“First that patients must be at the heart of everything we do, not just as beneficiaries of care but as participants in shared decision making. As patients there should be no decision about us without us.” Andrew Langsley, UK Secretary of State for Health, 2011.¹

Breast cancer is one of the most common cancers worldwide with approximately 1.4 million women diagnosed each year. Despite declining mortality rates since the early 1990s, largely attributable to improvements in adjuvant therapy for early disease,² breast cancer remains the leading cause of cancer death in women in the developed and developing world. One 10th of patients have metastatic disease at presentation and 30% of women with early breast cancer will develop advanced disease.³ Of these patients, 10% will live with metastatic disease for 10 years or more, with the majority surviving for several years. 

A lack of patient registers that measure relapse means that the true extent of advanced breast cancer (ABC) in many countries is unknown. Although improvements in therapy have changed the trajectory of ABC from acutely life-threatening to a chronic disease for many patients, it remains without cure and accounts for over half a million deaths worldwide a year. 

There is a growing body of evidence highlighting significant unaddressed psychological and quality of life needs among patients living with ABC. Traditionally, resourcing patients with breast cancer has focused on those with newly diagnosed and potentially curable disease. Many patients contrast the abundant support received when they are diagnosed to the dearth of support that is present at relapse, leaving patients feeling isolated and abandoned. 

ABC consensus conference 

The ABC consensus meeting stems from the establishment by the European School of Oncology (ESO), in 2004, of the Advanced Breast Cancer Task Force, to develop comprehensive, international guidelines for the management of the disease.

The first Advanced Breast Cancer Consensus Conference (ABC1), held in Lisbon, Portugal, in November 2011, facilitated the development of the first international guidelines specific to advanced breast cancer.⁴ These guidelines were updated by an expert panel at the second consensus conference (ABC2) in November 2013. The expert panel of 40 comprised world leaders in oncology and palliative care, ABC patients, advocates, specialised nurses and psycho-oncologists. 

The consensus panel ABC2

The updated guidelines will be developed in co-operation with the ESO and the European Society for Medical Oncology (ESMO) and endorsed by the European Society of Breast Cancer Specialists (EUSOMA), Federación Latinoamericana de Mastologia (FLAM) and the Senologic International Society (SIS). Publication of the ABC2 guidelines is expected early this year. 

Highlights from ABC2

Patient experience and advocacy 

Unique to this event is the strong presence and central role played by ABC patients and advocates. ABC2 saw the addition of a specific programme for breast cancer advocates co-ordinated by leading advocacy groups worldwide. An ABC Patient Advocacy Committee was established, involving 68 advocates, many with advanced breast cancer, from 45 organisations and representing 25 countries. 

Keynote speaker Doris Fenech, an advanced breast cancer patient, nurse and advocate, delivered a powerful account of the physical and emotional needs of women with metastatic disease, as distinct from those with early-stage disease. 

She highlighted the lack of clinician training in advanced disease management as well as a perceived lack of interest from clinicians to treat advanced breast cancer. 

“For most healthcare professionals a diagnosis of metastatic breast cancer is the beginning of the end and frequently they are at a loss as what to say to us and how to help. 

“These attitudes have contributed to misconceptions and marginalisation by the public, the media and healthcare professionals themselves,” said Ms Fenech.

This feeling of isolation is echoed in the final results of the Here & Now pan-European ABC patient and carer survey and ABC awareness consumer poll, both supported by Novartis Oncology. Completed by 158 ABC patients and 146 carers in nine countries, the Here & Now survey explores the psychological, social and economic impact of ABC on patients and their families. 

In this survey, eight out of 10 patients said that quality of life is the biggest area for improvement in the provision of care. Depression was reported by 41%, with over 50% of patients experiencing worry. More than one third of patients reported loss of confidence and personal identity, and 38% expressed fear of the future. Half of all respondents confirmed that pain interferes with their daily life. 

