Neoadjuvant chemotherapy in non-metastatic breast cancer: The surgeon's perspective.

Breast cancer is the most common non-skin cancer in Australia, affecting 1 in 7 women by the age of 85 years. Current management of early breast cancer is becoming increasingly variable and complex. The typical range of treatments include some combination of surgery, chemotherapy and targeted therapy, immunotherapy, radiotherapy, and endocrine therapy. Neoadjuvant chemotherapy (NACT) in carefully selected patients can facilitate increased rates of breast conservation therapy, and when successful, offers improved cosmesis due to less extensive resection of tissue. A neoadjuvant approach also provides biological insight into a patient's tumour, prognostication based on a patient's response to therapy, as well as enabling their treating oncologist to personalise adjuvant strategies based on the presence or absence of residual cancer at surgery. Neoadjuvant chemotherapy has become an integral element in the provision of breast conserving surgery to selected early-stage breast cancer patients. Appreciating the indications and understanding the likely outcomes from NACT in select situations, can result in significant improvements in patient tailored care.

Consumer and clinician perspectives on personalising breast cancer prevention information.

BACKGROUND: Personalised prevention of breast cancer has focused on women at very high risk, yet most breast cancers occur in women at average, or moderately increased risk (≤moderate risk). OBJECTIVES: To determine; 1) interest of women at ≤ moderate risk (consumers) in personalised information about breast cancer risk; 2) familial cancer clinicians' (FCCs) perspective on managing women at ≤ moderate risk, and; 3) both consumers' and FCCs reactions to iPrevent, a personalised breast cancer risk assessment and risk management decision support tool. METHODS: Seven focus groups on breast cancer risk were conducted with 49 participants; 27 consumers and 22 FCCs. Data were analysed thematically. RESULTS: Consumers reported some misconceptions, low trust in primary care practitioners for breast cancer prevention advice and frustration that they often lacked tailored advice about breast cancer risk. They expressed interest in receiving personalised risk information using iPrevent. FCCs reported an inadequate workforce to advise women at ≤ moderate risk and reacted positively to the potential of iPrevent to assist. CONCLUSIONS: While highlighting a potential role for iPrevent, several outstanding issues remain. For personalised prevention of breast cancer to extend beyond women at high risk, we must harness women's interest in receiving tailored information about breast cancer prevention and identify a workforce willing to advise women.

The impact and indications for Oncotype DX on adjuvant treatment recommendations when third-party funding is unavailable.

OBJECTIVES: Industry-supported decision impact studies demonstrate that Oncotype Dx (ODX) changes treatment recommendations (TR) in 24-40% of hormone receptor+/HER2- patients. ODX is not reimbursed by third-party payers in Australia, potentially resulting in more selective use. We sought to evaluate the impact of self-funded ODX on TRs. METHODS: Data collected included demographics, tumor characteristics, indication for ODX and pre- and post-recurrence score (RS) TR. Primary endpoint was frequency of TR change and associations with TR change were sought. RESULTS: Eighteen physicians contributed 382 patients (median age 54). A total of 232 (61%) of tumors were T1 and were grade 1, 2 and 3 in 49 (13%), 252 (66%) and 79 (21%). A total of 257 (67%) were node negative. Assay indications were: confirm need for chemotherapy (CT) (36%), confirm omission of CT (40%) and genuine equipoise (24%). RS was low (≤17) in 55%, intermediate (18-31) in 36% and high (≥32) in 9%. Thirty-eight percent of patients had TR change post-ODX. Sixty-five percent of patients recommended CT pre-ODX changed to hormone therapy alone (HT)-more likely if lower grade and if ER and/or PR > 10%. Fourteen percent of patients with pre-ODX TR for HT added CT-more likely if ER and/or PR ≤10% and if Ki67 > 15% Overall, TR for CT decreased from 47% to 24%. CONCLUSION: Patient-funded ODX changed TRs in 38% of patients, de-escalating 65% from CT to HT and adding CT to 14% of those recommended HT. These changes were greater than an industry-funded study suggesting that physicians can identify situations where the assay may influence decisions.

