate the relevant lifetime costs and health outcomes of chemotherapy regimens based on a societal perspective using a Markov model. Results: The results suggested that the adjuvant 5-FU/LV plus capecitabine as the first-line therapy for metastatic disease would be the most cost–effective chemotherapy. Conclusions: The adjuvant FOLFOX and FOLFIRI as the first-line treatment for metastatic disease would be cost–effective with an incremental cost–effectiveness ratio of 299,365 Thai baht per QALY gained based on a societal perspective if both prices of FOLFOX and FOLFIRI were decreased by 40%.

Final results of a multicenter phase II clinical trial evaluating the activity of single-agent lapatinib in patients with HER2-negative metastatic breast cancer and HER2-positive circulating tumor cells. A proof-of-concept study

This multicenter phase II trial was designed to evaluate the activity of lapatinib in metastatic breast cancer patients with HER2-negative primary tumors and HER2-positive circulating tumor cells (CTCs). In this study MBC patients with HER2-negative primary tumors and HER2-positive CTCs previously treated with at least a first-line therapy for metastatic disease received lapatinib 1500 mg/day. The CellSearch System® was used for CTCs isolation and bio-characterization. HER2 status was assessed on CTCs by immunofluorescence. A case was defined as CTCs positive if ≥2 CTC/7.5 ml of blood were isolated and HER2-positive if ≥50% of CTCs were HER2-positive. 139 HER2-negative patients were screened, 96 patients were positive for CTCs (mean number of CTCs: 85; median number of CTCs: 19; range 2-1637). Seven of the 96 patients (7%) had ≥50% HER2-positive CTCs and were eligible for treatment with lapatinib. No objective tumor responses occurred in this population. In one patient, disease stabilization lasting 254 days (8.5 months) was observed. From the findings of this study, we concluded that a subset of patients with a HER2-negative primary tumor presents HER2-positive CTCs during disease progression, although the HER2 shift rate seems to be lower than previously reported. Despite the lack of objective response, the durable disease stabilization observed in one patient cannot rule out the hypothesis that lapatinib may have some activity in this patient population. However, considering that only 1/139 screened patients may potentially have derived benefit from this approach, future trials designed according to the presented strategy cannot be recommended.

Molecular biology of androgen-independent prostate cancer: the role of the androgen receptor pathway

Prostate cancer (PC) cells express the androgen receptor (AR) and need the presence of androgens to survive. Androgen suppression is the gold standard first-line therapy for metastatic disease. Almost all PC patients initially respond to hormonal therapy, but most of them gradually develop resistance to castration. There is evidence that these tumours that are considered castration-resistant continue to depend on AR signalling. Several mechanisms that enhance AR signalling in an androgen-depleted environment have been elucidated: (1) AR mutations that allow activation by low androgen levels or by other endogenous steroids, (2) AR amplification and/or overexpression, (3) increased local intracrine synthesis of androgens, (4) changes in AR cofactors and (5) cross-talk with cytokines and growth factors. Today, there are a number of novel agents targeting the AR signalling pathway under development, including more effective antiandrogens; inhibitors of CYP17, inhibitors of HSP90, inhibitors of histone deacetylases and inhibitors of tyrosine kinase inhibitors.

A phase II study of trastuzumab and capecitabine for patients with HER2-overexpressing metastatic breast cancer: Japan Breast Cancer Research Network (JBCRN) 00 Trial

To determine the response rate and toxicity profile of trastuzumab and capecitabine in women with HER2-overexpressing advanced breast cancer. A total of 59 patients from 6 participating centers in Japan entered onto the study of trastuzumab and capecitabine. Eighty six percent of women had received prior chemotherapy as part of adjuvant (21.4%) or metastatic treatment (48.2%), or both (16.1%), including substantial portions of patients who had previously received either CMF (7.1%), anthracyclines (28.6%), taxanes (25.0%), or both types (25.0%) of chemotherapy. Responses were observed in 28 of 56 patients (overall response rate, 50%). The response rate was 65.0% in patients treated with trastuzumab and capecitabine as first-line therapy for metastatic disease, and 62.5% among HER2 +3 positive patients, while high response rates were also seen in women treated with second- or third-line therapy. Patients receiving trastuzumab and capecitabine as first-line therapy had a longer TTP than did patients receiving this treatment as second- or third-line therapy (median TTP, 280 vs. 130 days, P < 0.05). Further, patients receiving trastuzumab and capecitabine as first-line therapy had longer OS than did patients receiving this treatment as second- or third-line therapy (median OS, 780 days vs. 480 weeks, P < 0.05). The treatment-related adverse events were hand-foot syndrome (30.4%), nausea (25%), diarrhea (10.7%), stomatitis (10.7%), fatigue (7.1%), and vomiting (5.4%). However, the majority were Grade 1-2 adverse events and only six patients experienced Grade 3 adverse events. Further Grade 1 cardiac toxicity was observed in one patient, while there were no cases of alopecia and treatment-related death. Trastuzumab in combination with capecitabine is highly active in women with HER2-overexpressing metastatic breast cancer and is well tolerated.

