The Importance Of Data for Chemotherapy Treatment

Knowledge is power. With access to precise information about the impact of breast cancer treatment, patients can take back some measure of control in their fight against the disease.

Restoring power to cancer patients is highlighted in a new article by biostatistician Professor Val Gebski and colleagues, which was recently published in Pharmaceutical Statistics. These researchers have developed a technique to quantify the toxicity of chemotherapy over time, creating a detailed roadmap to predict and compare the side effects of chemotherapy.

The research, the result of dense statistical analysis and complex modelling, has a most human aim: to provide a more patient-centric way for clinicians to explain treatment options.

“Consider a patient whose breast cancer has come back,” Professor Gebski explains. “They feel depressed, are trying to cope and are offered a different set of treatments. They don’t know what to take! The clinician might say ‘we find patients tolerate this better’. But that’s a nebulous term: what does that actually mean for them?”

As the chief statistician with Breast Cancer Trials, Professor Gebski’s publication focuses on clinical trial data for two therapies used in breast cancer: the powerful but toxic combination therapy CMFP, and mitoxantrone, a single agent with lower toxicity. Clinical trials gather a wealth of data, but Professor Gebski says that details about AEs – adverse events, or side effects – tends to offer big picture information, like the basic incidence of hospitalisation.

The researchers zeroed in on three common side effects: nausea and vomiting, stomatitis (mouth ulcers) and neutropaenia (low white blood cell count), extracting rich detail about the incidence, timing and severity of side effects. “Our challenge was to do better than simply summarising the data – those who need hospitalisation versus those who don’t.”

The team created a “toxicity profile” for each therapy, to tell a more nuanced story. Professor Gebski and his co-authors then modelled the impact of toxicity over time, and devised a more patient-friendly way of expressing information and comparing options. Will the impact of this treatment be twice as bad? Half as bad? Much the same? Deliver a 20% lower risk of experiencing a serious toxicity episode?

Or, when does a side effect happen? Is it most severe at the start? How long does it take to reach peak impact? More detailed information is vital intelligence for patients planning for a life on long-term protective drug regimes.

“This data helps a patient or their clinician understand what the risk is and trade that off clinical benefits of one drug against another,” Professor Gebski explains.

“A patient who is fit but worried about the disease coming back, might say ‘I think I can handle the stomatitis, give me the more powerful therapy.’ A patient who is more sensitive might say, ‘I would hate that,

I’ve got my daughter’s wedding coming up and it is important to me that I’m feeling well’, and they make a choice to suit them.”

Publication:

Using recurrent time-to-event models with multinominal outcomes to generate toxicity profiles.
Gebski V, Marschner I, Asher R, Blyth K. Pharmaceutical Statistics. 2021;1-10. https://doi.org/10.1002/pst.2113

The PALLAS Clinical Trial

The PALLAS clinical trial has provided a wealth of material for future research into early-stage breast cancer.

The PALLAS trial studied the effects of adding a two-year course of palbociclib, a cell cycle inhibitor, to standard hormone-blocking treatment for patients with hormone-receptor-positive, HER2-negative early breast cancer.

PALLAS was an international clinical trial that recruited 5,795 patients worldwide, including more than 430 patients from Australia.

Researchers had hoped that palbociclib, currently used in patients with metastatic breast cancer to prolong the duration of cancer control and delay the need for chemotherapy, might reduce the risk of metastatic recurrence in patients with earlier stages of breast cancer.

“We were aiming to find patients who stood to gain the most from the study drug, based on their higher risk of recurrence,” says Dr Nicholas Zdenkowski, the Breast Cancer Trials Study Chair of the PALLAS clinical trial.

“All patients received standard hormone-blocking treatment and half received the additional palbociclib.

They had also received chemotherapy and radiotherapy if their treating doctor considered those treatments appropriate.”

However, interim results showed palbociclib wasn’t working in this setting, he says. “Over time, it was seen there was no difference between the groups, so the study drug was stopped in those who were still taking it as part of their planned two-year course.”