A survey of Australian and New Zealand clinical practice with neoadjuvant systemic therapy for breast cancer.

BACKGROUND: Neoadjuvant systemic therapy (NAST) has become an established treatment option for women with operable breast cancer. AIM: We aimed to better understand NAST treatment patterns, barriers and facilitators in Australia and New Zealand. METHODS: We undertook a cross-sectional survey of the current clinical practice of Australian and New Zealand breast cancer specialists. Questions included referral patterns for NAST, patient selection, logistics, decision making and barriers. RESULTS: Of 207 respondents, 162 (78%) reported routinely offering NAST to selected patients with operable breast cancer (median 9% of patients offered NAST). Specialty, location, practice type, gender or years of experience did not predict for offering NAST. In all, 45 and 58% wanted to increase the number of patients who receive NAST in routine care and in clinical trials respectively. Facilitators included the multidisciplinary team meeting and access to NAST clinical trials. Specialist-reported patient barriers included: patient desire for immediate surgery (63% rated as important/very important); lack of awareness of NAST (50%); concern about progression (43%) and disinterest in downstaging (32%). Forty-three per cent of participants experienced system-related barriers to the use of NAST, including other clinicians' lack of interest (27%); lack of clinical trials (24%) and unacceptable wait for a medical oncology appointment (37%). CONCLUSION: This group of Australian and New Zealand clinicians are interested in NAST for operable breast cancer in routine care and clinical trials. Patient- and system-related barriers that prevent the optimal uptake of this treatment approach will need to be systematically addressed if NAST is to become a more common approach.

Observation versus late reintroduction of letrozole as adjuvant endocrine therapy for hormone receptor-positive breast cancer (ANZ0501 LATER): an open-label randomised, controlled trial.

BACKGROUND: Despite the effectiveness of adjuvant endocrine therapy in preventing breast cancer recurrence, breast cancer events continue at a high rate for at least 10 years after completion of therapy. PATIENTS AND METHODS: This randomised open label phase III trial recruited postmenopausal women from 29 Australian and New Zealand sites, with hormone receptor-positive early breast cancer, who had completed ≥4 years of endocrine therapy [aromatase inhibitor (AI), tamoxifen, ovarian suppression, or sequential combination] ≥1 year prior, to oral letrozole 2.5 mg daily for 5 years, or observation. Treatment allocation was by central computerised randomisation, stratified by institution, axillary node status and prior endocrine therapy. The primary outcome was invasive breast cancer events (new invasive primary, local, regional or distant recurrence, or contralateral breast cancer), analysed by intention to treat. The secondary outcomes were disease-free survival (DFS), overall survival, and safety. RESULTS: Between 16 May 2007 and 14 March 2012, 181 patients were randomised to letrozole and 179 to observation (median age 64.3 years). Endocrine therapy was completed at a median of 2.6 years before randomisation, and 47.5% had tumours of >2 cm and/or node positive. At 3.9 years median follow-up (interquartile range 3.1-4.8), 2 patients assigned letrozole (1.1%) and 17 patients assigned observation (9.5%) had experienced an invasive breast cancer event (difference 8.4%, 95% confidence interval 3.8% to 13.0%, log-rank test P = 0.0004). Twenty-four patients (13.4%) in the observation and 14 (7.7%) in the letrozole arm experienced a DFS event (log-rank P = 0.067). Adverse events linked to oestrogen depletion, but not serious adverse events, were more common with letrozole. CONCLUSION: These results should be considered exploratory, but lend weight to emerging data supporting longer duration endocrine therapy for hormone receptor-positive breast cancer, and offer insight into reintroduction of AI therapy. CLINICAL TRIALS NUMBER: Australian New Zealand Clinical Trials Registry (www.anzctr.org.au), ACTRN12607000137493.

