Pilot Study of a Resource-Appropriate Strategy for Downstaging Breast Cancer in Rural Uganda

BREAST cancer is the most common cancer and an important cause of cancer-related mortality among women worldwide (1). The World Health Organization (WHO) estimates that by the year 2020, 70% of newly diagnosed breast cancer cases will occur in lowand middle-income countries (LMICs) (2). In Uganda, for example, the incidence of breast cancer is 32.3 per 100,000, and has increased by 5.2% per year over the past 15 years (1). Many Ugandan women with breast cancer are diagnosed in their thirties, an age when many are taking care of young children and managing their careers and households (3). For this and other reasons, breast cancer has become a major global health problem and has prompted the WHO to intervene (4). Low breast cancer awareness and absence of a screening program results in detection of 89% of all breast cancers in Uganda at later stages (stages III and IV) (5). Management of late-stage breast cancer is more expensive, technically demanding, and results in more morbidity and mortality (M&M) than that of early-stage breast cancer (3,5-8). This is true even in high-income countries (HIC). Thus, early detection is pivotal to cure and reduce M&M, irrespective of economical factors. The term “downstaging” may be used for shifting a population with late-stage breast cancers to early-stage cancers over a period of time through screening, or for an individual case where reduction in tumor size (stage) may be affected by neoadjuvant chemotherapy before curative surgery. Screening may be in the form of breast self-examination (BSE), clinical breast examination (CBE), mammography or ultrasound. In Uganda, breast cancer treatment is free through the Ugandan Cancer Institute (UCI), but neoadjuvant chemotherapy is not a viable option


Introduction
BREAST cancer is the most common cancer and an important cause of cancer-related mortality among women worldwide (1).The World Health Organization (WHO) estimates that by the year 2020, 70% of newly diagnosed breast cancer cases will occur in low-and middle-income countries (LMICs) (2).In Uganda, for example, the incidence of breast cancer is 32.3 per 100,000, and has increased by 5.2% per year over the past 15 years (1).Many Ugandan women with breast cancer are diagnosed in their thirties, an age when many are taking care of young children and managing their careers and households (3).For this and other reasons, breast cancer has become a major global health problem and has prompted the WHO to intervene (4).
Low breast cancer awareness and absence of a screening program results in detection of 89% of all breast cancers in Uganda at later stages (stages III and IV) (5).Management of late-stage breast cancer is more expensive, technically demanding, and results in more morbidity and mortality (M&M) than that of early-stage breast cancer (3,(5)(6)(7)(8).This is true even in high-income countries (HIC).Thus, early detection is pivotal to cure and reduce M&M, irrespective of economical factors.
The term "downstaging" may be used for shifting a population with late-stage breast cancers to early-stage cancers over a period of time through screening, or for an individual case where reduction in tumor size (stage) may be affected by neoadjuvant chemotherapy before curative surgery.Screening may be in the form of breast self-examination (BSE), clinical breast examination (CBE), mammography or ultrasound.In Uganda, breast cancer treatment is free through the Ugandan Cancer Institute (UCI), but neoadjuvant chemotherapy is not a viable option in large numbers of patients.Therefore, given the resources, the most resource-appropriate strategy seems to be downstaging through health awareness leading to increased rates of BSE and CBE.
According to the Breast Health Global Initiative (BHGI) guidelines, resource-appropriate strategies to downstage breast cancer in Uganda should include increased breast health awareness, so women begin to practice BSE and present early to their providers after self-detecting a lump (9,10).It is also important to train the providers in breast health to obtain appropriate history and physical examination including a proper CBE.Both BSE and CBE have the potential for a high false-positive rate and are, therefore, no longer recommended in countries where screening mammography is available (11)(12)(13).But, with one publically available mammography unit in the country, screening mammography is not a feasible option for most Ugandan women, particularly rural women.Ultrasound is more widely available, even in rural areas, and has the ability to characterize palpable masses detected by CBE as those requiring biopsy versus those that can safely be managed by imaging or clinical follow-up (14).
In accordance with the World Health Organization's recommendations to reduce the global burden of breast cancer (15), Imaging The World (ITW) developed a resource-appropriate strategy to downstage breast cancer.ITW is a non-profit organization with a global team of volunteers who provide ultrasound training, equipment and technology in LMICs to improve and sustain health outcomes (16).For this pilot study, we determined the feasibility of this breast cancer downstaging strategy in a rural, low-resource setting (Kamuli District, Uganda), specifically in terms of: (1) training village health teams (VHTs) to provide breast cancer awareness, and (2) training sonographers to perform and interpret breast ultrasound.

Study team and settings
Imaging the World Africa (ITWA) is a registered nongovernmental organization (NGO) in Uganda, and locally executes ITW's mission with a team of physicians, midwives, sonographers and support staff.This pilot project was conducted in the Kamuli District, at the Nawanyago Clinic Health Centre III (Nawanyago HCIII) and Kamuli Mission Hospital (Referral Hospital), between March and August 2013.