He’s not disheartened, though. “You read the headline, and you think it’s disappointing,” says Dr Zdenkowski. “But these large trials are always designed so we learn things, and we’ll continue to learn as we follow these patients up. We know recurrences can occur years down the track, and a difference may emerge over time between the two study groups.”

During the trial, researchers gathered a bio-bank of tissue samples from patients’ surgeries for analysis, along with blood samples over the course of their participation.

“That will provide some powerful information about the potential for some patients to benefit from palbociclib, about possible resistance mechanisms, and a range of other useful data,” says Dr Zdenkowski.

Data from ongoing patient questionnaires is also expected to provide insights into the patients’ perspectives on endocrine therapy and palbociclib, as well as their experience with breast cancer.

So, although this particular use of palbociclib has not been proven effective, its current use in patients with metastatic breast cancer will continue, and so will the research, says Dr Zdenkowski. “We’re not able to rest until all people have been cured of their cancer.” [ends]

Publication:

Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study.

Mayer EL, Dueck AC, Martin M, Rubovsky G, Burstein HJ, Bellet-Ezquerra M, Miller KD, Zdenkowski N, Winer EP, PFeiler G, Goetz M, Ruiz-Borrego M, Anderson D, Nowecki Z, Loibl S, Moulder S, Ring A, Fitzal F, Traina T, Chan A, Rugo HS, Lemieux J, Henao F, Lyss A, Antolin Novoa S, Wolff AC, Vetter M, Egle D, Morris PG, Mamounas EP, Gil-Gil MJ, Prat A, Fohler H, Metzger Filho O, Schwarz M, DuFrane C, Fumagalli D, Puyana Theall K, Ray Lu D, Huang Bartlett C, Koehler M, Fesl C, DeMichele A, Gnant M. Lancet Oncology. 2021; epub 15 January 2021; https://doi.org/10.1016/S1470-2045(20)30642-2.

IBIS II Clinical Trial Sub-Study

Doctors can now partly allay women’s concerns about bone density loss when taking breast cancer prevention drugs.

Women at high risk of developing breast cancer may benefit from the hormone therapy anastrozole, which has been shown by the International Breast Cancer Intervention Study (IBIS-II) to help prevent the disease.

However, one of anastrozole’s side effects is reduced bone density – which can have serious consequences.

“Bone density loss puts people at risk of breaking bones,” says Dr Nicholas Zdenkowski, Medical Advisor at Breast Cancer Trials, which co-led the study. “It might be 10 or 20 years’ time before they break their hip or have a compression fracture in their spine.” Such injuries can lead to chronic pain or kickstart a decline in health.

Because of this, the IBIS-II clinical trial included a sub-study on bone density in 1,410 postmenopausal women in Australia and New Zealand, who are more at risk of developing osteopenia and osteoporosis.

Patients were given anastrozole for five years, then the study tracked bone density between years five and seven. By year seven, bone density had improved by 1.25% in the lumbar spine.

This means when women stop taking anastrozole, bone density loss caused by the drug can be partially reversed. (It did not, however, improve at the hip.)

It’s a positive result, says Dr Zdenkowski. “This means we can reassure women that even if bone density does decline, it is expected to improve again after they stop anastrozole.”

Doctors now have more information to help patients weigh up the benefits and risks of taking anastrozole. As a safe medication that reduces the chance of breast cancer in high-risk women, it has some advantages over tamoxifen, as an alternative. But women can be reluctant to take it due to a potential reduction in bone density, particularly if they have low bone density, previous fractures or a family history of osteoporosis.

This research, says Dr Zdenkowski, “may mean there are more women willing to take anastrozole, because we now know their bone density does stabilise after they stop taking it.”

The study also showed risedronate, a bone-strengthening drug, can increase bone density after patients stop anastrozole.

The next step, says Dr Zdenkowski, is to study who is most likely to benefit from being on anastrozole in this setting. Anastrozole is not yet registered or covered by the PBS in Australia as a prevention medication. It is widely used for the treatment of early stage and metastatic breast cancer.

Publication:

Sestak I, Blake G, Patel R, Cuzick J, Howell A, Coleman R, Eastell R. Off-treatment bone mineral density changes in postmenopausal women receiving anastrozole for 5 years: 7-year results from the IBIS-II prevention trial. British Journal of Cancer 2021; epub 22 January 2021. https://doi.org/10.1038/s41416-020-01228-2.