Taxanes in breast cancer: An update

Over the past decade the taxanes have proved to be fundamental in the treatment of breast cancer. Initially found to have efficacy in metastatic breast cancer, the taxanes are now vital components in the treatment of early-stage disease, in which their addition to adjuvant treatment of early breast cancer has been shown to improve overall survival. In addition, the taxanes have demonstrated a role in first-line therapy for metastatic disease, with some of the highest efficacy of any class of chemotherapy. Targeted therapies in combination with the taxanes have further improved survival for both early and metastatic disease. New formulations of taxanes may both improve antitumor activity and reduce toxicity.

Immunotherapy of Metastatic Breast Cancer: Phase I Trial of Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation with Th2/Tc2 T-Cell Exchange

Rationale Despite the responsiveness of metastatic breast cancer (MBC) to available therapies, the prognosis for patients with MBC that fails to respond or progresses after first-line therapy for metastatic disease is poor and points to the need for new treatments in this clinical setting. High-dose chemotherapy with autologous stem cell rescue has achieved disappointing results when compared with conventional therapy. In contrast, immunotherapy using allogeneic hematopoietic stem cell transplantation (alloHSCT), which has achieved some success in the treatment of other solid tumors (eg, renal cell carcinoma), might offer a new therapeutic approach for advanced-stage MBC. Indeed, initial reports of efficacy using a full, myeloablative transplantation were encouraging.1,2 Pitfalls to the tolerability of alloHSCT include the intensity of high-dose preparative regimens, which are particularly challenging for patients who have received extensive chemotherapy for metastatic disease, and the development of graft-versus-host disease (GVHD). The development of less toxic preparative regimens, based on the observation that much of the therapeutic effect of allogeneic transplantation is mediated by the donor immune system (graft-versus-tumor [GVT] effects) rather than the cytotoxic chemotherapy that was traditionally given, has resulted in a more favorable therapeutic index.3

Bevacizumab in the treatment of breast cancer: rationale and current data.

Vascular endothelial growth factor (VEGF) has emerged as a key target for the treatment of cancer. As the ligand to the VEGF receptor, it plays a central role in promoting tumor angiogenesis. Overexpression of VEGF leads to poor outcomes in patients with breast cancer and other tumors. Preclinical studies have shown that the humanized monoclonal antibody to VEGF, bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA), can reduce tumor angiogenesis and inhibit the growth of solid tumors, either alone or in combination with chemotherapy. As a single agent or added to vinorelbine, bevacizumab has produced encouraging results in phase II clinical trials in patients with refractory metastatic breast cancer. When added to capecitabine chemotherapy in a phase III trial, bevacizumab produced a greater response rate, but did not prolong progression-free survival. This may reflect the late disease stage and poor prognostic factors in the patient population. A large, ongoing, phase III, cooperative group trial is evaluating the effect of bevacizumab in combination with paclitaxel as first-line therapy for metastatic disease. The adverse effect profile of bevacizumab differs from that of cytotoxic chemotherapy and includes hypertension, proteinuria, thrombosis, and epistaxis.

Fulvestrant: an estrogen receptor antagonist that downregulates the estrogen receptor

Fulvestrant, a novel antiestrogen classified as an estrogen receptor antagonist without known agonist effects, was recently approved in the United States for the treatment of postmenopausal, hormone receptor-positive women with progressive metastatic breast cancer after antiestrogen therapy. In a phase II trial, monthly administration of fulvestrant, 250 mg intramuscularly, conferred clinical benefit (partial response or stable disease for ≥ 24 weeks) in 69% of patients with tamoxifen-resistant advanced breast cancer. Furthermore, the median duration of response and survival for this population (26 and 54 months, respectively) was twice as high as those documented for a megestrol acetate-treated historical cohort (14 months and 30 months, respectively). Comparative phase III trials conducted in North America and internationally, which used time to progression as the primary endpoint, demonstrated fulvestrant’s tolerability and equivalence to anastrozole in postmenopausal women with tamoxifen-resistant advanced breast cancer, which led to its approval in this setting. Vasodilation and nausea were the principal treatment-related adverse events in the fulvestrant arms, and mild injection-site reactions occurred in 4.6% and 1.1% of monthly fulvestrant courses given in the North American and international trials, respectively. Recent subanalyses of the pivotal phase III data have found that fulvestrant produces a 30% longer mean duration of response compared with anastrozole and that fulvestrant-induced estrogen receptor downregulation does not preclude response to subsequent hormonal therapy. Ongoing trials in patients with advanced breast cancer will provide further insight into the relative merits of fulvestrant versus tamoxifen as first-line therapy for metastatic disease, the use of fulvestrant within combination and sequential regimens, and the efficacy of fulvestrant specifically in premenopausal women. Research efforts focusing on alternate administration schedules for fulvestrant and its potential as an adjuvant hormonal therapy are also anticipated.