Also presented were results from the multinational online survey Count Us, Know Us, Join Us, which captured similarly high levels of distress. This was completed by 1,273 female patients with metastatic breast cancer from 12 countries. Of these women, 68% stated that ABC had a moderate or severe negative impact on their quality of life. Almost two thirds of respondents (64%) reported a significant negative effect on their emotional wellbeing, and 57% said it had a negative impact on the emotional health of their loved-ones. Despite this high level of unmet need, only 51% had discussed quality of life issues with their healthcare provider and less than 40% had discussed the impact of ABC on their emotional health.⁵

Improved understanding and awareness of the significant psychological morbidity associated with ABC is essential. Approximately 40% of patients with ABC suffer from depression and/or anxiety that merits intervention. Lesley Fellowfield, professor of psycho-oncology, University of Sussex, highlighted the need for improvement in the current use of psychosocial resources, with a more targeted approach using systematic screening in order to identify those who require specialist referral. 

Identified healthcare system needs

In keeping with the strong multidisciplinary ethos established at ABC1, the updated recommendations will reflect an urgent need for specialist oncology nurses for advanced disease. A consistent theme put forward by patients was the ongoing need for continuity of care and improved communication; balancing hope and reality. 

Advocate groups emphasised the importance of access to relevant clinical trials for ABC patients, the need for standardised and affordable treatment worldwide, and equal access to appropriate palliative care from diagnosis. 

The establishment of patient registers and tumour boards should be prioritised. The value of information sharing and improved interaction between societies and support groups, both regionally and globally, rather than duplication of effort was also highlighted. A position paper by advocates at ABC2 is expected to be published in early 2014. 

Major therapeutic advances since ABC1

HER2-positive breast cancer 

The development of highly effective therapies directed at the human epidermal growth factor receptor 2 (HER2) has dramatically changed the therapeutic landscape for HER2-positive breast cancer of all stages over the past decade.

Approximately 20-30% of breast cancer patients have tumours that over-express HER2, associated with an aggressive tumour phenotype and poorer prognosis. The recombinant monoclonal antibody, trastuzumab has shown significant clinical benefit in early stage and metastatic HER2-positive disease. The development of eventual trastuzumab resistance has led to the development of alternative HER2-directed therapies.  

HER2, a valid target following progression on trastuzumab

Since ABC1, major developments include the approval of monoclonal antibody pertuzumab for advanced HER2-positive breast cancer. Pertuzumab and trastuzumab bind to different regions on the HER2 receptor and can have synergistic activity. The combination of pertuzumab plus trastuzumab plus docetaxel, compared with placebo plus trastuzumab plus docetaxel, as first-line treatment for HER2-positive metastatic breast cancer, significantly prolonged progression-free survival and overall survival, achieving an overall response rate of 80% with no increase in cardiac toxicity.^6,7

Sequence of HER2-directed therapy

Pertuzumab in combination with trastuzumab is now considered the new standard of care in the first-line setting. Studies to establish the most suitable chemotherapy partners are ongoing, the current recommendation being paclitaxel or docetaxel while further data is awaited.⁸ Although only licensed in the first-line setting, the availability of pertuzumab remains limited and, as yet, it is not available in Ireland. 

Phase II data investigating combination pertuzumab and trastuzumab for patients with metastatic breast cancer with progression on trastuzumab has demonstrated an overall response rate of 25% and a median progression-free survival of 5.5 months, suggesting a rationale for its use beyond first-line.⁹ The question as to whether pertuzumab should be given beyond progression with rotation of chemotherapy, like trastuzumab, is yet to be addressed in clinical trials.  

The preferred second-line agent is the antibody-drug conjugate trastuzumab emtansine (T-DM1). T-DM1 has been shown to be superior to capecitabine and lapatinib with improved overall survival, improved progression-free survival and a superior toxicity profile (see Figure 1).¹⁰

 (click to enlarge)

In heavily pre-treated patients, the THERESA study, which was presented at ESMO in September 2013, demonstrated a significant improvement in progression-free survival, with improved safety compared with treatment of physician’s choice in patients previously treated with trastuzumab and lapatinib with favourable interim overall survival data. Definitive data in the first-line setting is awaited. The preferred regimen in the third-line setting and beyond is uncertain, with a lack of studies in this population.

