Clinico-pathologic relationships with Ki67 and its change with short-term aromatase inhibitor treatment in primary ER + breast cancer: further results from the POETIC trial (CRUK/07/015).

Purpose: Ki67 assessed at diagnosis (Ki67) is an important prognostic factor in primary oestrogen receptor-positive (ER +) breast cancer. Proportional change in Ki67 after 2 weeks (∆Ki67) is associated with clinical benefit from endocrine therapies and residual Ki67 (Ki67) with recurrence-free survival. The aim was to define the association between Ki67 and after aromatase inhibitor (AI) exposure ∆Ki67 and Ki67 with key prognostic and biologic factors utilising data from the POETIC study.

Relationship between ER expression by IHC or mRNA with Ki67 response to aromatase inhibition: a POETIC study.

Background: In clinical practice, oestrogen receptor (ER) analysis is almost entirely by immunohistochemistry (IHC). ASCO/CAP recommends cut-offs of < 1% (negative) and 1-10% (low) cells positive. There is uncertainty whether patients with ER low tumours benefit from endocrine therapy.

HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer.

Background: Oestrogen receptor positive/ human epidermal growth factor receptor positive (ER+/HER2+) breast cancers (BCs) are less responsive to endocrine therapy than ER+/HER2- tumours. Mechanisms underpinning the differential behaviour of ER+HER2+ tumours are poorly characterised. Our aim was to identify biomarkers of response to 2 weeks' presurgical AI treatment in ER+/HER2+ BCs.

Abiraterone in patients with recurrent epithelial ovarian cancer: principal results of the phase II Cancer of the Ovary Abiraterone (CORAL) trial (CRUK - A16037).

Background: Recurrent epithelial ovarian cancer (EOC) remains difficult to treat, with an urgent need for more therapy options. Androgens bind to the androgen receptor (AR), commonly expressed in EOC. CYP17 inhibitor abiraterone irreversibly inhibits androgen biosynthesis.

Correction to: Combination of mTORC1/2 inhibitor vistusertib plus fulvestrant in vitro and in vivo targets oestrogen receptor-positive endocrine-resistant breast cancer.

After publication of the original article [1], we were notified that an author's surname has been erroneously spelled. Elisabetta Maragoni's family name should be replaced with Marangoni.

Combination of mTORC1/2 inhibitor vistusertib plus fulvestrant in vitro and in vivo targets oestrogen receptor-positive endocrine-resistant breast cancer.

Background: Endocrine therapies are still the main strategy for the treatment of oestrogen receptor-positive (ER+) breast cancers (BC), but resistance remains problematic. Cross-talk between ER and PI3K/AKT/mTORC has been associated with ligand-independent transcription of ER. We have previously reported the anti-proliferative effects of the combination of everolimus (an mTORC1 inhibitor) with endocrine therapy in resistance models, but potential routes of escape via AKT signalling can lead to resistance; therefore, the use of dual mTORC1/2 inhibitors has met with significant interest.

Association of p27 and Cyclin D1 Expression and Benefit from Adjuvant Trastuzumab Treatment in HER2-Positive Early Breast Cancer: A TransHERA Study.

To assess the prognostic and predictive value of selected biomarkers involved in cell-cycle regulation or proliferation in patients with HER2-positive early breast cancer. Protein expression of TOP2A, Ki67, cyclin D1, and p27 was immunohistochemically determined in tissue microarrays of surgical specimens from 862 patients randomized to trastuzumab (1 or 2 years; = 561) and observation ( = 301) arms of the HERA trial. The primary analysis endpoint was disease-free survival (DFS).

Discovery of naturally occurring ESR1 mutations in breast cancer cell lines modelling endocrine resistance.

Resistance to endocrine therapy remains a major clinical problem in breast cancer. Genetic studies highlight the potential role of estrogen receptor-α (ESR1) mutations, which show increased prevalence in the metastatic, endocrine-resistant setting. No naturally occurring ESR1 mutations have been reported in in vitro models of BC either before or after the acquisition of endocrine resistance making functional consequences difficult to study.

