Indraneel Mittra

Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial

Summary Background For women with oestrogen receptor (ER)-positive early breast cancer, treatment with tamoxifen for 5 years substantially reduces the breast cancer mortality rate throughout the first 15 years after diagnosis. We aimed to assess the further effects of continuing tamoxifen to 10 years instead of stopping at 5 years. Methods In the worldwide Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial, 12u2008894 women with early breast cancer who had completed 5 years of treatment with tamoxifen were randomly allocated to continue tamoxifen to 10 years or stop at 5 years (open control). Allocation (1:1) was by central computer, using minimisation. After entry (between 1996 and 2005), yearly follow-up forms recorded any recurrence, second cancer, hospital admission, or death. We report effects on breast cancer outcomes among the 6846 women with ER-positive disease, and side-effects among all women (with positive, negative, or unknown ER status). Long-term follow-up still continues. This study is registered, number ISRCTN19652633. Findings Among women with ER-positive disease, allocation to continue tamoxifen reduced the risk of breast cancer recurrence (617 recurrences in 3428 women allocated to continue vs 711 in 3418 controls, p=0·002), reduced breast cancer mortality (331 deaths vs 397 deaths, p=0·01), and reduced overall mortality (639 deaths vs 722 deaths, p=0·01). The reductions in adverse breast cancer outcomes appeared to be less extreme before than after year 10 (recurrence rate ratio [RR] 0·90 [95% CI 0·79–1·02] during years 5–9 and 0·75 [0·62–0·90] in later years; breast cancer mortality RR 0·97 [0·79–1·18] during years 5–9 and 0·71 [0·58–0·88] in later years). The cumulative risk of recurrence during years 5–14 was 21·4% for women allocated to continue versus 25·1% for controls; breast cancer mortality during years 5–14 was 12·2% for women allocated to continue versus 15·0% for controls (absolute mortality reduction 2·8%). Treatment allocation seemed to have no effect on breast cancer outcome among 1248 women with ER-negative disease, and an intermediate effect among 4800 women with unknown ER status. Among all 12u2008894 women, mortality without recurrence from causes other than breast cancer was little affected (691 deaths without recurrence in 6454 women allocated to continue versus 679 deaths in 6440 controls; RR 0·99 [0·89–1·10]; p=0·84). For the incidence (hospitalisation or death) rates of specific diseases, RRs were as follows: pulmonary embolus 1·87 (95% CI 1·13–3·07, p=0·01 [including 0·2% mortality in both treatment groups]), stroke 1·06 (0·83–1·36), ischaemic heart disease 0·76 (0·60–0·95, p=0·02), and endometrial cancer 1·74 (1·30–2·34, p=0·0002). The cumulative risk of endometrial cancer during years 5–14 was 3·1% (mortality 0·4%) for women allocated to continue versus 1·6% (mortality 0·2%) for controls (absolute mortality increase 0·2%). Interpretation For women with ER-positive disease, continuing tamoxifen to 10 years rather than stopping at 5 years produces a further reduction in recurrence and mortality, particularly after year 10. These results, taken together with results from previous trials of 5 years of tamoxifen treatment versus none, suggest that 10 years of tamoxifen treatment can approximately halve breast cancer mortality during the second decade after diagnosis. Funding Cancer Research UK, UK Medical Research Council, AstraZeneca UK, US Army, EU-Biomed.

Multicentricity of breast cancer: whole-organ analysis and clinical implications

We studied the spatial relationship within the breast between multicentric foci (MCF) and the primary tumour in 30 modified radical mastectomy specimens using Egans correlated pathological-radiological method using 5 mm slices of the whole breast. The relative positions within the breast of the primary tumour and MCF were used to calculate the relative distribution of primary tumour and MCF in the four quadrants of the breast and the per cent breast volume that would be required to be excised to include all MCF. Nineteen (63%) breast harboured MCF. The relative distribution of primary tumour and MCF in the four breast quadrants was significantly different (P = 0.034). MCF were present beyond the index quadrant (25% of breast volume including the tumour) in as many as 79% (15/19) of breasts that harboured MCF; and in half the cases (15/30) when all breast were considered. This is in variance with the suggestion put forward previously that MCF are contained within the index quadrant in 90% of cases. Although the number of patients in the present series is small, the probability of our finding being due to play of chance is 1 in 1500. In a large series of breast conservation studies > 90% of early breast recurrences have been found to occur in the index quadrant. Our finding, that in half the patients (15/30) MCF are present in quadrants other than the index quadrant, suggests that MCF do not give rise to early breast recurrence.

