Efficacy of late line pertuzumab with trastuzumab and chemotherapy in HER2-positive metastatic breast cancer: An Australian case series.

BACKGROUND: Pertuzumab, when combined with trastuzumab and chemotherapy, is a highly active human epidermal growth factor receptor 2 (HER2), targeting agent in the neoadjuvant, adjuvant and first-line metastatic HER2-positive breast cancer setting. The efficacy of late-line (after first/second-line) pertuzumab in combination with trastuzumab and chemotherapy is unknown. AIMS: To establish pertuzumab efficacy by performing an audit of patients who received pertuzumab after first-line HER2 directed therapy. We sought to establish whether efficacy differed by clinicopathological factors. METHODS: The primary endpoint was progression-free survival (PFS) and the secondary endpoint, overall survival (OS). Clinicopathological factors, PFS and OS data were collated and clinicopathological factors associated with PFS were evaluated using Cox regression models. RESULTS: Fourteen women were identified. Six (43%) had hormone receptor (HR) negative and eight (57%) had HR-positive, metastatic HER2-positive breast cancer. Median follow up was 22.8 months, median prior lines of therapy were 5 (range: 1-9). Median time from diagnosis of metastatic disease to receiving pertuzumab was 4.5 years (range: 4.2-5.8). All patients received initial chemotherapy with pertuzumab and trastuzumab (taxane-based 71%). Median PFS was 9 months (95% confidence interval [CI]: 7-not estimable [NE]) and median OS was not reached (95% CI, 16 months-NE). Univariable analysis demonstrated that HR-negative patients had a significantly longer PFS than HR-positive patients (hazard ratio = 0.11; 95% CI, 0.01-0.88; P = 0.04). CONCLUSION: This small cases series reports a favorable PFS and OS for pertuzumab with trastuzumab and chemotherapy in the later line metastatic setting. This finding warrants further study.

Recurrence in early breast cancer: Analysis of data from 3,765 Australian women treated between 1997 and 2015.

BACKGROUND: Evidence suggests recent improvements in outcome in early breast cancer (EBC). AIM: To analyse recurrence in women with EBC from our region from 1997 to 2015. METHODS: We analysed recurrence in 3,765 women with EBC. Median follow up was 83·0 months. 62·5% had a symptomatic presentation. 81·8% were hormone receptor positive and 38·5% were node positive. Lymphovascular invasion (LVI) was present in 24·3%. Of the 2,686 women entered from 2002 onwards tested for HER2 status, 72·7% had a luminal tumour, 15·2% had a HER2+ tumour and 12·1% had a triple negative (TN) tumour. RESULTS: Recurrence occurred in 459 (12·2%), predominantly in distant sites (71·7%). In women entered from 2002 onwards, the five and 10 year recurrence rates were significantly lower in the luminal group than the HER2+ and the TN groups. Few recurrences occurred in HER2+ and TN cancers after 36 months. On multivariate analysis the following were associated with a significantly increased risk of recurrence: nodal involvement (p < 0·0001), tumour grade (p < 0·0001), symptomatic presentation (p < 0·0001), presence of LVI (p = 0·001), non-luminal tumour type (p < 0·0001) and tumour size >50 mm (p = 0·02). CONCLUSION: The recurrence rate in this series was much lower than in previous older series. Lymph node involvement, tumour grade, symptomatic presentation, presence of LVI, non-luminal tumour type and tumour size (>50 mm) were associated with an increased risk of recurrence. We strongly recommend that clinicians include the presence of LVI and symptomatic presentation as well as the other established tumour factors, when assessing the risk of recurrence in women with EBC.

Surgical margins and risk of locoregional recurrence in invasive breast cancer: an analysis of 10-year data from the Breast Cancer Treatment Quality Assurance Project.

AIM: There is debate as to what constitutes an adequate excision margin to reduce the risk of locoregional recurrence (LRR) after breast cancer surgery. We have investigated the relationship between surgical margin distance and LRR in women with invasive breast cancer (IBC). METHODS: Tumour free margin distances were extracted from histopathology reports for women with IBC, treated by either breast conserving surgery or mastectomy, enrolled in the Breast Cancer Treatment Group Quality Assurance Project from July 1997 to June 2007. Cox proportional hazards regression analyses were conducted to compare the risk of LRR for involved margins compared with negative margins, measured in increments rounded to the nearest mm. RESULTS: 88 of 2300 patients (3.8%) experienced an LRR after a mean follow-up of 7.9 years. An involved margin, or a margin of 1 mm was associated with an increased risk of LRR (HR 2.72, 95% CI 1.30-5.69), whilst margin distances of 2 mm or greater were not. Risk of LRR with margin distances <2 mm was particularly high amongst those not receiving radiotherapy (RT). CONCLUSION: Based on our findings, we recommend that a tumour free margin distance of 2 mm be adopted as an adequate margin of excision for IBC, in the setting of patients receiving standard adjuvant RT and adjuvant drug therapies as dictated by the current clinical treatment paradigms.