Study overview
This IRB-approved prospective study evaluated the feasibility of the ITW breast cancer downstaging strategy (Figure 1).Women <18 years, pregnant or acutely ill were excluded.ITW trained VHTs to educate women on breast cancer and the importance of presenting early after self-detecting a breast lump.Women with a self-detected lump presented to Nawanyago HCIII for evaluation, which included a CBE by a trained provider.Women with a positive CBE received a triaging breast ultrasound by an ITWA-trained sonographer, and referred those women with a suspicious mass to the referral hospital for further evaluation and potential biopsy by an ITWA-trained surgeon.
Patients receiving a breast cancer diagnosis were referred to the UCI for treatment.Patients travelled to the UCI by bus and were met at the bus stop in Kampala by an ITWA patient navigator.The UCI provided standard-of-care treatment (17) at no cost to the patient, and the patient navigator helped arrange necessary medical tests, doctor's appointments, and treatment.

Breast ultrasound training
ITWA held a three-day workshop and five days of apprenticeship to teach a certified sonographer with prior breast imaging experience to perform and interpret breast ultrasound (Figure 2) using the American College of Radiology (ACR) Breast Imaging Reporting and Data System (BI-RADS) (18).

VHT training
ITWA trained VHTs to promote breast cancer awareness at events advertised through the local radio and television.VHTs educated women at these events on breast cancer and the importance of presenting early after self-detecting a lump.

Breast ultrasound imaging equipment and peer review
Ultrasound imaging at the Nawanyago HC III was performed on a Philips (Royal Philips, Amsterdam, Netherlands) ClearVue 350 with a L12-4 MHz transducer.The sonographer used a standardized volumetric scanning protocol performed by sweeping the transducer over the entire palpable area, as described previously.Ultrasound data was managed via a PACS-compatible electronic medical records system, which enabled site data entry and remote database access.An American board-certified radiologist reviewed all images remotely in the United States and signed off on their interpretations using peerVue (peerVue, Inc., Sarastoa, FL, USA), a commercial Webbased system, for quality assurance.The sonographer communicated any changes in the interpretation to the patient.

Data analysis
For this study, we collected the data at each point of care and their outcomes, including contacting women with negative and benign results one year after the examination.Performance measures for CBE and ultrasound included cancer detection rate (CDR; per 1,000 CBEs); abnormal CBE interpretation rate; positive predictive value (PPV) 2 (recommendation for tissue diagnosis); PPV3 (biopsy performed); sensitivity, specificity, and percent minimal cancers, according to the ACR BI-RADS manual, 5th edition (18).The percent of women managed locally with BI-RADS 1, 2, or 3 ultrasound findings that obviated the need for travelling to the referral hospital and concordance between the sonographer and the American board-certified radiologist were also calculated.Calculations were performed using Microsoft Excel (Microsoft Corporation, Redmond, WA).

Breast cancer downstaging strategy performance
The 212 women consenting to participate in this study averaged 33 years of age.(median: 29 years; range: 17-70).The observed and calculated performance of the ITW breast cancer downstaging strategy is depicted in Table 1.Forty-four women (21%) presenting for evaluation at the Nawanyago HCIII had a positive CBE and received a breast ultrasound.Eleven (25%) were interpreted as BI-RADS 1 or 2, 22 (50%) as BI-RADS 3, and 11 (25%) as BI-RADS 4 or 5.No breast ultrasound was interpreted as BI-RADS 0 or 6.
Four women (36%) with a biopsy recommendation (BI-RADS 4 or 5) traveled to the referral hospital and received a biopsy, and all were diagnosed with breast cancer (Figure 3).Of the seven women with a biopsy recommendation who did not receive a biopsy, three declined, one died prior to biopsy, two converted to BI-RADS 1 after antibiotic therapy or lactation ended, and one was lost to follow-up.

Breast cancer outcomes
Of the four cancers detected during the trial period, two represented early-stage and two late-stage breast cancer.Of the two women with late-stage breast cancer, one died prior to treatment at 11 months post-diagnosis, and one died during treatment at nine months post-treatment.The two women with early-stage breast cancer have completed treatment (chemotherapy, radiation, and surgery) at the UCI, are taking Tamoxifen and are being monitored for recurrence at the Nawanyago HC III.

Performance of front-line sonographers at Nawanyago HCIII
Interpretation by the sonographer at the Nawanyago HCIII showed 91% (40/44) concordance with the American board-certified radiologist.Three of the discordant examinations upgraded from BI-RADS 3 to BI-RADS 4 and one upgraded from BI-RADS 2 to BI-RADS 3. One of these discordant examinations (upgraded from BI-RADS 3 to BI-RADS 4) was biopsied and represented breast cancer.