A cluster randomized, controlled trial of breast and cervix cancer screening in Mumbai, India: methodology and interim results after three rounds of screening

Cervix and Breast cancers are the most common cancers among women worldwide and extract a large toll in developing countries. In May 1998, supported by a grant from the NCI (US), the Tata Memorial Hospital, Mumbai, India, started a cluster‐randomized, controlled, screening‐trial for cervix and breast cancer using trained primary health workers to provide health‐education, visual‐inspection of cervix (with 4% acetic acid‐VIA) and clinical breast examination (CBE) in the screening arm, and only health education in the control arm. Four rounds of screening at 2‐year intervals will be followed by 8 years of monitoring for incidence and mortality from cervix and breast cancers. The methodology and interim results after three rounds of screening are presented here. Good randomization was achieved between the screening (n = 75360) and control arms (n = 76178). In the screening arm we see: High screening participation rates; Low attrition; Good compliance to diagnostic confirmation; Significant downstaging; Excellent treatment completion rate; Improving case fatality ratios. The ever‐screened and never‐screened participants in the screening arm show significant differences with reference to the variables religion, language, age, education, occupation, income and health‐seeking behavior for gynecological and breast‐related complaints. During the same period, in the control arm we see excellent participation rate for health education; Low attrition and a good number of symptomatic referrals for both cervix and breast.

Effect of VIA Screening by Primary Health Workers: Randomized Controlled Study in Mumbai, India

BACKGROUNDnCervical cancer is the leading cause of cancer mortality among women in India. Because Pap smear screening is not feasible in India, we need to develop effective alternatives.nnnMETHODSnA cluster-randomized controlled study was initiated in 1998 in Mumbai, India, to investigate the efficacy of visual inspection with acetic acid (VIA) performed by primary health workers in reducing cervical cancer mortality. Four rounds of cancer education and VIA screening were conducted at 24-month intervals in the screening group, whereas cancer education was offered once at entry to the control group. The study was planned for 16 years to include four screening rounds followed by four monitoring rounds. We present results after 12 years of follow-up. Poisson regression method was used to calculate the rate ratios (RRs); two-sided χ(2) was used to calculate the probability.nnnRESULTSnWe recruited 75360 women from 10 clusters in the screening group and 76178 women from 10 comparable clusters in the control group. In the screening group, we achieved 89% participation for screening and 79.4% compliance for diagnosis confirmation. The incidence of invasive cervical cancer was 26.74 per 100000 (95% confidence interval [CI] = 23.41 to 30.74) in the screening group and 27.49 per 100000 (95% CI = 23.66 to 32.09) in the control group. Compliance to treatment for invasive cancer was 86.3% in the screening group and 72.3% in the control group. The screening group showed a statistically significant 31% reduction in cervical cancer mortality (RR = 0.69; 95% CI = 0.54 to 0.88; P = .003).nnnCONCLUSIONSnVIA screening by primary health workers statistically significantly reduced cervical cancer mortality. Our study demonstrates the efficacy of an easily implementable strategy that could prevent 22000 cervical cancer deaths in India and 72600 deaths in resource-poor countries annually.

Role of ultrasonography to detect axillary node involvement in operable breast cancer

Prompted by the concern about unnecessary axillary dissections, we prospectively studied the accuracy of clinical examination (CE) and conventional ultrasonography (USG, 7.5 MHz), to diagnose pre-operatively metastatic axillary lymph nodes in 200 operable breast cancer patients. USG had higher specificity (90% vs 77%, P = 0.025) and higher positive predictive value (ppv = 90% vs 76%, P = 0.02) than CE. Together, CE + USG had higher sensitivity (82% vs 58%, P = 0.00005) and higher negative predictive value (npv = 76% vs 58%, P = 0.008) than CE alone. In women < 45 years, CE + USG had higher sensitivity (91% vs 76%, P = 0.037) and npv (89% vs 67%, P = 0.018) than in older women. The sensitivity and npv of CE + USG to detect > 1 positive node were 97% (for both) in women < 45 years compared to 81% and 79% in older women. The high sensitivity of CE + USG (82% for the whole group) is probably due to the higher proportion of young women (median age = 45) in our population. It suggests that using CE + USG to avoid axillary dissection in some patients is feasible.

A meta-analysis of reported correlations between prognostic factors in breast cancer: Does axillary lymph node metastasis represent biology or chronology?

