WO2012143721A1

WO2012143721A1 - Assay

Info

Publication number: WO2012143721A1
Application number: PCT/GB2012/050860
Authority: WO
Inventors: Hugh Walter SIMPSON
Original assignee: SIMPSON, Bruce, Brian
Priority date: 2011-04-19
Filing date: 2012-04-19
Publication date: 2012-10-26
Also published as: GB201106615D0

Abstract

A method and device for measuring and analysing the temperature of a subject's breast or breasts is discussed that allows a vascularity score to be assigned to a subject's breast or breasts wherein the score can be indicative of future morbidity or mortality or cancer spread or outcome of a subject.

Description

ASSAY

Field of Invention

This invention relates to system for measuring and analysing the temperature of a subject's breast or breasts. This measurement and analysis can allow a vascularity score to be assigned to a subject's breast or breasts which can be indicative of future morbidity or mortality or cancer spread or outcome of a subject. The method can be performed at any time in the lifespan of an adult subject, including after surgery where there has been local lump removal. In examples, both breasts can be studied or after a mastectomy the method can be performed on the other breast.

Background of the Invention

Traditionally, in breast cancer, the disease has been detected by palpation and formally diagnosed by histopathology. Additionally, x-ray mammography may detect impalpable lesions.

UK Patent document GB 4492 803 discusses the monitoring of breast temperature at daily intervals for a span of at least one month or a menstrual cycle to allow detection of cancer, for example for pre-operative research into cancer. This is also discussed in the publication "Breast cancer prevention: a pathologist's approach. H. W. Simpson, 1995, Journal Royal College of Surgeons. Edinburgh, 41, 359-370".

The European Journal of Cancer (1995) Vol. 31A No. 11, pages 1768-1772, reported a procedure by which a precancerous breast can be distinguished from a normal breast. The report was concerned with evaluation of luteal heat cycle parameters (amplitude, phase and average) from control breasts and cancer associated breasts, to determine whether it is possible to detect a pre-clinical cancer state in a subject. Whilst these documents discuss detection of primary tumours, they do not provide teaching or suggestion that breast temperature might provide an indication of cancer or subject survival or outcome. Whilst previous tests have enabled determination of whether cancer or pre-cancer is present in a subject, it has required further diagnosis by a pathologist on the basis of cancer tissue histology to indicate the subject's cancer outcome. In particular, a determination as to whether lymphatic spread is present can provide an indication to a physician as to whether a subject will survive (not develop metastatic cancer) after surgery.

In westernised countries, breast cancer affects about one woman in eight during their lifetime and about a third of these are premenopausal women. Breast cancer spread is the most common cause of death from disease in women aged 35 to 55 years. Whilst survival rates have been improving, there remains the problems of drug regimen, post cancer diagnosis, patient worry and inadequate assays to determine the likely outcome at the time of surgery. It would be beneficial if the tumour "staging" and analysis of excised tumour tissue/cells to determine their structure, tumour stage, size, oestrogen receptor presence, expression of ERb-B2 oncogene in contemporary practice and the like could be complemented by new tests to enhance the determination of the likely outcome for a patient.

Accordingly, a first aspect of the invention provides a method for assessing survival of a subject to breast cancer the method comprising:

(i) providing a detected deep mammary temperature value which is adjusted for basal body temperature rhythm;

(ii) determining the phase in the menstrual cycle at which the deep mammary temperature of step (i) has been detected; (iii) comparing the deep mammary temperature of step (i) at a phase as determined by step (ii) to a Control temperature value at a phase as determined at step (if) or to a value from a previous subject with a breast cancer metastasis history; wherein when the deep mammary temperature at a determined phase in the menstrual cycle is greater than the Control temperature value or equivalent to a value from a previous subject with a breast cancer metastasis history it is indicative the subject has a greater likelihood of not surviving the cancer.

Preferably detected deep mammary temperature is obtaining a measured temperature value, but as will be appreciated an adjusted temperature taking into account basal temperature may be the output observed depending on the device used to detected the temperature.

It will be appreciated that the method can provide findings that can be of relevance to the assessment of survival of a cancer subject and may be combined with other findings of diagnostic relevance, such as phase advance of the menstrual rhythm of breast vascularity, short menstrual cycle periodicity, no breastfeeding by the subject, long interval of pregnancy free years of the subject prior to breast cancer or indicators from the Nottingham prognostic index.

The assay method of the present invention allows an indication of whether or not the subject will not survive the cancer and die and the attendant doctor will put metastatic cancer on the death certificate. Those subjects classified by the assay method as non-survivors will on average only survive 7 years following mastectomy, whereas the survival group, as classified by the present method, will still, on average, be alive at 22 years following breast cancer surgery. Suitably, each of the subjects of the survival group, as classified by the present method, will still be alive at 22 years following breast surgery, in particular still be alive for over 22 years following breast surgery.

The inventor has determined that the average deep mean breast temperature in the mid-luteal phase (4 to 12 days before the next menses) is 0.4 degrees C hotter in non-surviving subjects than those surviving 22 years after breast surgery, and that this difference allows potential survivors to be distinguished from subjects who will require additional treatment to improve their survival outcome. In embodiments, "greater than" can be a mean temperature of the deep mammary temperature being at least 0.2 °C greater than a Control temperature. In embodiments, "greater than" can be a mean temperature of the deep mammary temperature being at least 0.25 °C, at least 0.3 °C, at least 0.35 °C greater than a Control deep mammary temperature.

In embodiments "greater than" can be a mean temperature of the deep mammary temperature hotter a subject than a survivor group temperature being indicative that the subject is a non-survivor. In embodiments "less than" can mean a mean temperature of the deep mammary temperature being at least 0.2 °C less than a Control deep mammary temperature. In embodiments, "less than" can be a mean temperature of the deep mammary temperature being at least 0.25 °C, at least 0.3 °C, at least 0.35 °C less than a Control temperature.

By equivalent is meant no statistically significant difference between the value of the previous subject and the determined temperature in relation to survivor / non- survivor grouping in which the subject is placed. As will be appreciated, as different individuals can have different basal body temperature or a different basal body temperature rhythm (higher or lower basal temperature at particular phases in the menstrual cycle), to allow comparison of across subjects or between a subject and a control sample, the detected deep mammary temperature is adjusted to provide a deep mammary temperature such that it is more representative of the vascularity of the subject's breast(s). The deep mammary temperature of step (i) which is adjusted for basal body temperature at a phase as determined by step (ii) provides a "vascular score" of a subject, and the subject's vascular score can be compared against a Control vascular score determined from a deep mammary temperature of a Control adjusted for basal temperature of the Control.