Endocrine therapy (ET) in addition to HER2-directed therapy has demonstrated improvement in progression-free survival, however, it does not translate into an overall survival benefit.^11,12 It is recommended that this be considered for select patients only (asymptomatic, low-volume disease, high risk of toxicity from chemotherapy).

Despite improvements in therapy, HER2 resistance remains an important clinical problem and efforts must focus on strategies to overcome resistance, including the development of novel agents and the identification of functionally relevant biomarkers of resistance.  

Increasing attention is being drawn to the need to establish optimal strategies and sequencing of existing therapeutics, including cytotoxics and HER2-directed therapy rather than resources being monopolised in the development of novel targeted therapies that come at a high cost, often for limited clinical benefit.  

Hormone sensitive: Advance in endocrine therapy and endocrine resistance

Despite remaining the mainstay of treatment for oestrogen receptor-positive metastatic breast cancer, there is also a lack of high-level evidence guiding the sequencing of endocrine therapy (ET). Phase III trials published since ABC1 regarding the optimal use of ET suggest that fulvestrant (at a dose of 500mg) is superior to an aromatase inhibitor as first-line ET in ABC.^13,14

A major focus of current research is identifying strategies to overcome both de novo and acquired ET resistance. Previous efforts have focused on EGFR or HER2 over-expression with the addition of inhibitory agents to ET. More recent strategies focus on the up-regulation of alternative transduction pathways as potential mechanisms of resistance.¹⁵ BOLERO-2 demonstrated significant improvement in progression-free survival with the addition of mTOR inhibitor everolimus to exemestane in postmenopausal women with HR-positive disease.¹⁶

Studies investigating targeted agents, including IGFR1, FGFR, HDAC and PI3K/AKT inhibitors, are underway. The need for identification of biomarkers of enhanced benefit in light of the economic and clinical toxicity associated with these new therapies was highlighted.¹⁵

Future developments include the need for clinical trials to determine the role of intermittent ET in breast cancer, as used in prostate cancer, in order to reduce adverse hormonal side effects known to compromise treatment compliance. Studies are in progress investigating the androgen receptor as a predictive and prognostic biomarker, in particular exploring the relationship between levels of androgen receptor and PI3K mutation and cross-over between androgen receptor and HER2 pathways.¹⁵

Triple-negative breast cancer 

Triple-negative breast cancers (TNBC) account for approximately 15-20% of all breast cancers. TNBC is characterised by tumours that do not express oestrogen receptor or progesterone receptor at all, and do not over-express HER2. TNBC constitutes a highly diverse group of cancers exhibiting significant genomic heterogeneity with at least six subtypes identified.¹⁷

Although chemo-sensitive in the adjuvant setting, advanced TNBC is usually aggressive and drug-resistant with no significant improvement in the overall survival of advanced TNBC in recent years. At present, the only standard of care is chemotherapy with poor outcomes and associated toxicities. Although this is an area of significant research effort in recent years, clinical trials have failed to identify benefit from specific chemotherapy with similar findings with the anti-angiogenic agent bevacizumab.¹⁸

Recent research has focused on whether existing chemotherapies have preferential benefit depending on the TNBC subtype, that is BRCA 1+ may be more sensitive to anthracyclines than sporadic TNBC. 