A statistical overview of published results on correlations between various prognostic factors in breast cancer was undertaken. A distinction was made between clinical (or anatomical) prognostic factors--namely, axillary lymph node status and tumour size--and eight different biological prognostic factors. The latter included: tumour grade, oestrogen and progesterone receptor status, thymidine labelling index, DNA ploidy, S-phase fraction, epidermal growth factor receptor expression and c-erbB-2 gene amplification (or overexpression). 139 articles were eligible for review which reported a total of 432 individual correlations. A simple form of meta-analysis was employed: the counting method, in which the number of studies achieving a statistically significant correlation or not were counted. For each possible correlation examined, the proportion of studies showing a statistically significant correlation was calculated and an exact binomial 99% confidence interval determined for that proportion. If the 99% confidence interval included 5% (the proportion of correlations that would be expected to be statistically significant if the null hypothesis was true), it was taken as failing to exclude the null hypothesis of a zero correlation, while if it excluded 5% it was taken as rejecting the null hypothesis of a zero correlation. A broad agreement was found among published reports on the existence of a statistically significant correlation between the various biological prognostic factors in breast cancer. Of the 20 correlations examined, 18 had a 99% confidence interval excluding 5%, thus rejecting the null hypothesis of a zero correlation. On the other hand, a completely different result was obtained when reports on possible correlations between lymph node status and tumour size on the one hand and the eight biological prognostic factors on the other were analysed. Of the 16 correlations examined, 13 had a 99% confidence interval including 5%, failing to reject the null hypothesis of a zero correlation. These observations suggest the hypothesis that the prognostic influence of node status and tumour size cannot be explained by an analysis of the biology of breast cancer; and is compatible with the contention that axillary node status is merely a reflection of the relative chronological age of breast cancer.

Is clinical breast examination an acceptable alternative to mammographic screening

Breast cancer screening and mammography have almost become synonymous in the public perception, yet this should not necessarily be the case. Ideally, a screening tool for breast cancer would reduce mortality from breast cancer while having a low false alarm rate and being relatively cheap. Screening should not be at the expense of the symptomatic services nor inappropriately divert scarce resources away from equally deserving areas of the NHS that are less politically sensitive.1nnAn ideal screening test would be simple, inexpensive, and effective. Of the three modalities of breast cancer screening—breast self examination, clinical breast examination, and mammography—breast self examination fulfils the first two criteria, but early results of two randomised trials conducted in Russia and China suggest that it would not be effective in reducing mortality from breast cancer. 2 3 Clinical breast examination is also relatively simple and inexpensive, but its effectiveness in reducing mortality from breast cancer has not been directly tested in a randomised trial. Mammography is complex, expensive, and only partially effective. We believe that there is sufficient circumstantial evidence to suggest that clinical breast examination is as effective as mammography in reducing mortality from breast cancer and that the time has come to compare these two screening methods directly in a randomised trial.nn#### Summary pointsnnThe goal of breast screening is to prevent death and not simply to detect cancers by mammographynnMammography does detect some cancers “early,” but many of these are not potentially lethal and their detection causes needless anxietynnClinical breast examination is more likely to detect cancers that are potentially lethalnnResults of the second Canadian national breast screening study suggest that mammographic detection of cancers that are not palpable does not affect mortalitynnNew GMC guidelines on informed consent state that women in the NHS breast screening programme should …

Single-Injection Depot Progesterone Before Surgery and Survival in Women With Operable Breast Cancer: A Randomized Controlled Trial

PURPOSEnMany nonrandomized studies have suggested better outcome for patients with breast cancer who undergo surgery during the luteal (progestogenic) phase of their menstrual cycle, but this is controversial. We investigated the effect of a single preoperative injection of hydroxyprogesterone in women with operable breast cancer (OBC) in a randomized controlled trial (ClinicalTrials.gov identifier, NCT00123669).nnnPATIENTS AND METHODSnOne thousand patients with OBC were randomly assigned to receive surgery or an intramuscular injection of depot hydroxyprogesterone 500 mg 5 to 14 days before surgery. Primary and secondary end points were disease-free survival (DFS) and overall survival (OS), respectively. An analysis by axillary lymph node status was preplanned.nnnRESULTSnAt a median follow-up of 65 months among 976 eligible patients, 273 recurrences and 202 deaths were recorded. In the progesterone group versus control group, 5-year DFS and OS rates were 73.9% v 70.2% (hazard ratio [HR], 0.87; 95% CI, 0.68 to 1.09; P = .23) and 80.2% v 78.4% (HR, 0.92; 95% CI, 0.69 to 1.21; P = .53), respectively. In 471 node-positive patients, the 5-year DFS and OS rates in the progesterone group versus control group were 65.3% v 54.7% (HR, 0.72; 95% CI, 0.54 to 0.97; P = .02) and 75.7% v 66.8% (HR, 0.70; 95% CI, 0.49 to 0.99; P = .04), respectively. In multivariate analysis, DFS was significantly improved with progesterone in node-positive patients (adjusted HR, 0.71; 95% CI, 0.53 to 0.95; P = .02), whereas there was no significant effect in node-negative patients (P for interaction = .04).nnnCONCLUSIONnA single injection of hydroxyprogesterone before surgery did not improve outcomes in all women with OBC. This intervention showed significant improvement in node-positive women that may be considered hypothesis generating. If replicated in other studies, this could be a simple and inexpensive intervention, especially in developing countries where the incidence of lymph node metastasis is high.