Heterogeneity in global gene expression profiles between biopsy specimens taken peri-surgically from primary ER-positive breast carcinomas.

Background: Gene expression is widely used for the characterisation of breast cancers. Variability due to tissue heterogeneity or measurement error or systematic change due to peri-surgical procedures can affect measurements but is poorly documented. We studied the variability of global gene expression between core-cuts of primary ER+ breast cancers and the impact of delays to tissue stabilisation due to sample X-ray and of diagnostic core cutting.

Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170.

We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.

Antiproliferative Effect of Lapatinib in HER2-Positive and HER2-Negative/HER3-High Breast Cancer: Results of the Presurgical Randomized MAPLE Trial (CRUK E/06/039).

Purpose: Not all breast cancers respond to lapatinib. A change in Ki67 after short-term exposure may elucidate a biomarker profile for responsive versus nonresponsive tumors.

Experimental Design: Women with primary breast cancer were randomized (3:1) to 10 to 14 days of preoperative lapatinib or placebo in a multicenter phase II trial (ISRCTN68509377).

ER and HER2 expression are positively correlated in HER2 non-overexpressing breast cancer.

Introduction: Estrogen receptor-α (ER) and human epidermal growth factor receptor 2 (HER2) positivity are inversely correlated by standard criteria. However, we investigated the quantitative relation between ER and HER2 expression at both RNA and protein levels in HER2+ve and HER2-ve breast carcinomas.

Methods: ER and HER2 levels were assessed with immunohistochemistry (IHC) and (for HER2) fluorescent in situ hybridization (FISH) and by quantitative reverse transcription-polymerase chain reaction (q-RT-PCR) in formalin-fixed primary breast cancers from 448 patients in the National Cancer Research Institute (NCRI) Adjuvant Breast Cancer Trial (ABC) tamoxifen-only arm.

Extreme loss of immunoreactive p-Akt and p-Erk1/2 during routine fixation of primary breast cancer.

Introduction: Very few studies have investigated whether the time elapsed between surgical resection and tissue fixation or the difference between core-cut and excision biopsies impact on immunohistochemically measured biomarkers including phosphorylated proteins in primary breast cancer. The aim of this study was to characterize the differences in immunoreactivity of common biomarkers that may occur (a) due to tissue handling at surgery and (b) between core-cuts and resected tumours.

Methods: Core-cuts taken from surgical breast cancer specimens immediately after resection (sample A) and after routine X-ray of the excised tumour (sample B) were formalin-fixed and paraffin-embedded and compared to the routinely fixed resection specimen (sample C).

A marker of homologous recombination predicts pathologic complete response to neoadjuvant chemotherapy in primary breast cancer.

Purpose: To assess the prevalence of defective homologous recombination (HR)-based DNA repair in sporadic primary breast cancers, examine the clincopathologic features that correlate with defective HR and the relationship with neoadjuvant chemotherapy response.

Experimental Design: We examined a cohort of 68 patients with sporadic primary breast cancer who received neoadjuvant anthracylcine-based chemotherapy, with core biopsies taken 24 hours after the first cycle of chemotherapy. We assessed RAD51 focus formation, a marker of HR competence, by immunofluorescence in postchemotherapy biopsies along with geminin as a marker of proliferative cells.

Pre-surgical study of the biological effects of the selective cyclo-oxygenase-2 inhibitor celecoxib in patients with primary breast cancer.

Cyclo-oxygenase 2 (COX-2) is implicated in the regulation of aromatase transcription in malignant breast tissue and has been considered as a potential target for tissue specific aromatase suppression. We initiated a randomised controlled pre-surgical study of celecoxib versus no treatment in women with primary breast cancer to determine the effects of COX-2 inhibition on markers of biological response. Postmenopausal women (50-80 years of age) with stage I or II, primary breast cancer, were randomised 2:1 to receive 400 mg/day celecoxib or no treatment for 14 days prior to surgery.

Comparative validation of the SP6 antibody to Ki67 in breast cancer.

Aim: To compare SP6 and MIB1 antibodies for Ki67 staining in breast cancer.

