A brief summary of the population impact of current knowledge and common interventions
Causation and prevention While much is known about the multistage and multifactorial causal biology of breast cancer, practical interventions that change outcomes, here meaning preventing clinical breast cancer, are limited to relatively small populations of high-risk individuals, who are most frequently citizens of highincome countries. Broad preventive interventions that change outcomes for populations are not available. For examples, avoidance of obesity in postmenopausal women and early age at first full-term pregnancy appear to reduce the risk of disease but applying this knowledge to populations is unfeasible and impractical.
Down-staging "Early detection" of breast cancer that results in lower stage disease at the time of diagnosis, generically called "down-staging," has been long promoted as a strategy for improving outcomes from treatment. Intuitively, this concept is compelling, but in practice it has been remarkably difficult to support with rigorous data and even more challenging to apply to populations with convincing proof of benefit.
In clinical practice at present, only two downstaging strategies are applicable: mammography and clinical breast examination. Broadly, true "screening" mammography, that is mammography done in women without any signs or symptoms of clinical breast cancer, appears to be beneficial in populations of women aged 50 and older with higher incidence rates. 5 There are variable, but not insignificant, costs associated with applying this technology to such populations; the most important is diagnosis and treatment of premalignant lesions which would never have progressed to become clinical breast cancer in patients' lifetimes, (overdiagnosis). 5 In individual women of any age and risk level, with no signs or symptoms of clinical breast cancer, the benefits of periodic breast examination are unproven, whether conducted by women themselves or by health professionals. 5 As applied to populations in low-and middleincome countries (LMCs), with broad-based population pyramids and low absolute incidence rates, the practical implications of these state-of-theart assessments have been well summarized by Harford: "Resources in LMCs might be better used to…encourage more women with palpable breast lumps to seek and receive treatment in a timely manner." 6 Diagnosis The potential benefits of prompt diagnosis, which may include less costly treatment, can only be realized in populations with strong primary health care systems and their associated greater public trust. The most remarkable demonstration of this truth occurred in the International Agency for Research on Cancer (IARC) trial of breast self-examination in the Philippines. 7 Women were successfully taught to find their own smaller breast tumors but decided not to seek diagnostic interventions because they did not believe that they could be successfully treated or that they had the financial resources for treatment. 7 The repeated assessment that more women need to be "made aware" of the significance of breast lumps is misplaced. Women of all levels of education and in multiple cultures easily recognize when they have an abnormality in one of their breasts. "Awareness" is not the barrier that prevents women from seeking medical assistance. 7 The strength of their local primary care networks and the prevailing human rights barriers are far more important issues.
Beyond these practical issues concerning if and when women present for diagnosis, the local surgical pathology capacities in many LMCs are so limited that histological diagnosis is often not accomplished when women do present with clinical signs of breast cancer. 8 In high-income countries, molecular characterization of histologically invasive tumors contributes to choosing more effective treatments, but the monetary costs and low availability of genomic testing prevent widespread application in LMICs. 9 Treatment The primary treatment for operable invasive breast cancer is mastectomy which is widely available under the care of qualified surgeons in most LMICs. A second major surgical intervention, adjuvant surgical oophorectomy, is worthy of consideration in premenopausal hormone receptor positive women, a number approaching half of all global new breast cancer cases annually, yet is significantly underapplied. 10 Human rights issues, barriers to care, and financial conflict of interest all play unfortunate roles in this situation. 10 This is particularly tragic because of provocative data strongly suggesting that, once women with prolonged follicular phases are exempted, the average benefit of surgical oophorectomy to women in follicular or luteal phases (easily confirmed by progesterone testing) exceeds the level of benefit from optimally given adjuvant treatments which are not received among high percentages of women in LMICs in any case. 11 The widespread presentation of this treatment option to women in LMICs could save 100,000 lives annually 12 .
A major contributor to improved outcomes with breast cancer in high income countries has been the development of effective systemic therapies. In the decade from 2008-2017 in the United States, breast cancer mortality declined by 16% 14 . However, selection of optimal systemic therapies for individual patients is remarkably complex and ever-evolving. 9 In LMICs, the dearth of well-trained medical oncologists, as well as multiple operational barriers, stand in the way of applying these new treatments widely. Even with remarkably effective and cheap systemic treatments with limited side effects, such as oral tamoxifen for the two-thirds of global cases with hormone receptor positive tumors, the benefits are highly limited by poor long-term adherence. 13 Current evidenced-based treatment guidelines recommend adjuvant radiation therapy to the chest wall and regional lymph nodes in patients with high risk but operable breast cancer. 14 The availability and feasibility of such treatment in the high fraction of women in LMICs who could benefit are painfully limited. 17 Approximately half of all breast cancer patients in LMICs have incurable recurrent disease and need palliative care. Very few women, however, have access to such care, and when available, few receive care of a caliber to make a difference in their quality of life. 1516 Big picture realities and lessons of the time The dominance of business models in medicine, and lessons from the COVID pandemic in the United States suggest that more public health thinking needs to be applied to this disease if significantly better outcomes for populations are to be achieved (Table 1). 4,20 Table 1. Lessons from COVID pandemic 1516 Widespread lack of access to medical care Overdependence on doctors Overdependence on clinics and hospitals Inadequate systems for chronic care and prevention Lack of attention to mental health Massive disparities in healthcare Specifically, current educational activities emphasize biology and ignore social determinants of health, explicit values, and important quality-of -care metrics. 1718 Service models are relatively inattentive to this chronic disease, have limited community accountability, and are dysfunctional and poorly organized. Transformational service models are needed with increased paraprofessional staffing, implemented diagnostic and treatment guidelines, major information technology systems, and disruptive business systems (Table 2). 1920212223 Specific targeting activities identified Firstly, the foregoing summary is clear in suggesting unproductive as well as potentially beneficial activities in our educational endeavors (Table 3). Table 2. Medical service models compared modified from 18 Secondly, our system challenges can most practically be met by development of local demonstration/experimentation initiatives. Greater consideration needs to be given to community activities and organizations directed to addressing the social determinants of health. In the clinical setting, it is of significant importance to recognize that while specific breast cancer care components should be targeted (surgical pathology or radiation therapy, for example), improving outcomes for populations is going to require strengthening primary care systems. Trust in the local medical care system is critical to prompt diagnosis, efficient management, and sustained adherence to evidence-based treatment. Such trust is grounded in truly community-oriented primary care.