Women's reflections on fertility and motherhood after breast cancer and its treatment.

Breast cancer and its treatment have complex ramifications for women of reproductive age, including reduced fertility. With the aim of increasing understanding of what it means to women to manage fertility and motherhood in the years after a diagnosis of breast cancer, in-depth qualitative interviews were conducted with 10 women aged 26-45 years, living in Victoria, Australia, who had been diagnosed with breast cancer aged 25-41. Transcripts were analysed thematically and interpreted within narrative theory. Six themes linking breast cancer to fertility and motherhood were identified: diagnosis as a pivotal life event, robbed of time and choice, significance of fertility, being a mother, narrative justification, and life after breast cancer treatment. Women without children described a preoccupying sorrow about lost fertility. Women's accounts yielded evidence of narrative meaning-making, including justifying their decisions and actions in relation to survival, treatment and fertility, and coping with adversity by developing consoling plots. Breast cancer, fertility and reproductive health are inter-linked in diverse ways which have immediate and long-term consequences. Even if women are receiving optimum fertility management, it is evident that some women of reproductive age will need continuing post-cancer care to manage and ameliorate ramifications of diminished or lost fertility.

Reoperative sentinel lymph node biopsy in ipsilateral breast cancer relapse.

Sentinel lymph node biopsy (SLNB) is controversial following ipsilateral breast tumour relapse (IBTR) and previous axillary surgery. We retrospectively assessed the feasibility, outcomes and utility of this procedure. Eighteen patients with IBTR who underwent reoperative SLNB were identified. Fifteen women had previously undergone axillary lymph node dissection and three SLNB for breast cancer. Twelve of 16 patients underwent successful lymphoscintigraphy (LSG). Lymphatic drainage patterns varied widely - ipsilateral axilla (5), contralateral axilla (5), and ipsilateral internal mammary (5). Two patients had drainage to more than one nodal basin. Nine of 12 patients demonstrated drainage outside of the ipsilateral axilla. Reoperative SLNB was successful in 12/18 of patients - 4 ipsilateral axilla, 1 ipsilateral internal mammary, 1 ipsilateral intramammary, 4 contralateral axilla. Two patients had sentinel nodes in multiple nodal basins. Positive sentinel node was found in one successful case (contralateral axilla) and isolated tumour cells in two (1 contralateral axilla, 1 ipsilateral internal mammary). In conclusion, reoperative SLNB is feasible. Lymphatic drainage patterns vary widely and preoperative LSG is vital to facilitate identification of sentinel nodes in unusual sites. Its prognostic and therapeutic significance warrants further study.

The prognostic impact of isolated tumor cells in lymph nodes of T2N0 gastric cancer: comparison of American and Japanese gastric cancer patients.

BACKGROUND: The clinical significance of immunohistochemically detected isolated tumor cells (ITC) in lymph nodes of gastric cancer patients is controversial. This study examined the prognostic impact of ITC on patients with early-stage gastric cancer in two large volume centers in the United States and Japan. METHODS: Fifty-seven patients with T2N0M0 gastric carcinoma who underwent gastric resection between January 1987 and January 1997 at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York and 107 patients resected at National Cancer Center Hospital (NCCH) in Tokyo between January 1984 and December 1990 were studied. The sections were newly prepared from each lymph node for immunohistochemical staining for cytokeratin. Lymph nodes and original specimens from MSKCC were examined by pathologists in NCCH. The prognostic significance of the presence of ITC in lymph nodes was investigated in patients of both institutions. RESULTS: ITC were identified in 30 of 57 patients (52.6%) at MSKCC and in 38 of 107 patients (35.5%) at NCCH. In both institutions, there was no significant difference in the prognosis of the studied patients with or without ITC (P= .22, .86 respectively). CONCLUSIONS: The presence of ITC detected by immunohistochemistry in the regional lymph nodes did not affect the prognosis of American and Japanese patients with T2N0M0 gastric carcinoma who underwent gastrectomy with D2 lymph node dissection.