IBCSG VIII and IX Clinical Trial DNA Follow Up

Researchers are improving and refining breast cancer treatments by delving into the DNA of patients who have previously volunteered for breast cancer clinical trials.

“We already have the ability to distinguish between different levels of ‘severity’ of breast cancer, but we need to develop this further,” says Dr Nicholas Zdenkowski, Medical Advisor at Breast Cancer Trials.

While breast cancer treatments can already be targeted and personalised, Dr Zdenkowski says new and highly accurate tools could help determine which triple negative breast cancer patients can be cured with surgery alone. Triple negative breast cancer accounts for 15 per cent of all breast cancers.

“The standard approach is to offer women with the triple negative subtype of early stage breast cancer a fairly intensive treatment with chemotherapy, because there are no sufficiently accurate tests to determine which patients definitely don’t need any further treatment beyond surgery,” he says.

“Many patients worry that triple negative breast cancer has a worse prognosis than other breast cancer types, however, this is not always the case.”

Breast Cancer Trials provided data from previous trials called IBCSG VIII and IX, which had enrolled 228 and 330 patients respectively, towards the development of molecular tools to predict the recurrence of breast cancer after chemotherapy treatment.

The lab-based analysis looked at specific DNA methylation markers, or profiles, in the genes of breast cancers that had been surgically removed from patients. The study was centred around blood and tumour specimens held from clinical trials between 1985 and 2009.

The methylation markers helped categorise the early-stage triple negative patients into three groups: those who were cured with surgery to remove the cancer and so didn’t need further treatment; those who needed chemotherapy to prevent the cancer from returning after treatment; and those for whom chemotherapy was not effective, where the cancer came back elsewhere in their body despite that treatment.

However, Dr Zdenkowski says this test method needs further research before it can be considered for routine use in the clinic.

“As with any new test or treatment, the method requires rigorous evaluation to ensure it does what it promises to,” he says.

The use of well-collected and ‘clean’ clinical trial data in this way also illustrates the value in continuing to study and learn from patients who volunteered for previous trials.

“Ultimately, from this research, we hope to be able to reassure some patients that they can be cured with surgery alone,” Dr Zdenkowski says.

“We can also reassure others they will be cured with chemotherapy.”

“The third group, whose cancer will return even with surgery and chemotherapy, is the group in need of better treatments that we hope to find through ongoing research – so we can give them the best chance of being cured of cancer.”

Publication:

DNA methylation markers predict recurrence-free interval in triple-negative breast cancer.
Fackler MJ, Cho S, Cope L, Gabrielson E, Visvanathan K, Wilsbach K, Meir-Levi D, Lynch C.F., Marks J, Geradts J, Regan MM, Viale G, Wolff AC, Sukumar S, Umbricht CB. npj Breast Cancer 2020; 6Article No. 3;, https://doi.org/10.1038/s41523-020-0145-3.

Chemotherapy and BMI: BIG 2-98 Clinical Trial Follow-Up

The role of obesity as a risk factor is a common theme in breast cancer research. That’s not about to change anytime soon.

“In Western society there are more and more women who are overweight and, because being overweight increases your risk of getting breast cancer after menopause, we certainly see this in our clinic,” says Associate Professor Prue Francis, Chair of the Breast Cancer Trials Scientific Advisory Committee.

Some lipophilic, or fat-soluble, drugs are known to act differently in someone who has a high versus a low body mass index (BMI). What hasn’t been studied systematically is the relationship between the efficacy of anticancer drugs and BMI.

To learn more, researchers reanalysed data from the BIG 2-98 trial that included approximately 600 women enrolled by Breast Cancer Trials, some of whom were randomised to receive the lipophilic chemotherapy drug docetaxel as part of treatment.

They found that among the women who received docetaxel, those in the overweight or obese BMI categories had a lower chance of remaining disease-free or surviving compared to women with a lean BMI, despite receiving the same treatment.