The methods of the invention can therefore determine whether an adjusted deep mammary temperature of a subject is more similar to that of a non-survivor or a survivor for a particular data set. According to the present data, if the subject's adjusted deep mammary temperature is -1.7 °C (vascular score is -1.7) over the mid- luteal phase (4 to 12 days before the next menses), the subject is likely to be a survivor. Suitably, in embodiments, according to the present data, if the subject's adjusted deep mammary temperature over the mid-luteal phase is more negative than -1.65 °C (vascular score is -1.65), more negative than -1.6, the subject is likely to be a survivor.

Alternatively, according to the present data, if the subject's adjusted deep mammary temperature over the mid-luteal phase is -1.2 °C (vascular score of -1.2) or more positive, the subject is likely to be a non-survivor. Suitably, according to the present data, in embodiments, if the subject's adjusted deep mammary temperature (vascular score) is more positive than -1.5, more positive than -1.45, more positive than -1.4, more positive than -1.35, more positive than -1.3, more positive than -1.25 the subject is likely to be a non-survivor. In embodiments when a subject is determined to have a vascularity score more negative than that of a mean vascular score of a non-survivor group, the subject is likely to be a survivor.

In embodiments a vascularity score equal to or greater than -1.2°C over the mid- luteal phase it is indicative that the subject is hyper- vascular. In embodiments a vascularity score equal to or less than -1.7°C (for example -2.0°C) is indicative that the subject is hypo-vascular.

In embodiments a subject classed as hypo-vascular will have an increased cancer survival expectancy. For example an increased likelihood of survival from death from cancer of greater than 22 years.

Deep temperature mammary temperature is the temperature of the internal tissues of the breast. As will be appreciated by those in the art, in normal environmental temperature conditions, this deep temperature will be relatively stable, unlike the temperature of the outer body surfaces, which are affected by the environment.

Basal body temperature is the core temperature of the subject at rest, as when the deep mammary temperature is being measured. Basal body temperature does not include increased body temperature measurements which might be obtained during physical activity. As will be understood by those in the art, in women, ovulation can cause an increase of one-quarter to one-half degree Celsius in basal body temperature. Further, changes in body temperature may occur at different points in the day or following infection, for example in fever. Thus, it is important to determine basal body temperature at the same time point as the deep mammary temperature or account for such rhythms of temperature change.

In embodiments a Control temperature can be the temperature obtained from an age matched women who has not had cancer and who has not developed breast cancer during a defined follow up time span, for example, as discussed herein, a 22 years follow up span. In embodiments a Control value can be a mean value obtained from a data set comprising age matched women who have not had breast cancer and have not developed breast cancer during a defined follow up time span. In embodiments a Control temperature value can be obtained from a suitable data set of women matched to the subject being assessed. A suitable data set may be generated by considering women of, for example similar age, lifestyle, pregnancy history or the like, or combinations of such factors. In embodiments wherein the mid-luteal deep mammary temperature is less than the Control temperature value, it is indicative that the subject will have a greater likelihood of survival from a breast cancer.

The phase of the menstrual cycle may be determined using, for example; a menses calendar, daily saliva progesterone measurements, oestrogen measurements, oral temperatures or combinations of these. In embodiments, the method is applicable to female subjects, in particular premenopausal female subjects. In embodiments the method is applicable for adult females. In particular, while the data discussed herein relate to premenopausal women, without wishing to be bound by theory, the inventor considers the data would likely be similar for post menopausal female subjects, even though there is no menstrual cycle and the mammary tissue is less vascular.

In embodiments, the method can be performed on a subject following a mastectomy when a tumour has been removed from a first breast by measuring the other breast. Alternatively, a breast from which a lump has been removed locally can be measured.

The method of the invention can be predictive of metastasis risk pre, during and post surgery. Although development of secondary tumours (metastasis) can be stalled with treatment for some time, in cancers which result in metastasis they will almost inevitably be fatal in the end, with therapeutic agents killing off a proportion of the tumour cells, but not all.

In embodiments the deep mammary temperature is monitored daily such that the menstrual rhythm characteristics of the breast, for example in response to menstrual variations in oestrogen or prolactin or the like, can be detected. In embodiments, measurements may be made substantially continually over the period of a day. This would allow circadian rhythms in the subject to be taken into account. Typically, in embodiments measurement of deep mammary temperature may be for at least 90 minutes per day. Measurement of deep mammary temperature may be made for a period of at least 15 minutes, at least 30 minutes, at least 60 minutes, at least 2 hours, at least 3 hours. Typically, around 30 menstrual cycle measurements may be taken, wherein each measurement is taken on a daily basis. Preferably, the deep mammary temperature of the breast may be measured each day through one complete menstrual cycle.

In embodiments, where multiple temperature measurements are made, smoothing techniques as will be known in the art, for example an exponential smoothing algorithm, may be applied to the measurements. This can be applied to deep mammary temperatures and / or basal temperatures of a subject.

Measurement of deep mammary temperature may suitably be made in the evening. To ensure accuracy and consistency, measurements are preferably undertaken under semi-controlled or controlled circumstances. For example, during the temperature measurement, the subject should preferably be located in a room with a stable ambient temperature, the temperature of the subject should not be unduly influenced by clothing, direct heat sources or the like or, and the subject should be at rest. By stable ambient temperature is meant a typical room temperature where a subject would feel comfortable for example in the range 20°C to 24°C. Further, it there should be minimal air currents which might cool or heat objects in the room in differently from the ambient temperature. Typically a women working away from home during the day may prefer to make measurements, for example whilst watching television in the evening.

The method may further comprise providing saliva samples provided by the subject. In embodiments, saliva samples can be provided each day, such that the level of progesterone can be measured, for example by radioimmunoassay. Measuring progesterone hormone daily can confirm the ovulatory status, timing, and the pre- menopausal status of the patient. This can provide the timing of the luteal phase of the menstrual cycle to be established in the subject.

Whilst it is appreciated temperature measurements may only be taken for a short span of days (two-three days) depending on the menstrual phase in order to obtain an assessment of breast vascularity, it is considered that measurements over longer time spans (a menstrual cycle or cycles) will likely provide improved signal/noise ratios. In particular, it is considered to be advantageous to measure temperatures from the subject around the peak of the level of progesterone in the subject. Preferably the temperatures are detected at the mid-luteal phase of the menstrual cycle.

