Susan Cleator

Triple-negative breast cancer: therapeutic options.

Triple-negative breast cancers are defined by a lack of expression of oestrogen, progesterone, and ERBB2 receptors. This subgroup accounts for 15% of all types of breast cancer and for a higher percentage of breast cancer arising in African and African-American women who are premenopausal. Because of the absence of specific treatment guidelines for this subgroup, triple-negative breast cancers are managed with standard treatment; however, such treatment leaves them associated with a high rate of local and systemic relapse. Histologically, such cancers are poorly differentiated, and most fall into the basal subgroup of breast cancers, characterised by staining for basal markers (ie, cytokeratin 5/6). Analyses of microarray gene-expression profiling data show that they form a homogeneous group (or so-called cluster) in transcriptional terms and, increasingly, research studies are identifying basal cancers on the basis of exhibiting this distinctive transcriptional profile. Histologically and transcriptionally, triple-negative breast cancers have many similarities to BRCA1-associated breast cancers, which suggests that dysfunction in BRCA1 or related pathways occurs in this subset of sporadic cancers. In this review, we discuss the molecular features of triple-negative breast cancers and consider how the use of existing cytotoxic agents can be optimised for this patient group. We discuss the implications of a possible underlying BRCA1-pathway dysfunction in this subgroup in terms of treatment and we also investigate the predominant proliferative signals and the on-going research addressing the suitability of these signals as therapeutic targets.

Treatment of HIV-associated invasive anal cancer with combined chemoradiation

There is an increased frequency of invasive anal cancer in HIV-seropositive men. Early treatment strategies in this patient group employed reduced dosages of chemotherapy or radiotherapy alone to reduce toxicity. Since 1989 we have used combined modality treatment consisting of chemotherapy 5-fluorouracil (5-FU) and mitomycin C, and concomitant radical radiotherapy to the pelvis (38-51 Gy in 20-30 fractions), with most patients receiving a perineal boost (10-18 Gy). 12 homosexual HIV-positive men have been treated. The median CD4 count at diagnosis of anal cancer was 209 cells/microl (range: 29-380 cells/microl), 5 had prior AIDS defining diagnoses. No patients had metastatic disease. Complete remissions were obtained in 9/11 evaluable patients and in 1 further patient following surgery. 2 patients relapsed both within 6 months of diagnosis. At a median follow-up of 4.8 years (range: 0.4-10 years), 4 patients have died (2 from anal cancer, 1 from treatment-related consequences and 1 from opportunistic infection in remission). Actuarial 2-year survival is 60% (95% confidence interval (CI): 29-91%). Grade 3 haematological toxicity was recorded in 3 patients, grade 4 and 5 gastrointestinal toxicity in 1 patient each and grade 3 skin toxicity in 1 patient. Radical chemoradiation may be given safely at conventional doses in HIV-positive patients, with a high complete response rate.

A 2009 Update on the Treatment of Patients with Hormone Receptor—Positive Breast Cancer

In up to 75% of breast cancers, estrogen receptor (ER) signaling is a key promoter of tumor proliferation, and inhibition of this pathway has clear therapeutic efficacy. The principal clinical means of inhibiting ER signaling comprise selective ER modulators, such as tamoxifen, that act as partial receptor agonists; measures to reduce the circulating level of estrogen, including ovarian ablation, gonadotropin-releasing hormone analogues, and aromatase inhibition; and antagonism and downregulation of ER by the antiestrogen fulvestrant. Each of these therapies is effective in a proportion of ER-positive breast cancers, but de novo and acquired resistance remain significant problems. Emerging knowledge of the biology of ER signaling will provide insights into the mechanisms of resistance and help guide development of therapeutic strategies to maximize response. This review summarizes the contemporary treatment of early-stage and advanced ER-positive breast cancer in premenopausal and postmenopausal women, with an emphasis on recently published or presented data. Mechanisms of resistance to endocrine interventions and trials exploring strategies to overcome them will also be discussed.