“If you’re giving any drug that might have short-term but also longer-term side effects, the question is, are you getting the bang for your buck?” says Associate Professor Francis, who was one of the researchers in the study.

Docetaxel and other drugs of the same family (taxanes) can cause nerve damage, and occasionally permanent hair loss. The risk of experiencing such side effects must be balanced with the benefit an individual patient might receive.

Associate Professor Francis says that chemotherapy for obese patients should not change based on these results, but more research is needed. If the results of this study are confirmed in other studies, this could lead to a rethinking of treatment risks and benefits for these patients.

“If the taxane drugs were thought not to be working or distributed properly in the body of obese patients [we could consider] whether a modification of the dose would be appropriate or whether it’s just not worth adding those drugs,” she explains.

“If an obese patient may not be deriving so much benefit from that particular drug, maybe you could give a different drug, or stop it earlier if nerve damage symptoms are developing.”

Publication:

Differential benefit of adjuvant docetaxel-based chemotherapy in patients with early breast cancer according to baseline body mass index.
Desmedt C, Fornili M, Clatot F, Demicheli R, De Bortoli D, Di Leo A, Viale G, de Azambuja E, Crown J, Francis PA, Sotiriou C, Piccart M, Biganzoli E. Journal of Clinical Oncology. 2020; 38(25):2883-2891, epub 20/05/20 https://doi.org/10.1200/JCO.19.01771.

SOFT/TEXT Clinical Trial Follow-Up

Among premenopausal women with breast cancer, 80% have hormone-responsive breast cancer, where the hormone oestrogen can stimulate the growth of cancer cells.

To stop this from happening after the primary cancer has been removed, women may be treated with one or more drugs that either prevent the uptake of oestrogen by cells (oestrogen blockers like tamoxifen), switch off the production of oestrogen in the ovaries (ovarian function suppression), or block oestrogen production in body fat (aromatase inhibitors).

The SOFT and TEXT clinical trials investigated the effects of different treatment combinations in premenopausal women on survival and recurrence of cancer. Researchers also collected and analysed information about a common and distressing side effect of such treatments: sexual problems including low libido and difficulty becoming aroused.

The impact of treatment on sexual function can be so important for quality of life that it can affect adherence to treatment, says Associate Professor Prue Francis, Chair of the International Steering Committee responsible for the SOFT and TEXT clinical trials.

“Sometimes women just don’t want to take their treatment at all because they’re having problems and they just stop,” says Associate Professor Francis.

The researchers wanted to identify factors that, if present six months into the five-year treatment, predict whether a premenopausal woman will experience sexual difficulties later.

They found that women who reported vaginal dryness, sleep disturbance and bone or joint pain at the six-month mark were more likely to report sexual problems in the first two years.

Recognising these predictors in their patients may guide clinicians to ask about sexual problems, which patients may not otherwise bring up. These conversations might equip clinicians to take a more nuanced and individualised approach to treatment, she says.

Take, for example, a woman experiencing significant side effects from treatment with both aromatase inhibitor and ovarian suppression therapy. Clinicians might consider “the absolute benefit that they’re likely to obtain from having that more intense endocrine therapy,” says Associate Professor Francis.

“Should they really be encouraged to persevere because they have a very high-risk breast cancer and therefore they’re likely to derive more of a differential benefit from that maximal endocrine therapy? Or might their breast cancer not be at such high risk for recurrence, and perhaps it would be reasonable then to dial back to a less intense endocrine approach?”

Publication:

Treatment-induced symptoms, depression and age as predictors of sexual problems in premenopausal women with early breast cancer receiving adjuvant endocrine therapy.

Ribi K, Luo W, Walley BA, Burstein HJ, Chirgwin J, Ansari RH, Salim M, van der Westhuizen A, Abdi E, Francis PA, Chia S, Harvey VJ, Giobbie-Hurder A, Fleming GF, Pagani O, Di Leo A, Colleoni M, Gelber RD, Goldhirsch A, Coates AS, Regan MM, Bernhard J. Breast Cancer Research and Treatment. 2020; 181(2):347-359, epub 09/04/20 doi.org/10.1007/s10549-020-05622-5.