In the step of providing a detected deep mammary temperature value which is adjusted for basal body temperature rhythm this can comprise subtracting the oral or aural temperature of the subject from the deep mammary temperature value. This typically provides a negative value. It is considered advantageous if the oral or aural temperature is taken at the same time as the deep mammary temperature such that a change in the temperature of the subject due to daily or menstrual rhythms can be taken into account.

In embodiments, the method can further comprise measuring oral or aural temperature. In embodiments the method step of adjusting for the affect of basal body temperature rhythm on deep mammary temperature comprises subtracting oral or aural temperature from the determined deep mammary temperature. Each individual typically has a slightly different "normal" temperature set by their hypothalamic thermostat. By subtracting basal or blood temperature from the deep mammary temperature measurement, data can be compared across individuals.

In embodiments the deep mammary temperature can be determined by positioning at least one temperature sensor, for example a thermistor or other temperature monitoring device on the breast. The temperature measured should be indicative of the generality of the mammary vascularity and not local temperature effects. Those skilled in the art would be aware of equilibration procedures required to ensure that deep mammary temperature and not merely surface breast temperature is measured. In embodiments where breast cancer has resulted in a first breast being significantly removed, the deep mammary temperature of the remaining breast may be measured. Such measurements may be provided, for example, daily for one menstrual cycle. In embodiments, the device to measure the deep mammary temperature can comprise at least one temperature sensor. In preferred embodiments of the method, temperature may be measured using a sensor or sensors arranged around or in a bra-cup. For example a net or array of sensors can be arranged to measure deep mammary temperature. In embodiments such an array may, in use, be arranged around the nipple of the breast. A net or array arrangement is more likely to result in average values of deep mammary temperatures being determined. The provision of such average temperatures can minimise the risk of a single sensor being placed over a vein or other hot spot on the breast, which might result in too high temperature readings.

In embodiments a temperature sensor or array of temperature sensors may be arranged around the breast by providing a device or an insert which can be placed around or in a bra or around a breast to position a sensor or an array of sensors at the breast. Suitably in embodiments a or a plurality of temperature sensors may be provided in or on an insert to be placed at the breast. Suitably a device or an insert may be formed or foam, silicone, elastomeric material or other suitable material adapted to be shaped, mouldable or to resiliently deform to and / or around the shape of the breast. As will be appreciated, inserts for use in combination with bras to enhance the size, shape or presentation of a breast(s) are known in the art and could be adapted to include a temperature sensor or a plurality of temperature sensors. In embodiments, a temperature sensor or sensors can be provided in combination with microprocessors to allow a sensor to communicate with a base station or another sensor, to perform computer processes on the temperature signals received or to associate a temperature signal to a time period or period of a menstrual cycle.

To determine the vascular score of a subject, the deep mammary temperature of a subject is provided and adjusted for basal body temperature by subtracting arterial blood temperature, for example, aural or oral temperature. The adjusted temperature is typically assigned a phase, based on the point in the menstrual cycle at which the temperature was determined. The blood-temperature adjusted mammary temperature of the subject can be compared with the temperature from a Control with the same phase, in particular an adjusted temperature in the luteal phase of the menstrual cycle can be compared with a Control at the same span in the luteal phase. This provides a score of vascularity of the subject relative to the Control. Suitably, the adjusted mammary temperature of the subject as determined in the luteal phase of the menstrual cycle, -12 to day -4 of the cycle, is compared with Control measurements from the same phase in the cycle.

When the deep mammary temperature is greater (hotter breast) than in a Control, this is indicative that the subject will be a non-survivor.

When the deep mammary temperature is less (cooler breast) than in a Control this is indicative that the subject more likely will be a survivor. In embodiments a vascular score Control value can be about -1.5 °C, wherein an average age of the Controls is 38.8 years ± standard error of 0.1 years. However, it will be appreciated that appropriate age matched Control data, as provided by figure 4, can be used as appropriate. Moreover, a vascular score Control value may be generated using an appropriate dataset of survivors and non-survivors to match the subject being assessed. This can take account of different age, race, and / or ethnicity as required. Without wishing to be bound by theory it is considered that the Control data provided herein will be representative across a wider age range of women between 25 to 55 years.

In embodiments, "greater than" can be a mean temperature of the deep mammary temperature being at least 0.2 °C greater than a Control temperature. In embodiments, "greater than" can be a mean temperature of the deep mammary temperature being at least 0.25 °C, at least 0.3 °C, at least 0.35 °C greater than a Control deep mammary temperature. In embodiments "less than" can mean a mean temperature of the deep mammary temperature being at least 0.2 °C less than a Control deep mammary temperature. In embodiments, "less than" can be a mean temperature of the deep mammary temperature being at least 0.25 °C, at least 0.3 °C, at least 0.35 °C less than a Control temperature.

In embodiments, if the subject's adjusted deep mammary temperature is -1.66, the subject is likely to be a survivor. Suitably, in embodiments, according to the present data, if the subject's adjusted deep mammary temperature is more negative than -1.66, e.g. -1.7, the subject is likely to be a survivor. Since the data were collected from a spectrum of different breast cancer subjects, the outcome opinion is thought to have generality.

Alternatively, in embodiments, according to the present data, if the subject's adjusted deep mammary temperature is -1.2 or more positive, e.g. -1.1, the subject is likely to be a non-survivor.

Examples of such data are shown in figure 4 wherein a detected deep mammary temperature value which is adjusted for basal body temperature rhythm of all 18 survivors is in the region of -1.7 deg C with a standard deviation of 0.2, 67 healthy controls (-1.4 deg C) with a standard deviation of 0.1 deg C and 18 non-survivors -1.2 dec C with a standard deviation of 0.1 deg C. The methods of the invention can therefore determine whether an adjusted deep mammary temperature of a subject is more similar to that of a non-survivor or a survivor for a particular data set. According to the present data (see figure 4), if the subject's adjusted deep mammary temperature is -1.7, the subject is likely to be a survivor. Suitably, according to the present data, if the subject's adjusted deep mammary temperature is more negative than -1.65, more negative than -1.6, more negative than -1.55, more negative than -1.5, the subject is likely to be a survivor.

Alternatively, according to the present data, if the subject's adjusted deep mammary temperature is -1.2 or more positive, the subject is likely to be a non-survivor. Suitably, according to the present data, if the subject's adjusted deep mammary temperature is more positive than -1.5, more positive than -1.45, more positive than -1.4, more positive than -1.35, more positive than -1.3, more positive than -1.25 the subject is likely to be a non-survivor.