Rational use of trastuzumab in metastatic and locally advanced breast cancer: implications of recent research.

The management of HER2-positive metastatic breast cancer, a disease renowned for its aggressive natural history, has been revolutionized by the introduction of trastuzumab. Indeed, outcomes for patients with HER2-positive advanced breast cancer are now equivalent to, if not better than, those of their HER2-negative counterparts. Since the pivotal registration trial, a wealth of new clinical data has emerged regarding the use of trastuzumab in a variety of clinical contexts - adding to the evidence but also highlighting areas of uncertainly and debate. These include the optimal partner chemotherapy(ies) to trastuzumab; the effectiveness of combining trastuzumab with endocrine therapy; the benefits of continuing trastuzumab after progression on a trastuzumab-containing regimen; and the role of trastuzumab in locally advanced and inflammatory breast cancer. In this paper we review major clinical trials addressing these questions, clinical recommendations that can be made as a result, and the strength of evidence that supports them. Finally, we identify areas of ongoing uncertainty, and propose recommendations for future research in this field.

Variation in the management of early breast cancer in rural and metropolitan centres: implications for the organisation of rural cancer services.

The study examines the management and outcomes of women with early invasive breast cancer treated in rural and metropolitan centres over a nine-year observation period. A prospective audit of the treatment and outcomes of 2081 women with early breast cancer who underwent potentially curative surgery between 1997 and 2006 in metropolitan Canberra or in the surrounding rural region was completed. Overall, there was good agreement between published guidelines and the treatment received by the women in the study. However, women treated in rural centres were less likely to receive postoperative radiotherapy after breast-conserving surgery, or to undergo axillary lymph node surgery or sentinel lymph node biopsy compared with women treated in metropolitan centres. Surgery in a rural centre was associated with increased breast cancer recurrence (HR = 1.54, p < 0.001) and increased breast cancer mortality (HR = 1.84, p < 0.001), after adjustment for age and tumour characteristics. Non-cancer related mortality was increased in women treated in rural centres compared with women travelling to a metropolitan centre for surgery (HR = 2.08; p = 0.005). There were differences in both the care provided and treatment outcomes between women treated in rural centres and women treated in metropolitan centres. However, the increased non-cancer related mortality in women treated in rural centres suggests an increased medical comorbidity in this group. Initiatives supporting rural-based surgeons to adopt new procedures such as sentinel node biopsy may help to optimise rural breast cancer treatment.

Optimal adjuvant endocrine therapy for early breast cancer.

Adjuvant endocrine therapy substantially reduces tumor recurrence and mortality in pre- and post-menopausal women with hormone receptor-positive early breast cancer but is ineffective in women with hormone receptor-negative tumors. Tamoxifen has been the standard adjuvant endocrine therapy for both pre- and post-menopausal women with hormone receptor-positive early breast cancer and remains the standard of care for premenopausal women. In addition to tamoxifen, ovarian ablation by surgery or radiotherapy remains an option for selected premenopausal women and trials are evaluating the role of ovarian function suppression using luteinizing hormone-releasing hormone agonists. For postmenopausal women, aromatase inhibitors are more effective than tamoxifen therapy and aromatase inhibitors and tamoxifen are regarded as standards of care. Prolonging adjuvant endocrine therapy in postmenopausal women by the sequencing of aromatase inhibitors and tamoxifen can improve outcomes further. Adjuvant endocrine therapy will probably be used for longer durations in selected postmenopausal women.

Does routine psychological screening of newly diagnosed rural cancer patients lead to better patient outcomes? Results of a pilot study.