Additional systemic therapy after isolated local/regional TNBC recurrence has been shown to improve outcome. The benefit varies according to phenotype, with the data being strongest for those with oestrogen receptor-negative recurrence.¹⁹

Eribulin, a microtubule inhibitor, has been demonstrated to have a significant and clinically meaningful improvement in overall survival compared with TPC in women with heavily pre-treated metastatic breast cancer.²⁰ The phase III EMBRACE study, comparing eribulin to capecitabine, did not demonstrate statistically significant superiority of eribulin to capecitabine in either overall survival or progression-free survival. A trend favouring eribulin was evident in patients with oestrogen receptor-negative tumours, however, this improvement did not meet the pre-defined criteria for statistical significance.²¹

Several potentially targetable, although low frequency, genetic events have been described in TNBC.²² Increasingly recognised is the role of alteration in DNA damage repair pathways in TNBC. PARP1 inhibitors have been shown to induce tumour response in BRCA-mutated TNBC and may sensitise cisplatin in the triple- negative population as a whole.²³

Other targeted agents being developed with the hope of overcoming the heterogeneity in this setting include EGFR, FGFR2, mTOR and NOTCH inhibitors.

Locally advanced inoperable breast cancer, inflammatory and non-inflammatory

Locally advanced breast cancer (LABC) and inflammatory breast cancer (IBC), corresponding to American Joint Committee on Cancer stage IIIA and B, are frequently inoperable at presentation. The tumour node metastasis classification defines LABC by either involvement of the chest wall (T4a); ulceration (T4b); ipsilateral satellite skin lesions or oedema, or both (T4c), and IBC is classified as T4d. 

The shift in breast cancer epidemiology due to the introduction of screening programmes, improved education and therapeutic advances has seen an increase in the number of cases of breast cancer diagnosed at an early stage, and a corresponding decrease in locally-advanced and advanced-stage tumours worldwide. However, socio-economically deprived groups and ethnic/racial minorities remain at high risk. In recent US data (National Cancer Database 2010), stage III breast cancer constituted 10.7% of all invasive breast cancer cases. The highest incidence was seen in younger women, perhaps contributed to by the lack of screening in this group, and among women of African and Latino descent. Data in developing countries is lacking, however, the mortality-incidence ratio is highest in less developed nations in Africa and Asia where screening and treatment options are suboptimal. 

The incidence of IBC varies from 1% in Western Europe to 10% in North Africa. LABC occurs more frequently, the incidence varying from 4.5% in Western Europe/US up to 40% in some African nations. IBC most commonly affects women of African descent, typically occurs in younger patients and is associated with high body mass index. IBCs are usually higher-grade tumours and are frequently oestrogen receptor-negative (50%). A hallmark of IBC is E-Cadherin overexpression, MUC1 and p53 mutation. Recent research suggests ALK amplification and activation of the ALK pathway as a potential therapeutic target. 

The main recommendations are that all patients require multidisciplinary care with accurate staging. In the case of inoperable disease, systemic therapy is essential for down-staging patients who may become operable with either mastectomy or, in selected cases, breast-conserving surgery. All patients need radiotherapy. Clinical benefit with systemic chemotherapy ranges from 50-80%, however, the majority are partial responses.²⁴

Although clinical trials in the first-line metastatic setting have included patients with inoperable, locally recurrent disease, these numbers are often small and it is uncertain if the survival advantages can be generalised to this group.¹⁵

 (click to enlarge)

Conclusion

The need for high-quality, collaborative, internationally standardised guideline-based multidisciplinary care is gaining increased attention in oncology.²⁵ The ABC conference has seen the development of the first truly international consensus guidelines for advanced breast cancer, now being implemented worldwide. Dr Larry Norton, ABC co-chair and deputy physician-in-chief for Breast Cancer Programs at Memorial Sloan-Kettering Cancer Center, US, summarised: “The spirit of working together towards a common purpose and not separating physicians from patients is what makes this a special meeting and why it is successful and will make a difference.” 

While the awareness and understanding of the distinct challenges affecting this patient group is improving, there is still a great deal of work to be done. ‘Stop Cancer Now’ – an appeal by international experts following World Cancer Day last year – calls for new strategies in accessing evidence-based care for all patients and improved collaboration between physicians, researchers and pharmaceutical companies in the development of new therapies, with acceleration of the delivery of affordable and accessible therapies with real benefits worldwide.²⁶

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