An example of such data is shown in figure 4, wherein a detected deep mammary temperature value which is adjusted for basal body temperature rhythm of a survivor is in the region -1.7°C with a standard deviation 0.1 °C, a Control -1.4 °C with a standard deviation 0.1 °C and a non-survivor -1.2 °C with a standard deviation 0.1.

The inventor has further determined that the "vascular score" of a breast can be inferred by the temperature of the other breast left after surgery. Thus, measurements obtained from one breast can give valid data about both breasts' vascularity. Studies of Control subjects (age matched normal non-breast cancer suffering women, but whom may have a family history of cancer), show that the right and left breast exhibit a similar cycle of increased vascularity during the monthly pregnancy rehearsal and lactation (figure 2). The peak vascularity of the cycle in the luteal phase (this is when the progesterone rises i.e. between ovulation and the menses - the last two weeks before the period starts) is considered to be an important measurement. Pre-ovulating breast temperature rise can also considered to be considered to be a feature of pre and post breast cancer. In embodiments a vascularity score can be determined as an average -11 to +2 day of the recorded cycle wherein period onset is conventionally day +1 and day -11 is 11 days before the period starts.

In embodiments a vascularity score equal to or greater than -1.2°C is indicative that the mammary tissue is hyper- vascular.

In embodiments a vascularity score equal to or less than -1.7°C (for example -2.0°C) is indicative that the subject is hypo-vascular.

As will be appreciated from considering the data presented at for example figure 4, these values fall on either side of the normal value of vascularity as seen in the Control subjects.

In embodiments a subject with mammary tissue classed as hypo-vascular will have an increased cancer survival expectancy. For example an increased likelihood of survival from death from cancer of greater than 22 years post operatively. In embodiments a vascularity score equal to or greater than -1.2°C "hotter" can be helpful to a surgeon in deciding further treatment options and the options for follow up scans, etc.

A vascularity score determined as set out above may be affected by risk factors. Nulliparae and those subjects with no or little breast feeding history are at a higher risk of being non-survivors (poor cancer outcome). Further, those with short menstrual cycles (less than 27 days) are at increased risk of being non-survivors (poor cancer outcome). These factors can be further considered using multivariate analysis, although, without wishing to be bound by theory, it is also considered these factors cause luteal hyper- vascularity and thus are detected and measured in the present method. Other complementary signals can be added to these temperature signals to enhance the survivor / non-survivor signal. For example, as compared to Controls, an early phase of the temperature rhythm (89%), history of short menstrual cycles (<28 days) etc. can be provided to the temperature measurements of the method discussed using multivariate analysis to provide an enhanced result.

For example, when Controls and breast cancer survivors are compared in terms of breast temperature vascularity rhythm with non-survivors, the non-survivors are significantly phase advanced. Based on studies by the present inventor, of the menstrual vascularity rhythm relative to the onset of menses, non-survivors show a peak of vascularity on day 20.7 of a 28 day cycle, whereas the controls and survivors peak at day 23.7. Thus there is a phase advance in non-survivors of three days.

Moreover, based on studies by the inventor of thirty six breast cancer subjects, survivors averaged a 28 day periodicity in their menstrual cycle whereas non- survivors averaged a 25.7 day cycle. Those having a longer cycle than the average, lived on average, 17 years post-operatively, whereas those with a short cycle lived only 9.2 years. Other factors which can be taken into account are the pregnancy free interval preceeding breast cancer surgery and the Nottingham Prognostic Index.

It is of particular benefit if a prognostic test can show a wide separation of the outcome of groups of subjects. Presently, the Nottingham Prognostic Index combines nodal status, tumour size and histological grading to provide a prognostic result. The method of the present invention may be used not to provide a diagnostic or prognostic result, but to provide a signal which can be combined with other parameters.

As will be appreciated, home collected temperature data may be measure at an offsite location at a separate time from the analysis of the data. Alternatively, or additionally, the data analysis may be conducted to provide a signal to the subject from which the deep mammary temperature data has been detected or to another. Accordingly, a second aspect of the present invention can comprise the steps:

(ii) determining the phase in the menstrual cycle at which the deep mammary temperature of step (i) has been detected;

(iii) comparing the deep mammary temperature of step (i) at a phase as

determined by step (ii) to a Control temperature value at a phase as determined at step (ii); wherein when the deep mammary temperature at a determined phase in the menstrual cycle is greater than the Control temperature value a first signal is provided and when the deep mammary temperature at a determined phase in the menstrual cycle is less than the Control temperature value a second signal is provided.

In embodiments, the deep mammary temperature of step (i) at a phase as determined by step (ii) can be compared to a value from a previous subject with a breast cancer metastasis history instead of or as well as a Control and wherein the deep mammary temperature at a determined phase in the menstrual cycle is equivalent to the value of the previous subject with a breast cancer metastasis history a first signal is provided and when the measurement is different a second signal is provided.

As will be appreciated and as taught herein, the temperature values are adjusted for basal temperature to allow comparison across subjects. The embodiments as discussed with respect to the first aspect can accordingly be applied to the second aspect of the present invention.

The signal may be an electronic signal or electronic report. In such an embodiment, the signal provided is only an intermediate result obtained by measuring one parameter and does not enable a decision to be made on the treatment necessary. In embodiments of this aspect of the invention, this aspect of the invention can further comprise the step of weighting the signal provided and the results of other parameters, for example histological grading, tumour size, pregnancy free years before cancer, and / or menstrual cycle length.

It will be appreciated that the detected deep mammary temperature and determined phase can be provided as an electronic signal to be compared and processed as described herein in relation to the first aspect of the invention.