Nucleic acids in circulation: Are they harmful to the host?

It has been estimated that 1011–1012 cells, primarily of haematogenous origin, die in the adult human body daily, and a similar number is regenerated to maintain homeostasis. Despite the presence of an efficient scavenging system for dead cells, considerable amounts of fragmented genetic material enter the circulation in healthy individuals. Elevated blood levels of extracellular nucleic acids have been reported in various disease conditions; such as ageing and age-related degenerative disorders, cancer; acute and chronic inflammatory conditions, severe trauma and autoimmune disorders. In addition to genomic DNA and nucleosomes, mitochondrial DNA is also found in circulation, as are RNA and microRNA. There is extensive literature that suggests that extraneously added nucleic acids have biological actions. They can enter into cells in vitro and in vivo and induce genetic transformation and cellular and chromosomal damage; and experimentally added nucleic acids are capable of activating both innate and adaptive immune systems and inducing a sterile inflammatory response. The possibility as to whether circulating nucleic acids may, likewise, have biological activities has not been explored. In this review we raise the question as to whether circulating nucleic acids may have damaging effects on the host and be implicated in ageing and diverse acute and chronic human pathologies.

Abstract S2-02: Surgical removal of primary tumor and axillary lymph nodes in women with metastatic breast cancer at first presentation: A randomized controlled trial

BACKGROUND: The role of loco-regional treatment, in women with metastatic breast cancer (MBC) at first presentation, is debatable. Preclinical evidence suggests that such treatment may facilitate growth of metastatic disease. On the other hand, many retrospective analyses in clinical cohorts have suggested favorable impact of loco-regional treatment in these patients. However, these results are likely to be influenced by selection bias. We conducted a prospective randomized controlled trial to assess the impact of loco-regional treatment on outcome in women with metastatic breast cancer at initial diagnosis. [NCT00193778] METHODS: Women with metastatic breast cancer at initial diagnosis and planned to be treated with anthracycline based chemotherapy (CT) were registered for the study. Those who had objective tumor response after 6 cycles of CT were randomized to one of the following arms: ‘LRT’ (loco-regional treatment) or ‘No-LRT’ (no loco-regional treatment). Patients were stratified by endocrine receptor (ER) status, site of metastases (visceral Vs bone Vs both) and number of metastatic lesions ( 3). Women in LRT arm received surgery (breast conservation or mastectomy plus axillary lymph node dissection) followed by radiation therapy (RT), as per standard adjuvant guidelines. Women in No-LRT arm were followed up without surgery and RT. Both groups received standard endocrine therapy after last cycle of chemotherapy, if indicated. They were regularly followed up with clinical evaluation. Appropriate imaging was performed within 6 months after randomization and thereafter as clinically indicated. The primary endpoint was overall survival (OS). RESULTS: Between Feb 2005 and Jan 2013, 350 women were randomized, 173 in LRT and 177 in No-LRT arm. The data cutoff was in May 2013. The two arms were balanced with respect to age, clinical tumor size, HER2 receptor status and stratification factors. Eight (5.8%) patients in the LRT arm did not undergo loco-regional therapy while 19 (10.7%) patients in the No-LRT arm underwent surgical removal of primary tumor because of palliative reasons. The median follow-up was 17 months and 218 deaths (LRT = 111/173, No-LRT = 107/177) had been recorded at data cutoff. The median OS in LRT and No-LRT arms were 18.8 and 20.5 months (HR = 1.07, 95%CI = 0.82-1.40, p = 0.60) and the corresponding 2-year OS were 40.8% and 43.3%, respectively. After adjusting for age, ER status, HER2 receptor status, site of metastases and number of metastatic lesions in a Cox regression model, there was no significant difference in OS between LRT and No-LRT arms (HR = 1.00, 95%CI = 0.76-1.33, p = 0.98). There was no interaction between the effect of LRT and covariates in the model. CONCLUSIONS: Loco-regional treatment of the primary tumor and axillary nodes has no impact on OS in patients diagnosed with MBC at initial presentation, who have responded to frontline chemotherapy. We were unable to identify any subgroups that are likely to benefit from LRT. Such treatment should be reserved for women who need it for palliative reasons. Detailed analysis will be presented at the Symposium. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S2-02.