Background: Immunohistochemical detection of Ki67 has been widely used to assess the proliferative fraction in breast cancer. Ki67 is used prognostically and is the primary end-point for some presurgical trials.

Prognostic value of Ki67 expression after short-term presurgical endocrine therapy for primary breast cancer.

Tumor expression of the proliferation antigen Ki67 is widely used to assess the prognosis of cancer patients. A change in the expression of Ki67 after short-term exposure of patients to therapeutic agents is frequently used as a pharmacodynamic marker of efficacy, particularly among breast cancer patients before undergoing surgery. To determine the clinical significance of the level of tumor cell proliferation during endocrine therapy for breast cancer, we measured the expression of Ki67 in tumor biopsy samples taken before and after 2 weeks of presurgical treatment with anastrozole or tamoxifen or the combination of anastrozole plus tamoxifen in 158 patients with hormone receptor-positive primary disease.

Proliferation and apoptosis as markers of benefit in neoadjuvant endocrine therapy of breast cancer.

The study of changes in proliferation as a marker of treatment benefit during presurgical endocrine treatment of breast cancer has become increasingly popular, particularly using the nuclear marker Ki67, and holds the potential for prioritizing new treatments for full clinical development. There are weakly significant relationships between Ki67 change and clinical response that differ according to data handling. In the neoadjuvant Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen trial, suppression of Ki67 at both 2 and 12 weeks was greater with the aromatase inhibitor anastrozole than with either tamoxifen or the combination of anastrozole and tamoxifen.

Biomarker changes during neoadjuvant anastrozole, tamoxifen, or the combination: influence of hormonal status and HER-2 in breast cancer--a study from the IMPACT trialists.

Purpose: To investigate the relationships between biomarker changes in breast cancer during neoadjuvant (preoperative) endocrine therapy.

Patients And Methods: The IMPACT trial compared the preoperative use of tamoxifen with anastrozole alone or in combination in postmenopausal women (n = 330) with primary breast cancer. Biomarkers were measured in tumor biopsy specimens taken at baseline, and after 2 and 12 weeks of treatment.

Short-term changes in Ki-67 during neoadjuvant treatment of primary breast cancer with anastrozole or tamoxifen alone or combined correlate with recurrence-free survival.

Purpose: Neoadjuvant (preoperative) therapy for breast cancer may allow for the development of intermediate markers of treatment benefit, thereby circumventing the need for efficacy trials of adjuvant therapy, which require much larger patient numbers and longer follow-up. The aim of this study--as part of the Immediate Preoperative "Arimidex" (anastrozole), Tamoxifen, or Arimidex Combined with Tamoxifen (IMPACT) trial (n = 330)--was to test the hypotheses that changes in Ki-67 after 2 weeks and/or 12 weeks: (i) differed between treatments, (ii) predicted clinical tumor response, and/or (iii) may predict long-term outcome differences between treatments in adjuvant therapy.

Experimental Design: The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial compared these same agents in the adjuvant setting.

Correlation between cyclooxygenase-2 expression and angiogenesis in human breast cancer.

Purpose: Cyclooxygenase (COX)-2 is overexpressed in breast cancer and may have a role in regulating tumor growth via effects on angiogenesis, cell proliferation, or apoptosis. This study aimed to derive data from human breast carcinomas to help substantiate or refute these relationships.

Experimental Design: We performed immunohistochemical analysis of a set of 86 breast tumors for COX-2, estrogen receptor (ER), progesterone receptor (PGR), HER-2, Ki67 (a marker of proliferation), and CD31 (an endothelial cell marker of angiogenesis).

Comparison of the systemic and intratumoral effects of tamoxifen and the aromatase inhibitor vorozole in postmenopausal patients with primary breast cancer.

Purpose: To determine biologic differences, if any, between presurgical endocrine treatment with an aromatase inhibitor (vorozole) and tamoxifen in patients with postmenopausal primary breast cancer.

Patients And Methods: Randomization was to 12 weeks of 2.5 mg of vorozole per day or 20 mg of tamoxifen per day, both orally.