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Report from the San Antonio Breast Cancer Symposium

Breast cancerrOLe Of LOcaL cONtrOL iN metastatic disease

Caroline Lohrisch, MD, FRCPC bc cancer agency, Vancouver centre

TRiaL SuMMaRy: Surgery and radiation for metastatic breast cancerbadwe r, Parmar V, Hawaldar r, et al. surgical removal of primary tumour and axillary lymph nodes in women with metastatic breast cancer at first presentation: a randomized controlled trial, sabcs s2-02.

This study randomized 350 patients with metastatic breast cancer who had received and responded to chemotherapy to either breast surgery with subsequent radiation therapy or to no local therapy. Salvage local therapy was allowed for bleeding or wound control. At 72 months, overall survival (OS) was 20.5% for patients who underwent surgery and 19.2% for those treated without surgery. The hazard ratio (HR) for surgery was 1.04 and was not significant. Although local progression-free survival (PFS) was better with local therapy (HR=0.16), distant PFS was worse (HR=1.42; p=0.01), suggesting that removal of the primary tumour may enable growth of distant metastases.

TRiaL SuMMaRy: Resection in de novo stage iV breast cancersoran a, Ozmen V, Ozbas s, et al. early follow up of a randomized trial evaluating resection of the primary breast tumour in women pre-senting with de novo stage iV breast cancer; turkish study (protocol mf07-01) sabcs s2-03.

This study involved 278 patients randomized to receive either initial local therapy (surgery with appropriate radiation) plus systemic therapy, or systemic therapy alone. Patients received hormone therapy (86.4% of patients in the surgery arm and 72.3% in the systemic treatment arm had estrogen receptor/progesterone receptor [ER/PR]-positive disease) and trastuzumab (30.7% of patients in the surgery arm and 30.4% in the systemic treatment arm were human epidermal growth factor receptor 2 [HER2]-positive) as per standard of care. All patients received chemotherapy. Median followup was 18 months in the surgery arm and 17 months in the systemic treatment arm.

FinDingSOverall, 38 deaths occurred in the surgical treatment arm and 48 deaths occurred in the systemic treatment arm. Median OS was 46 months in the surgery group and 42 months in the systemic treatment group. The HR of 0.76 (95% confidence interval [CI], 0.49–1.16) for death favoured surgery, but was not statistically different from the no-surgery group. Surgery appeared to numerically improve outcome

for patients with ER/PR-positive tumours (HR=0.77; 95% CI 0.45–1.31) but worsen outcome in ER/PR-negative tumours (HR=1.47; 95% CI 0.70–3.12), however in both cases the differences were not statistically significant. The role of surgery was explored in other subsets, such as bone-only metastases (HR=0.6; 95% CI 0.3–1.22), solitary bone metastases (HR=0.23; 95% CI 0.06–0.89), age less than 55 years (HR=0.62; 95% CI 0.34–1.14), and multiple liver or pulmonary metastases (HR=3.85; 95% CI 1.12–13.25), however most of these were not significant and the study was not powered for multiple comparisons.

CoMMenTaRy: Whether optimal locoregional control of the primary tumour influences survival in breast cancer presenting with disseminated metastases has long been debated. Some retrospective series support and others refute a benefit for local therapy, but all are plagued with selection bias. Patients with minimal metastatic burden or excellent response to induction therapy are more likely to undergo surgery of the primary tumour, characteristics which are also associated with more indolent disease and a longer natural history.

Patients and clinicians have polarized opinions about this question, making prospective randomized trials challenging to execute. For example, a North American trial was forced to adjust its target after 5 years, due to slow accrual. In this respect, investigators of the 2 randomized trials presented at the 2013 San Antonio Breast Cancer Symposium are to be congratulated for successfully completing accrual in tri-als addressing this important question.

These trials are worth considering together, given they addressed the same question. Systemic therapy was uniform in the surgical and non-surgical groups in both trials. In the Badwe trial, cancers had to respond to induction chemo-therapy to be eligible, whereas in the Soran trial, random-ization preceded any systemic therapy. Thus the Badwe trial explored the question of local control in more responsive, potentially more indolent, disease than did the Soran trial, both having survival as the primary endpoint. Surprisingly, survival was shorter in the Badwe study, though this is likely due to several factors, including lack of anti-HER2 therapy in HER2+ cancers (28% of the Badwe study population), fewer ER+ cancers (60% versus 80% in the Soran study), higher disease burden (74% in the Badwe study had >3 disease sites; 40% in Soran study had >1 organ involved), and differences between the 2 trials in downstream systemic therapies, which were not discussed.

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More importantly, neither trial could demonstrate a favourable impact on survival of aggressive local therapy.

In BrIEFalready known• Physiciansarepolarizedaboutthebenefitsoflocal

surgery and radiation in patients presenting with metastatic breast cancer at initial diagnosis.

What this study showed• Neitherstudyfoundanybenefitfromlocaltherapy

in Pfs or Os for any patient subgroup.• Distantmetastasesactuallyincreasedwithaggressive

local therapy in some subgroups.

next steps• Thisquestionhasbeendifficulttostudyandthese2trials

present some of the only data likely to be produced.• Physicianscandefendthepositionthatlocaltherapy

does not influence survival in patients presenting with metastatic breast cancer, and focus on systemic management.

HRs were close to 1, CIs crossed unity, and p values were not significant, suggesting a larger trial is unlikely to con-tradict their findings. Although not powered for multiple subset analyses, Soran and colleagues were not able to identify any subgroup for which aggressive local control might be an advantage. In fact, Badwe showed a HR for PFS of 1.42 (1.01–1.85, p=0.01) favouring no local surgery, suggesting that aggressive local control might adversely affect distant disease control.

These 2 randomized trials show no role in enhancing survival with aggressive local management among patients presenting with metastatic breast cancer at initial diagnosis, and it is unlikely that a greater wealth of data on this ques-tion is forthcoming. While the finding of decreased local control among patients undergoing surgery is intriguing, it can only be considered hypothesis-generating. For the occasional patient with a low burden of distant disease that is highly responsive to initial therapy, it may remain attrac-tive or appropriate to optimize local therapy. However, cli-nicians can use these data to defend the position that local management does not influence survival in the majority of cases presenting with primary and disseminated disease simultaneously. Optimal systemic management in such cases should remain the primary focus of care.

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