Fasciitis ossificans with a radial neuropathy: a benign differential diagnosis for soft tissue sarcoma.

A soft tissue mass with an associated neuropathy suggests a malignancy with nerve compression or infiltration. However, there are benign diagnoses to consider. We report a case of an axillary mass with a radial nerve neuropathy, initially suspected to be a soft tissue sarcoma. The final diagnosis was fasciitis ossificans. This is the first such reported case. The presence of severe pain and tenderness suggested an inflammatory process. Fasciitis ossificans is a rare form of heterotopic bone formation, commonly presenting with signs of local inflammation or pain.

Targeting lymphangiogenesis to prevent tumour metastasis.

Recent studies involving animal models of cancer and clinicopathological analyses of human tumours suggest that the growth of lymphatic vessels (lymphangiogenesis) in or nearby tumours is associated with the metastatic spread of cancer. The best validated molecular signalling system for tumour lymphangiogenesis involves the secreted proteins vascular endothelial growth factor-C (VEGF-C) and VEGF-D that induce growth of lymphatic vessels via activation of VEGF receptor-3 (VEGFR-3) localised on the surface of lymphatic endothelial cells. In this review, we discuss the evidence supporting a role for this signalling system in the spread of cancer and potential approaches for blocking this system to prevent tumour metastasis.

Gastrointestinal stromal tumour treated with neoadjuvant imatinib.

This report describes a case of unresectable primary gastrointestinal stromal tumour (GIST) treated with imatinib on a neoadjuvant basis, before subsequent successful surgical resection. After six months of imatinib, computed tomography and positron emission tomography imaging demonstrated a significant size reduction and complete metabolic response to treatment, rendering the tumour resectable. Mutational analysis showed an activating KIT mutation in exon 11. The pathological appearance of the resected tumour was heterogeneous with extensive necrosis, cystic and myxoid change, extensive hypocellularity, and patchy foci of residual viable tumour. The implications for this management option of radiological, pathological, and molecular assessment are discussed.

Quality of care for women presenting with benign breast conditions.

The aim of the study was to investigate the management of women with benign breast problems. A consecutive sample of women (n = 194) was assessed who presented to public or private sector providers. The main reasons for referral were breast lumps (62%); 56% of women who attended the public sector did not receive any recommendation compared to 40% who attended the private sector and clinical/general practitioner reviews were recommended to more women in the private sector (54%). Reasons for the discrepancy between public and private patients require further investigation.

Carbon localisation of impalpable breast lesions.

BACKGROUND: Hookwire localisation (HL) is the most widely used technique for excision of impalpable breast lesions. This method has several drawbacks, particularly with logistics. Carbon localisation (CL) is an alternative procedure which is logistically superior to HL, but comparisons of accuracy and costs have not been reported. METHODS: A consecutive case series of all patients from Northwestern BreastScreen undergoing either CL or HL between January 1999 and March 2001. FINDINGS: Of 511 procedures, 219 CLs and 292 HLs were performed. The accuracy of excision did not vary significantly. Where a preoperative diagnosis of malignancy had been made by percutaneous needle biopsy (PNB), the margins were <1mm in 27 of the CL group (18.9%) and 21 of the HL group (29.2%) (P=0.087). Cost analysis was very favourable for CL performed concurrently with PNB since the costs were incremental. INTERPRETATION: At service delivery level, CL is an accurate alternative to HL with better logistics and favourable costs. Nationally, it has the potential to improve the cost effectiveness of breast screening programmes.

Immunohistochemically detected micrometastases of the lymph nodes in patients with gastric carcinoma.