BACKGROUND: Few studies have reported on the impact of screening on patient outcomes or clinical practice and research describing the implementation of psychosocial screening in rural services is scarce. AIMS: This study investigated the feasibility and utility of a psychological screening program in Australian rural oncology clinics. SUBJECTS & METHODS: A total of 83 newly diagnosed adult cancer patients, seen at one of three rural outpatient oncology clinics participated in this study. RESULTS: Nineteen of forty-three (44%) participants in the screening phase scored above cut-off score on the Distress Thermometer (DT), a validated screening tool for distress in cancer patients. The DT had acceptable sensitivity (86%) and specificity (77%) as a screening tool using another validated self-report measure of psychological symptoms, the Psychological Symptoms Subscale of the Somatic and Psychological Health Report Short form, as a'gold standard'. Screening with the DT did not significantly increase the rate of referrals to psychosocial staff of distressed individuals. However, screening with the DT reduced time to referral. The screened group reported significantly greater unmet needs in univariate (P = 0.01) and multivariate analyses (P = 0.01). CONCLUSIONS: Psychological screening did not increase rates of referral to psychosocial support staff for patients with psychological morbidity. However, given the methodological limitations of this pilot study, the results should be interpreted with caution. The DT was found to have acceptable sensitivity and specificity to detect likely cases of psychological morbidity. Barriers to implementation of psychological screening in rural clinics and recommendations for future psychological screening programs at outpatient oncology clinics are discussed.

What survival benefits do premenopausal patients with early breast cancer need to make endocrine therapy worthwhile?

BACKGROUND: Adjuvant endocrine therapies such as tamoxifen, goserelin, and oophorectomy improve survival for premenopausal women diagnosed with early-stage breast cancer. However, these treatments often result in menopausal symptoms, sexual dysfunction, permanent infertility, or the need to delay pregnancy. We aimed to quantify the survival gains that premenopausal patients with early-stage breast cancer require to justify the side-effects and inconvenience of adjuvant endocrine treatments. METHODS: Participants consisted of 102 women who had been diagnosed with early-stage (stage I-II) breast cancer 6-60 months previously, who were aged 40 years or younger at diagnosis, and who had been treated for a minimum of 3 months with endocrine therapy (67 with tamoxifen alone, seven with goserelin alone, and 28 with tamoxifen and goserelin or oophorectomy). 76 patients also received chemotherapy, and 75 received radiotherapy. Participants attended a face-to-face patient-preference interview, in which they were presented with four hypothetical clinical scenarios that were used to quantify the gains in survival rate and life expectancy that women judged necessary to make their endocrine therapy worthwhile. They also completed a questionnaire on standard psychological measures. FINDINGS: About half of participants thought that adjuvant endocrine therapy was worthwhile for an absolute gain in survival of 2% from a baseline of either 65% or 85%, and for a gain in life expectancy of 3 months from a baseline of 5 years and of 6 months for a baseline of 15 years. Women who had had more severe endocrine side-effects required larger gains to make endocrine therapy worthwhile (univariate p=0.02, multivariate p=0.04). INTERPRETATION: Modest gains in survival are sufficient to make adjuvant endocrine treatment worthwhile for premenopausal women with early-stage breast cancer. Knowing and incorporating what women think should enhance shared decision-making.

The development of the Canberra symptom scorecard: a tool to monitor the physical symptoms of patients with advanced tumours.

BACKGROUND: Patients with advanced (incurable) tumours usually experience a diverse burden of symptoms. Although many symptom assessment instruments are available, we examined whether these addressed tumour-related symptoms. METHODS: We reviewed existing symptom assessment instruments and found a number of deficiencies such as instruments being too long or burdensome, too short, or measuring quality of life rather than tumour-related symptoms. Others focused on emotional, rather than physical symptoms. Therefore, we decided to devise a new symptom instrument. A list of 20 symptoms common in patients with advanced tumours generated from the literature and existing instruments, was ranked according to prevalence by 202 Australian clinicians. Following clinicians' responses, the list was revised and two severity assessment scales (functional severity and distress severity) added. The resultant 18-item list was assessed in 44 outpatients with advanced tumours. RESULTS: Patient responses indicated that a shorter questionnaire of 11 items, reflecting three main symptom clusters, provided a good representation of physical symptoms. An additional symptom that is an important predictor of survival was added, making a 12-item questionnaire, which was entitled "The Canberra Symptom Scorecard" (CSS). For symptom severity, the distress severity scale was more appropriate than the functional severity scale. CONCLUSION: The CSS focuses on tumour-related physical symptoms. It is about to be assessed in patients with advanced tumours receiving palliative treatments, when it will also be validated against existing instruments.