An example of a device for monitoring the temperature of the breast for use in the method is described by GB 1 492 803. It is believed that breast temperature is a measure of the blood perfusion through the tissue. In view of this, breast glandular blood flow may be used as an alternative measurement. Doppler ultras onagraphy may provide a non-invasive test to determine the menstrual cycle of blood flow through the breast and results which could be used in the present method. Alternatively, volumetric analysis of the breast and its component tissue by magnetic resonance imaging might be effective. According to a further aspect of the invention there is provided a composition for the treatment of metastatic breast cancer for use in the treatment of a subject identified as having a deep mammary temperature at a determined phase in the menstrual cycle or vascular score greater than a Control temperature value or vascular score or equivalent to a value from a previous subject with a breast cancer metastasis history. In embodiments the composition can be systemic medical therapy, comprising chemotherapy, endocrine therapy, biologic therapies and combinations of these. For example therapy can include taxanes (paclitaxel, docetaxel, abraxane), anthracyclines (epirubicin or doxorubicin), tamoxifen, monoclonal antibodies and / or combination therapies. In embodiments the subject can have been previously diagnosed with breast cancer. According to a third aspect of the invention, there is provided a deep mammary temperature sensing device comprising a temperature sensor adapted to determine at least a first breast temperature at a first time point, and a second temperature sensing device adapted to detect ambient temperature and means to enable the effect of ambient temperature on deep mammary temperature to be determined.

In embodiments a plurality of temperature sensing devices to detect ambient temperature can be provided such that temperature sensing devices can be located at different layers in a subject's clothing to detect changes in deep mammary temperature caused by different clothing layers. In such an embodiment, a plurality of temperature measurements Tl, T2, T3 may be obtained which can be advantageous in determining deep mammary temperature measurements. Preferably, the raw data provided by each of these plurality of sensors is kept intact. In embodiments, the data collected by each of the plurality of sensors can be used to assess if the subject is obtaining the deep mammary temperatures as requested under controlled conditions, for example not wearing abnormal excess clothing, performing physical exercise while collecting the data or shortly before collecting the data or collecting the data whilst exposed to non-control or abnormal environmental temperature influences (for example raised room temperature or cooling air currents). For example if each of the temperatures Tl, T2, T3 rise in a similar fashion, this would be indicative that non-control or abnormal clothing is being worn by the subject. Preferably, the day and time of the data collection of the each of the temperature measurements Tl, T2, T3 are collected and linked to the temperature measurements. In embodiments a device of the invention of or for use in a method of the invention can allow other variables, for example meal times, to be recorded, for example colour temperature of the skin or veins as used in "pulse oxymetry" in which the haemoglobin saturation of finger blood is tested or for example, electrical resistance of breast tissue or the like. This may advantageously allow the measurements to be taken more easily and may allow continuous measurements to be achieved in waking hours. In embodiments, the device may be provided as a bra insert which can be placed over the breast of a subject and held in place by a bra cup. In embodiments a temperature sensor or array of temperature sensors may be arranged around the breast by providing a device or an insert which can be placed around or in a bra or around a breast to position a sensor or an array of sensors at the breast. Suitably in embodiments a or a plurality of temperature sensors may be provided in or on an insert to be placed at the breast. Suitably a device or an insert may be formed or foam, silicone, elastomeric material or other suitable material adapted to be shaped, mouldable or to resiliently deform to and / or around the shape of the breast. As will be appreciated, inserts for use in combination with bras to enhance the size, shape or presentation of a breast(s) are known in the art and could be adapted to include a temperature sensor or a plurality of temperature sensors. In embodiments, a temperature sensor or sensors can be provided in combination with microprocessors to allow a sensor to communicate with a base station or another sensor, to perform computer processes on the temperature signals received or to associate a temperature signal to a time period or period of a menstrual cycle. Alternatively, a chip device put under the subject's or patient's own bra may be used.

In embodiments the temperature sensors may be provided with heat transfer devices to allow the sensors to be heated to ambient temperature to allow more rapid measurement of deep mammary temperature. In such embodiments the temperature sensor can comprise a thermistor, a heat-flow sensor and a heater. The sensor detects heat flow from the skin; the heater then compensates for the heat lost and consequently the skin is effectively insulated from the ambient microenvironment. Skin temperature beneath the sensor is therefore determined by the deep body temperature.

In embodiments, the device may comprise a data storage device, for storing said at least a first deep mammary temperature at a first time point and at least a second temperature at a second time point, and any further temperatures at multiple time periods, for example the data storage device may be a flash drive. In embodiments, the device can comprise a data signal output device, for example a data transmitter to allow the data to be provided by wireless protocols (for example Wi-Fi or bluetooth) to a computer.

In embodiments, the deep mammary temperature sensing device can be provided on a garment to be worn by a user. In embodiments, the garment can be a brassiere. In embodiments, the temperature sensing device can be located on the garment such that in use it is located below the nipple. An array of temperature sensors in a net may be provided over the breast. For example, in embodiments the sensor(s) may be located in the cup of the brassiere. Alternatively, infra red measuring technology or ultrasonic doppler technology may be used to monitor deep mammary temperature.

In embodiments, the device of the third aspect of the invention can comprise a device for determining oral and/or aural temperature. In such embodiments the deep mammary temperature sensing device and the device for determining oral and/or aural temperature can communicate with each other, preferably wirelessly, for example using a radio telemetry system, to enable an adjusted temperature measurement (breast temp - oral and aural temp) to be gained. The objective is to the correct the temperatures for arterial blood temperature.

In embodiments an array of sensors can be provided to monitor deep mammary temperature a multiple locations on the breast such that an average deep mammary temperature of an individual can be obtained at a time point. In embodiments the device may measure deep mammary temperature averaged over a defined time span, for example 30 minutes, to save memory and minimise noise.

As will be appreciated the methods discussed herein may be performed using a system or kit, preferably in a home enviroment. According to a fourth aspect of the present invention, there is provided a kit for use in the method of the first aspect of the invention comprising a deep mammary temperature sensing device and at least a second temperature sensing device to detect ambient temperature.

Suitably, in embodiments, the deep mammary temperature sensing device can comprise at least a first temperature sensor to determine at least a first breast temperature at a first time point, wherein the temperature sensing device is provided in or on an insert to be placed over a breast wherein the insert is formed from material adapted to be shaped, mouldable or to resiliently deform to and / or around the shape of the breast. The deep mammary temperature sensing device may comprise an array of temperature sensors in a net which, in use, is provided over a subject's breast.

In embodiments a kit can further comprise a plurality of temperature sensing devices to detect temperatures at different layers in the subject's clothing. Suitably, in embodiments there can be provided a temperature sensor to determine oral and/or aural temperature. In embodiments of the kit, the kit can comprise a processor to receive signals from at least one of the at least first temperature sensor, the second temperature sensing device to detect ambient temperature, any one of the plurality of temperature sensing devices to detect temperatures at different layers in the subject's clothing, and a temperature sensor to determine oral and/or aural temperature. In embodiments a kit can comprise a signal generator to transfer any of the signals received from at least one of the at least first temperature sensor, the second temperature sensing device to detect ambient temperature, any one of the plurality of temperature sensing devices to detect temperatures at different layers in the subject's clothing, and a temperature sensor to determine oral and/or aural temperature or a combination thereof to a computer means to allow for processing, manipulation or display of the signal(s).