BACKGROUND: Lymph node status is a major determinant of disease recurrence after patients undergo curative resection for gastric carcinoma. A proportion of patients without lymph node metastasis develop systemic recurrences. Recent studies in a range of solid tumors have found a high incidence of micrometastases in the regional lymph nodes of patients with apparently negative lymph nodes. In patients with breast and colorectal carcinoma, the presence of micrometastases has been associated with a poorer prognosis. In patients with gastric carcinoma, the significance of micrometastases in lymph nodes remains controversial. Most published reports on this subject suffer from the problems of small sample size and selection bias. METHODS: One hundred seven patients with pathologic T2N0M0 (tumor invades muscularis propria or subserosa [T2], no regional lymph node metastasis [N0], and no distant metastasis [M0]; pT2N0M0) gastric carcinoma who underwent gastric resection between 1984 and 1990 at the National Cancer Center Hospital were studied. Two consecutive sections were newly prepared from each lymph node for hematoxylin and eosin staining and immunohistochemical staining (IHC) with antibody against cytokeratin. Associations between clinicopathologic factors and the presence of micrometastases as well as micrometastases and survival were sought. RESULTS: Micrometastases were identified in 38 of 107 patients (35.5%) and in 87 of 4484 lymph nodes (1.94%) by IHC. The incidence of micrometastases was significantly higher in patients with infiltrative tumors than in patients with expansive, growing tumors (P = 0.02). Other clinicopathologic findings had no statistically significant correlation with the incidence of micrometastases. The 5-year survival rates of patients with and without micrometastases were 94% and 89%, respectively. Similarly, the 10-year survival rates were 79% and 74%, respectively. The survival curves of patients with or without micrometastasis were nearly superimposed (P = 0.86). CONCLUSIONS: The presence of immunohistochemically detected micrometastases in the regional lymph nodes did not affect the survival of Japanese patients with pT2N0M0 gastric carcinoma who had undergone gastrectomy with D2 lymph node dissection.

Utilization of evidence-based teaching in U.S. dental hygiene curricula.

PURPOSE: The purpose of this research was to survey U.S. dental hygiene program directors to determine: (1) demographic information, (2) specific Evidence-Based (EB) student instruction methods used, (3) if and how programs use an EB philosophy, (4) perceptions of faculty skills in incorporating EB instruction, and (5) opinions and attitudes regarding future need to incorporate EB philosophies in dental hygiene education. METHODS: Data were gathered by surveying all 235 United States dental hygiene program directors in 1999. The survey included 20 closed items and 1 open-ended item. Initially, the survey was pilot tested using a convenience sample of seven U.S. dental hygiene program directors. A final, revised survey was mailed to the cohort population. A response rate of 70% (n = 164) was achieved after two mailings, and responses were analyzed using descriptive statistics. RESULTS: The demographic results of this study revealed the majority of respondents were from associate degree/certificate dental hygiene programs (77%). Results revealed that most dental hygiene programs are beginning to include some fundamental EB concepts and skills into their curriculum, primarily by incorporating analysis of scientific literature. Most programs provide students with formal library orientation (88%), instruct students in the use of library indices or library databases (86%), and teach the use of the Internet for conducting literature searches (79%). Respondents indicated the major barriers for fully incorporating an EB approach in their dental hygiene program were: lack of faculty skills (37%), no available time (34%), lack of financial resources (33%), and lack of technical support (28%). CONCLUSION: Findings of this study suggest dental hygiene educators have made small strides in creating an EB philosophy dental hygiene curriculum. However, the future of dental hygiene education must address the need for faculty development and training in areas such as computer utilization in core dental hygiene courses, strategies to improve the curriculum to stimulate students' critical thinking skills, and to develop educators' skills in the use of evidence for clinical decision-making.

Six-year follow-up of patients with microinvasive, T1a, and T1b breast carcinoma.