Rechallenging with anthracyclines and taxanes in metastatic breast cancer

Adjuvant use of anthracycline–taxane combination therapy is an accepted strategy in the management of high-risk early-stage breast cancer. However, the introduction of this regimen raises the question of how best to manage those patients who relapse following adjuvant therapy, and whether there is a role for rechallenging in the metastatic setting with the same agent, or class of agent, that has been utilized in the adjuvant setting. This Review examines the evidence for rechallenging with both anthracyclines and taxanes, and highlights the issues that need to be examined in the context of future clinical trials.

Treatment of primary rectal squamous cell carcinoma by primary chemoradiotherapy: Should surgery still be considered a standard of care?

Rectal squamous cell carcinoma is a rare tumour accounting for only 0.25% of all rectal carcinomas, yet it carries a significant mortality and morbidity. Radical surgery has been advocated as the primary treatment modality with or without adjunctive therapies despite the proven benefits of primary chemoradiotherapy for squamous cell carcinoma (SCC) of the anus. This report describes 7 cases of rectal squamous cell carcinoma from a single institution over a four-year period, treated with primary chemoradiotherapy. All patients demonstrated significant tumour regression, and surgery to the primary tumour was avoided in all but one of these cases. Primary chemoradiotherapy can achieve excellent local control for rectal squamous cell carcinoma with surgery employed only for unresponsive or recurrent tumours.

The role of SRC-3 in human breast cancer

Members of the nuclear receptor superfamily are ligand-regulated transcription factors involved in the control of a broad range of normal physiological and disease processes. The estrogen receptor alpha (ERα) is a member of the steriod receptor family, which is part of the nuclear receptor superfamily. ERα it is important for many biological processes and plays a key role in the pathogenesis of breast cancer. Gene regulation by ERα requires the recruitment of a multitude of transcriptional co-regulators to the promoters of estrogen-responsive genes. There is evidence in support of the involvement of these co-regulators in breast cancer progression. We review the role of steroid receptor co-activator-3 (SRC-3), which is frequently amplified in breast cancer, and its role in breast cancer risk, outcome and response to endocrine therapy in patients with breast cancer.

Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer Relapsing Post-Adjuvant Trastuzumab: Pattern of Recurrence, Treatment and Outcome

BACKGROUND The purpose of this study is to evaluate the response to and benefit of first-line metastatic treatment (including re-exposure to trastuzumab) for patients relapsing after exposure to adjuvant trastuzumab (AT). PATIENTS AND METHODS All HER2-positive breast cancer cases relapsing after exposure to AT at our institutions were identified. Clinico-pathologic details, pattern of relapse, and treatment in the metastatic setting were documented. Response to treatment and outcome were assessed. RESULTS Twenty-nine relapses were recorded. The median time to relapse was 18.4 months from diagnosis, and 8.7 months from AT initiation. At a median time of observation of 9.9 months, 18 patients had progressed on first-line therapy. The median time-to-progression (TTP) was 8.6 months. Fifteen patients received trastuzumab as first-line treatment, with no statistical difference in TTP between this group and those not re-exposed to trastuzumab. TTP was not statistically different between those relapsing on or after AT. Overall survival was longer for those who relapsed after completion of 1 year of AT as well as those who received further trastuzumab at relapse; however, this did not reach statistical significance. CONCLUSION Overall survival was longer in patients who relapse after completion of AT and who received further trastuzumab at progression.

Management and outcome of HER2-positive early breast cancer treated with or without trastuzumab in the adjuvant trastuzumab era.