Preferred features and embodiments of each aspect of the invention are as for each of the other aspects mutatis mutandis unless context demands otherwise. Each document, reference, patent application or patent cited in this text is expressly incorporated herein in their entirety by reference, which means it should be read and considered by the reader as part of this text. That the document, reference, patent application or patent cited in the text is not repeated in this text is merely for reasons of conciseness.

Reference to cited material or information contained in the text should not be understood as a concession that the material or information was part of the common general knowledge or was known in any country.

Throughout the specification, unless the context demands otherwise, the terms 'comprise' or 'include', or variations such as 'comprises' or 'comprising', 'includes' or 'including' will be understood to imply the includes of a stated integer or group of integers, but not the exclusion of any other integer or group of integers.

Brief description of the drawings

An embodiment of the present invention will now be provided by way of example only with reference to the accompanying figures wherein, Figure 1 illustrates an embodiment of a device (Chronobra) which can be used to measure deep mammary breast temperature, the device being a custom built sixteen channel automated thermometry for measurement of the deep breast temperature cycle. Two external sensors are shown as black dots on the upper part of each cut. There are also fourteen sensors in the inner cup against the breast surface. The 176 gram instrument pack is shown centrally. This includes a sampling clock e.g. every 60 seconds and a 4k semi-conductor memory store for the temperatures. A chip was manufactured specifically for the study described in the patent proposal. Figure 2 illustrates a comparison of left versus right breast temperature in controls over the menstrual cycle, wherein (L) indicates a left breast temperature measurement and (R) indicates a right breast temperature measurement with the X axis showing time : Days prior to Menses (M) onset and the Y axis showing Temperature (°C) : Daily Mean and standard error. The data on the graph are collected by the Chronobra from over fifty normal women, that is women with no breast cancer, taking daily measurements for one menstrual cycle. At the same time, daily saliva samples were collected and the progesterone data obtained there from show the expected rise of progesterone at the time of ovulation and the progesterone data confirms the pre-menopausal status of the women.

Figure 3a illustrates a time plot comparing the vascularity of 18 survivors (defined as 22 years post-operative) and 18 non-survivors who died within the 22 year follow up. In this instance vascularity is given as the difference between breast temperature and oral temperature, which in effect is arterial temperature. In each day the mean of 18 subjects is plotted with ± one standard error. The graph shows that in the second half of the menstrual cycle, that is the luteal phase, the non- survivors are consistently hotter.

Figure 3b illustrates days of the menstrual cycle against vascularity (degrees Celsius) to show the comparison between the breast vascularity of 18 survivors (S) at 22 years post operation vs 18 non-survivors (NS). A least square fit of 28 day cosine has been fitted to the average at each days data. The non-survivors have an earlier cycle relative to menses onset.

Figure 4 tabulates the temperature vascularity series data (°C) for the middle and late luteal spans (-11 to +2). The average for non-survivors is -1.2. The average for survivors is -1.6. Thus, non-survivors and survivors fall into statistically distinct groups, as shown by the t ratios provided.

Figures 5a, b, c and d shows sensitivity and specificity of assays using inspection selected different cut off values wherein figure 5A shows average temperatures for each patient over days -12 to +2 and illustrates a -1.5°C cut off, figure B illustrates a peak phase (acrophase) of a 28 day fit cosine (360° = menses; ovulation 208° = day menses -16) shows a 275° cut off, Figure C shows menstrual periodicity cut off, Figure D shows pregnancy free years before breast cancer surgery.

Figure 6 shows a summary of survival indeces as at 22.2 years after breast cancer surgery in 36 patients.

Detailed Description of the Invention

Definitions

Breast Cancer as used herein is defined as a malignant growth of cells derived from the epithelium, one of the four tissue types found in the human body (others are nerve, muscle and connective tissue). Breast cancer comes from a subset of the epithelial covering tissues, namely a modified sweat gland. Menses as used herein is defined as the monthly flow of blood and cellular debris from the uterus. Conventionally in physiological descriptions of the menstrual cycle the day of the onset of the period is day one. The day before the menses is -1 and the day before that -2. The last three weeks of the menstrual cycle consists of events of a fairly constant length, with variation between women occurring after menses is finished, so by counting backwards from the menses it is possible to synchronise women across their cycles.

Luteal Phase as used herein is defined as the period post ovulation and pre menses, in particular the last 16 days of the menstrual cycle before the next period.

Disseminated breast cancer as used herein is defined as breast cancer wherein mutated epithelial tumour cells disseminate by the vascular system, for example, the veins and lymphatics to other parts of the body. Vascularity is inferred from deep mammary temperature as measured by a temperature measuring device, such as a chronobra (see for example a device as disclosed by GB 1 492 803, incorporated herein by reference, or as taught herein). The terms "hypo-vascularity" and "hyper- vascularity" interpreted from deep temperature refer to a state in which the number and size of vessels in a unit area of tissues is decreased as in hypo-vascular and increased in hyper- vascular.

A hypo-vascular subject as defined herein is a subject at decreased risk of disseminated breast cancer and death related to cancer due to cancer spread.

A hyper-vascular subject as defined herein is a subject particularly, but not always, at increased risk of disseminated breast cancer and cancer related death due to cancer spread.

Survivor as defined herein is a subject who has not died of disseminated breast cancer by at least 22 years after removal of a primary breast cancer tumour.

Specificity as defined herein is the proportion of negatives which are correctly identified (number of survivors correctly identified).

Sensitivity as defined herein is the proportion of positives which are correctly identified (number of non-survivors correctly identified).

Figure 2 shows "M" = menses onset and the time scale counting back 28 days and a transient rise of the surface breast temperature at around day -22. The rise in temperature beginning day -16 reflects the increasing vascularity as the monthly rehearsal for possible pregnancy (and lactation). The rise on day -16 pinpoints ovulation. The small standard errors at this point indicate good synchronisation of subjects' data counting back from the menses.

In figure 3b the 28 day cosine function is provided in a format wherein 360° is equal to the menses and ovulation is equivalent to 206°. The non survivors peak at less than 267°, whereas the survivors are greater than 287°. The signal is exemplified in figure 3a, where it is seen increasing progressively from before ovulation to after the onset of menses.