BACKGROUND: Management of patients with breast cancers < or = 1 cm remains controversial. Reports of infrequent nodal metastases in tumors < or = 5 mm has led to suggestions that axillary dissection should be selective, and that tumor characteristics should guide adjuvant therapy. METHODS: A retrospective review of 290 patients with breast cancer 1 cm in size or smaller from 1989 to 1991 was done. Distant disease-free survival (DDFS) was the primary outcome measure. RESULTS: There were 95 T1a (< or = 5 mm) and 196 T1b (6-10 mm) cancers. Nodal metastases were found in 8 T1a and 26 T1b tumors. Larger size, poorer differentiation, and lymphovascular invasion (LVI) were associated with more nodal metastases, but none of these trends reached statistical significance. The 6-year DDFS was 93% for node-negative and 87% for node-positive patients (P = .02). Overall, breast cancers with poorer differentiation and LVI trended toward a poorer outcome. For patients with node-negative tumors, LVI was associated with a poorer outcome (P = .03). The size of the primary tumor was not predictive of outcome. There were no nodal metastases or recurrences in the 18 patients with microinvasive breast cancer. CONCLUSIONS: Lymph node status is the major determinant of outcome in breast cancers 1 cm in size or smaller. Accurate axillary assessment remains crucial in management of small breast cancer.

Adult soft tissue sarcoma.

BACKGROUND: Soft tissue sarcomas (STS) are a group of anatomically and histologically diverse tumours. They account for about 1% of adult malignancies, and about 50% of patients diagnosed with sarcoma eventually die of the disease. These tumours are grouped together because of shared biological characteristics and treatment responses. METHODS: A review of the key literature on STS was undertaken, complemented by data taken from the prospectively accumulated database of 3442 patients treated for STS at Memorial Sloan-Kettering Cancer Center (MSKCC) from July 1982 to December 1997. RESULTS: Despite advances in knowledge of the molecular genetics of STS, the aetiology in most cases remains elusive. Management has been gradually refined over the last two decades. Core biopsy usually provides enough material for diagnosis. Computed tomography and magnetic resonance imaging provide a similar amount of information, which is usually adequate for surgical planning. Amputation as standard treatment for extremity lesions has been replaced by limb-sparing surgery in about 90% of patients. The role of adjuvant radiation has been further defined: it has been shown to be unnecessary for completely excised tumours less than 5 cm in diameter, but effective in decreasing local recurrence for others. Adjuvant chemotherapy has been controversial for many years. Recent meta-analysis of randomized trial results has found a small reduction in local and distant relapse, and a trend to better overall survival. Recurrent or metastatic disease should be completely excised if possible. CONCLUSIONS: Soft tissue sarcoma requires multidisciplinary care tailored to the individual patient and tumour for optimal results.

Does the extent of operation influence the prognosis in patients with melanoma metastatic to inguinal nodes?

BACKGROUND: The role of pelvic lymphadenectomy in melanoma metastatic to the superficial inguinal region remains controversial. Some researchers advocate aggressive surgical management, whereas others feel that outcome depends more on extent of disease rather than extent of treatment. We reviewed our recent experience to investigate possible therapeutic effects of extended surgery. METHODS: We performed a retrospective clinical and pathological review of 227 consecutive patients having superficial (SLND) or combined inguinal lymphadenectomy (CLND) for cutaneous melanoma. RESULTS: A total of 174 SLNDs and 53 CLNDs were performed. Overall 5-year survival for node-positive patients was 39%. Survival for patients with positive superficial nodes was 40%; for those with positive deep nodes it was 35% (P = ns). In node-positive patients, number and size of involved lymph nodes and the presence of extranodal spread, failure to receive adjuvant therapy, and tumor ulceration were associated with poorer prognosis. Extent of surgery was not associated with differential survival, although CLND patients had worse pathological features. Subgroup analysis showed no significant survival difference between SLND and CLND. CONCLUSIONS: Some patients with deep nodal involvement apparently are cured by CLND. However, it is the biology of the disease and not the extent of surgery that primarily governs outcome. Patients with clinical or radiological evidence of pelvic nodal disease without evidence of systemic disease should have a CLND, but we find no evidence to support CLND if the pelvic nodes are clinically and radiologically negative.