Discussion
Currently, women presenting to the Nawanyago HCIII with symptoms receive a CBE, and those with a positive CBE are referred to a regional hospital located a long distance away for further evaluation and potential biopsy.The costs associated with travel and time away from work and family responsibilities represent a significant barrier to breast cancer detection services.This is partially responsible for delayed diagnosis and high mortality (19).For this pilot project, we trained certified sonographers with previous breast ultrasound experience to perform and interpret breast ultrasound using BI-RADS following a positive CBE at the Nawanyago HCIII.
Using the data from this pilot study, we demonstrate the feasibility of the ITW breast cancer downstaging strategy in rural Uganda.ITW leveraged existing VHTs to promote breast cancer awareness in the community and trained a sonographer with breast imaging experience to perform and interpret breast ultrasound using BI-RADS at the Nawanyago HCIII.We further demonstrate how this strategy reduced by 75 percent the number of women travelling to the referral hospital, in many cases long distances, just for diagnostic breast ultrasound.Through ITWA's health awareness program and ultrasound we detected breast cancers in stages earlier than they would have been detected without our interventions (i.e.downstaged).Shortage of regional referral centers in the country limits patient access to centers where women can receive imaging evaluation for palpable lumps.Other NGOs in Uganda are involved in training sonographers to use basic ultrasound techniques at community health centers (HCIIIs) to triage pregnant women with potential obstetric complications to district hospitals (20)(21)(22).Similarly, ITWA's efforts to train sonographers to characterize breast masses at the level of HCIIIs would not only help to downstage breast cancer, but also reduce the number of women travelling unnecessarily to referral hospitals for nonmalignant breast lumps.
Aiming to downstage breast cancer using available resources represents an essential starting point for interventions addressing breast cancer mortality in LMICs.While this pilot study was performed to determine feasibility of the ITW strategy, we note that two of the four breast cancers (50%) detected by this strategy represented early-stage disease, which is lower than the proportion of early-stage disease reported in the Ugandan literature (10%)   (5).While there is no evidence for improved survival from our intervention, both women diagnosed with early-stage breast cancer received curative treatment (surgery, chemotherapy, and radiation) at the UCI and have returned to their communities.CBE performed by ITW-trained providers demonstrated a CDR of 19 breast cancers per 1,000 women evaluated.A previous study from India showed a CDR of 10.4 per 1,000 women (23).We attribute the higher CDR observed in our study to the higher incidence of breast cancer in Uganda (32.3 per 100,000) compared to India (20 per 100,000) and the inclusion of only symptomatic women in our study (23,24).We further demonstrate interpretive performance for PPV2 and 3 that are within the performance ranges published previously (2-96%) (25-28).Our specificity was lower than in these studies (49-97%), which reflects the high proportion of women presenting with masses assessed as BI-RADS 3 (46%), and also the high proportion of young women presenting for evaluation.Since BI-RADS 3 masses were followed by ultrasound locally, these women did not require travel to the referral hospital for further evaluation.The performance of the ITW strategy in this setting highlights the success of the ITW training program and suggests that training sonographers to perform and interpret breast ultrasound at HCIIIs is a resource-appropriate strategy for breast cancer detection in Uganda.The sonographer's 91% concordance rate with an Americantrained radiologist was within the expected inter-observer variability observed in other studies (29,30).Future efforts to train sonographers to perform and interpret breast ultrasound at HCIIIs should improve the telemedicine capacity of Ugandan radiologists to provide peer review and ensure sustainability.
There are several potential limitations of this pilot study.First, CBE and BSE as screening strategies are no longer recommended in the United States; however, these recommendations do not apply in Uganda, where screening mammography is not available.Indeed, the National Comprehensive Cancer Network (NCCN) recommends BSE because it is essential for women to first detect abnormalities in their own breasts before they can present for evaluation (31).In addition, seven women recommended for a biopsy did not receive one, which may have reduced performance measures.This low adherence to biopsy recommendations also emphasizes the challenges facing downstaging efforts in Uganda.As this program expands, we will add curricula to VHT training programs that will address barriers to adhering to biopsy recommendations.
In summary, we demonstrate the feasibility of the ITW breast cancer downstaging strategy in rural Uganda.This strategy combines VHTs providing breast cancer awareness in the community to encourage women to present early after self-detecting a lump, and CBE plus breast ultrasound provided at a HCIII to reduce the number of women traveling to the referral hospital.In the future, we will expand this program into other districts, in collaboration with the Ugandan Ministry of Health and local providers, and collect pre-intervention tumor sizes to demonstrate downstaging with this strategy.

Figure 1 .
Figure 1.Imaging The World breast cancer downstaging strategy.

Figure 2 .
Figure 2. Ugandan sonographer undergoing ultrasound training on a breast phantom.

Figure 3 .
Figure 3. Ultrasound images of a mass from a woman presenting with a palpable lump to Nawanyago HCIII.Biopsy of this mass showed breast cancer.

Table 1 .
Performance Measures of Breast Ultrasound.

Variable Observed Outcomes -Health Center III Number
CBE: Clinical Breast Examination US: Ultrasound BR: BI-RADS PPV: Positive Predictive Value