By considering control data of the menstrual cycle (120 right and left breast menstrual-long-series) of age matched women, it was determined that the prevailing physiological natural mammary vascularity varied during the luteal phase from about -3°C from arterial temperature (here measured as oral temperature) to values close to arterial. Comparison of data from the other breast of age matched post breast cancer surgical patients with control data values at the same phase, showed that on average non- survivors were on the hot side of the normal distribution curve of breast temperature seen in the 67 controls whereas the survivors were on the cold side. Non-survivors were hyper-vascular and survivors hypo-vascular (Figure 3a) and the differences were highly significant. The controls were in between the non survivors and survivors. It appears that such vascularity, which presumably prevails pre- and post-operatively, raises into question the importance of the extent of surgery and post operative treatment. The hyper-vascular breasts were from patients who gave a history of short menstrual cycles (less than 28 days) nulliparae (no children) or more than 18 year pregnancy-free intervals before the cancer developed. These observations on non- survivors were complemented by the findings in survivors that they had tended to have menstrual cycles each lasting more than 28 days and their parity was accompanied on at least one occasion by breast feeding lasting for more than a month. These findings were accompanied by mammary hypo-vascularity and the fact that the subject was still alive 22 years later.

In terms of the sensitivity and specificity, with respect to the averaged data extending from day -12 to +2 preceding and during the recorded menses, the sensitivity was positive in 14 out of 18 cases of non-survivors and the specificity of the test was 11 out of the 18 for the survivors. It is believed that a decrease in variance of the temperatures obtained in control and subject data would be achieved by taking into account the time from the previous pregnancy. The effect of this variable can be included using a multi-variate analysis.

Additional data, such as a history of short menstrual cycles (less than 28 days), no births (nulliparae) or a long interval (more than 18 years) between the last pregnancy and cancer, can be included. Control Data

Figures 2 illustrates control data. Since each individual has a different menstrual periodicity, in order to achieve alignment, the data are plotted backwards from the next menses. As illustrated in the attached figures, it goes from M (which means menstrual) -1, -2 etc to -28. It can be assumed that the first 21 days counting backwards in this form will mean that the data across subjects is well synchronised. Between day -24 and -28 there can be confusion because of different length of menstrual cycle in different women.

Figure 2 shows that the Control subjects, whether measuring the right or the left breast have a phase frequency synchronised rhythm with a period close to 28 days which is the periodicity of the least squares fitted cosine function.

The daily progesterone data, as shown in figure 2, enable the data to be categorised in terms of the premenopausal status of the subjects and the timing of ovulation 16 days before the next menses.

Results from the Cancer Subjects

On the basis of the observed outcome of death from metastatic disease, or survival for 22 years post-operatively, subjects' data can be divided into two groups; survivor and non-survivor. When these two groups were analysed in the same way as the Controls (see Figure 2) it is seen that the survivors and the non-survivors both have a phase and frequency synchronised rhythm with a period of about 28 days, but that the mammary tissue of the non-survivors is running at a higher temperature, more vascular, level. Figures 3a and 4 show the difference in temperature observed for survivors and non-survivors. Figure 4 (tabulation) indicates the differences between the non-survivors, the Controls and the survivors on a day by day basis where each respective box represents the average of all 18 non-survivors, 67 controls and 18 survivors. In nearly every one of the menstrual cycle days looked at in this way, the non- survivors breasts are hotter than the Control breasts and the Control breasts are hotter than the survivor's breasts.

If a survivorship signal is generated of vascularity against the timing of the menstrual cycle, and the vascularity (determined by subtracting breast temperature from blood temperature) of the survivors is expressed as a ratio to the non- survivors it is seen that the signal increases fairly steadily from the earliest part of the oestrogen driven menstrual cycle and starting well before ovulation and continuing in the luteal phase. The distribution of signal makes it look distinctly as if the risk factor is mediated through oestradiol. This phased response in the subjects before ovulation is in distinction to the controls whose deep breast temperature rises after ovulation (see figure 3a) and this is the basis of the phase risk signal discussed in terms of sensitivity and specificity. It is now standard to give Tamoxifen, an oestradial blocking drug in cases of breast cancer.

Example I

67 controls and 36 breast cancer subjects/patients were recruited totalling 103 subjects altogether. The average age of the controls was 38.8 years ± standard error of 0.1 years. The average age of the subjects at study was 40.5 for the survivors and 39.4 for the non-survivors. Both controls and the subjects were white Caucasian women living in the Glasgow area and educated up to the secondary level. By and large the controls were recruited from church mothers groups. The subjects were recruited from a Breast Cancer Clinic at the University Department of Surgery, Glasgow Western Infirmary.

Reasons for exclusion included lack of secondary education, advance state of illness or poor social conditions. In order to effect the study there had to be an understanding of how to use the electronic device to measure breast temperature, to take body temperatures accurately and to systematically collect saliva samples each day of a menstrual cycle in order that the progesterone profile could be obtained.

Contemporary best practice outcome studies were carried out for the surgeon in charge Regius Professor of Surgery, Professor David George, with the histological "grade" being made by a senior consultant pathologist who specialised in this area. Assessment of this histopathology analysis of survival carried out some 30 years later indicated that the assessment was unhelpful except in the case where the pathologist concluded that, the cancer was non-invasive or that there was vascular invasion (see Table 1).

Premenopausal Breast Cancer Outcomes

of 36 Breast Cancer Subjects Studied

The most evident outcome predictor to guide the subject's management (e.g. follow- up frequency, chemotherapy, herceptin prescription etc) is the finding of lymphatic spread. It was only present in one of the survivors, but in 7/18 of the non-survivors. One case of non-invasive cancer was correctly assigned to the survivor group. However, 'Grade 3' cancer was reportedly seen in a similar number of survivors as non-survivors. All the 7/18 cases with lymphatic spread seen are positives and recorded positive by the present method in the test of the peak phase of luteal vascularity.

Follow-up of the breast cancer subjects, and indeed all the subjects, was carried out by a link with Tyndall House in Edinburgh which, for research purposes, records the deaths and has the death certificates of the subjects in question. After a 22.2 years follow-up, 18 of 36 the breast cancer subjects had died with "disseminated breast cancer" on their death certificate (SM8).

Table 2

Ages at Surgery and Study; Post-op follow-up of Non-Survivors

Notes to Table 2 * A 'Control' who developed clinical breast cancer after the Chronobra test and not considered as "precancer" then

** SM8 recorded "disseminated breast cancer" but she also suffered from a malignant melanoma and there was no post mortem examination to enable the SM8 diagnosis to be confirmed.