BACKGROUND Adjuvant trastuzumab (AT) is known to significantly improve survival of women with HER2(+) early breast cancer. This study explores the use and nonuse of AT in early breast cancer, as well as the efficacy in a neoadjuvant and adjuvant population, within a routine clinical setting. PATIENTS AND METHODS Histopathology reports of invasive breast cancer resected at Imperial College Healthcare NHS Trust (ICHT) between January 2006 and December 2008 were reviewed. HER2(+) patients were identified and their case notes reviewed. In addition, patients who received AT at our center but underwent surgery elsewhere were included in the efficacy and safety analyses. RESULTS The local HER2(+) rate was 13.1%, with 54.5% of these patients receiving AT. A total of 128 patients received AT (85 local and 43 referrals from elsewhere). Neoadjuvant chemotherapy (CT) followed by postoperative AT was associated with a significantly increased risk of recurrence compared with adjuvant CT and then AT (hazard ratio [HR] 18.6 [95% CI, 1.8-152.2]; P = .013). The proportion of patients who were disease free at 3 years from primary therapy was 96.4% (95% CI, 89.8%-100%) for adjuvant therapy, compared with 72.0% (95% CI, 56.5%-91.6%) for neoadjuvant therapy. AT was omitted in 49 HER2(+) patients; the main reason for AT omission was clinical judgment that the breast cancer was low risk. Patients treated with AT had a significantly decreased risk of recurrence (HR 0.27 [95% CI, 0.08-0.97]; P = .04) compared with the untreated patients. The majority of untreated relapses were in patients in whom there was an original intent to use AT. The proportion alive at 3 years for adjuvant CT, neoadjuvant CT, and untreated AT was 100%, 74.5%, and 92.7% respectively. CONCLUSION The overall efficacy and safety of AT in our routine clinical setting is comparable to the large randomized trials. HER2(+) patients who underwent neoadjuvant CT had a significantly increased risk of disease recurrence compared with patients treated with adjuvant CT followed by trastuzumab. Untreated patients had an increased risk of recurrence.

Sentinel lymph node biopsy after neo-adjuvant chemotherapy in patients with breast cancer: Are the current false negative rates acceptable?

The advent of sentinel lymph node biopsy has revolutionised surgical management of axillary nodal disease in patients with breast cancer. Patients undergoing neo-adjuvant chemotherapy for large breast primary tumours may experience complete pathological response on a previously positive sentinel node whilst not eliminating the tumour from the other lymph nodes. Results from 2 large prospective cohort studies investigating sentinel lymph node biopsy after neo-adjuvant chemotherapy demonstrate a combined false negative rate of 12.6-14.2% and identification rate of 80-89% with the minimal acceptable false negative rate and identification rate being set at 10% and 90%, respectively. A false negative rate of 14% would have been classified as unacceptable when compared to the figures obtained by the pioneers of sentinel lymph node biopsy which was 5% or less.

Patient attitudes towards undergoing additional breast biopsy for research

BACKGROUND Acquisition of additional breast tissue has become integral to breast oncology research. This questionnaire study examines patient willingness to undergo research-dedicated breast biopsies either at time of diagnostic biopsy (T1) or after carcinoma diagnosis has been confirmed and eligibility for a specific study established (T2), and influencing factors thereof. METHODS Prior to consultation, patients attending breast clinics were recruited to complete a questionnaire examining willingness to undergo an extra fine needle aspirate (FNA) and/or core needle biopsy (CNB) for research either at T1 or T2. Descriptions of FNA and CNB procedures were supplied to those with no prior experience. Patient perspectives towards donating surplus tissue remaining from a diagnostic procedure and/or surgery for future research were also explored. FINDINGS A total of 100 patients were recruited, 42% with prior history of breast carcinoma (BC), 22% with family history of BC (FHBC) and 65%/42% with previous experience of CNB/FNA respectively. Overall, 57% were willing to undergo additional biopsy at one or both time points. Willingness to undergo additional biopsy was greater for T1 than T2, but equivalent for CNB and FNA (willingness CNB T1, 50% vs T2, 26%, willingness FNA T1 50% vs T2 29%). A statistically significant increase in willingness to undergo CNB and/or FNA at T1 and/or T2 was seen in association with prior diagnosis of BC, FHBC, previous visit to breast clinic and prior experience of breast biopsy. 83% of patients expressed a willingness to allow surplus tissue to be stored in a biobank for future research. INTERPRETATION Where possible patients should be approached to undergo baseline research biopsies at time of diagnostic process rather than subsequently. Patients do not find FNA more acceptable than core biopsy. Prior exposure to the biopsy procedure increases willingness to undergo research-dedicated biopsies.