The data indicate that the average survival of the non-survivors was 7.8 years post operatively, whereas the survivors were still alive after an average of 22.2 years follow-up. None of the 36 subjects died of other causes, but 3/67 controls died of non-breast cancer cause (mesothelioma, hypercholesterol, and a heart attack) during the 22.2 year study.

In the present method, each subject was asked to wear a device to measure breast temperature, for example (an electronic thermo graphic Chronobra) for 2-3 hours (Figure 1) each night of a menstrual cycle under a provided "T" shirt. During the measuring period the subject had to sit in the same chair in the same position. A house visit by a nursing sister observed this position and determined whether there were any heat sources which might interfere with the results obtained; also there was a direct reading thermometer provided to the subject to be put at breast height to measure ambient temperature and to allow control of the room temperature between 20°C and 24 °C. Each day the subject was instructed to collect saliva for progesterone analysis. The oral and breast-height ambient temperature were documented. As will be appreciated the temperatures collected ideally should be linked to the calendar date on which they were collected, such that the measurements can be related to menses onset and calendar month since premenopausal cancer deaths are reportedly different for summer and winter. Suitably in the methods described herein the post-operative breast cancer subject wears a device to measure breast temperature, for example a Chronobra, for a menstrual cycle and collects saliva for progesterone analysis as described earlier. The breast temperature and the peak phase in a 28-day cosine least-squares-fit analysis can be compared against control/non-survivor/survivor data to achieve an objective risk status score of metastatic cancer spread. The inputs for this analysis are summarised in Figure 6 and its subsets of risk factors. In the present analysis survivors and non-survivors were put in rank order of temperature averaged over day -12 to +2 (as illustrated in figures 5a to 5d). The cut was then selected to give the closest prediction to the actual which is known.

This provides a vascular score which would be useful to a surgeon to assess the likelihood of survival of the subject, (the risk of disseminated breast cancer) and allow them to consider what treatment options might be appropriate.

Although the invention has been particularly shown and described with reference to particular examples, it will be understood by those skilled in the art that various changes in the form and details may be made therein without departing from the scope of the present invention.

Claims

1. A method of assessing survival of a subject to breast cancer the method comprising:

(iii) comparing the deep mammary temperature of step (i) at a phase as determined by step (ii) to a Control temperature value at a phase as determined at step (ii) or to a value from a previous patient with a breast cancer metastasis history; wherein when the deep mammary temperature at a determined phase in the menstrual cycle is greater than the Control temperature value or equivalent to a value from a previous subject with a breast cancer metastasis history it is indicative the subject has a greater likelihood of not surviving the cancer.

2. The method as claimed in claim 1 wherein the step of comparing the deep mammary temperature of step (i) at a phase as determined by step (ii) to a Control temperature value at a phase as determined at step (ii) provides for the comparison of a vascular score of the subject with the Control wherein a more negative vascular score determined from the subject than the Control is indicative that the subject will have a greater likelihood of survival from a cancer.

3. The method as claimed in claim 1 or 2 wherein the subject of the method is a premenopausal female subject, preferably in the age range 25 years to 55 years.

4. The method of any of claims 1 to 3 wherein the method is performed on a subject following a mastectomy when a tumour has been removed from a first breast by providing a detected deep mammary temperature value from the other breast.

5. The method as claimed in any previous claim wherein the deep mammary temperature is monitored daily.

6. The method as claimed in any previous claim wherein the method further comprises determining the level of progesterone in a saliva sample provided from the subject.

7. The method as claimed in any previous claim wherein the method comprises providing a detected deep mammary temperature value when the subject is in the follicular or luteal phase of the menstrual cycle.

8. The method as claimed in any previous claim wherein a vascular score of a Control is -1.4 °C.

9. The method as claimed in any previous claim wherein a greater temperature than a Control temperature is at least 0.2 °C greater than a Control temperature.

10. The method of any previous claim wherein a detected deep mammary temperature value of a subject, which is adjusted for basal body temperature rhythm, of -1.7°C is indicative the subject is a survivor.

11. The method of any of previous claims 1 to 9 wherein a detected deep mammary temperature value of a subject, which is adjusted for basal body temperature rhythm, of -1.2 °C is indicative the subject is a non-survivor.

12. A deep mammary temperature sensing device comprising at least a first temperature sensor to determine at least a first breast temperature at a first time point, wherein the temperature sensing device is provided in or on an insert to be placed over a breast wherein the insert is formed from material adapted to be shaped, mouldable or to resiliently deform to and / or around the shape of the breast.

13. A deep mammary temperature sensing device of claim 12 comprising an array of temperature sensors in a net which, in use, is provided over a subject's breast.

14. A kit for use in the method of any one of claims 1 to 11 comprising a deep mammary temperature sensing device as claimed in claim 12 or in claim 13 and at least one of a second temperature sensing device to detect ambient temperature and a temperature sensor to determine oral and / or aural temperature.

15. A kit as claimed in claim 14 further comprising a plurality of temperature sensing devices to detect temperatures at different layers in the subject's clothing.

16. A kit of any of claims 14 or 15 further comprising a temperature sensor to determine oral and/or aural temperature.

17. A kit as claimed in any one of claims 14 to 16 further comprising a processor to receive signals from at least one of the at least first temperature sensor, the second temperature sensing device to detect ambient temperature, any one of the plurality of temperature sensing devices to detect temperatures at different layers in the subject's clothing, and a temperature sensor to determine oral and/or aural temperature.

18. A kit as claimed in any of claims 14 to 17 further comprising a signal generator to generate and transfer any of the signals received from at least one of the at least first temperature sensor, the second temperature sensing device to detect ambient temperature, any one of the plurality of temperature sensing devices to detect temperatures at different layers in the subject's clothing, and a temperature sensor to determine oral and/or aural temperature or a combination thereof to a computer means to allow for processing, manipulation or display of the signal(s).

19. A composition adapted for use for the treatment of metastatic breast cancer, preferably comprising a taxane, for use in the treatment of a subject, previously diagnosed as having breast cancer, having a deep mammary temperature at a determined phase in the menstrual cycle greater than a Control temperature value or equivalent to a value from a previous subject with a breast cancer metastasis history.

20. A composition as claimed in claim 19 wherein the subject has a deep mammary temperature being at least 0.2 °C greater than a Control temperature.